Part 1: Foundational Biochemistry & Cell Biology

This section covers the fundamental chemical building blocks and processes that are essential for understanding neurotransmitter function, receptor synthesis, and drug action. While not the primary focus of clinical psychiatry, a firm grasp of these basics is crucial for the MRCPsych exam.

1.1. Basic Building Blocks

Neurochemistry is built upon the interaction of specific organic molecules. Understanding their basic nature is important.

• Purines: These are a class of nitrogen-containing aromatic heterocyclic compounds. In neurochemistry, they are vital for two main reasons:
  1. Components of Nucleic Acids: Adenine (A) and Guanine (G) are the two purine bases that form the building blocks of DNA and RNA. This is the foundation for the genetic code that dictates the synthesis of all proteins in the neuron, including receptors, transporters, and enzymes.
  2. Signaling and Energy: Adenosine Triphosphate (ATP) is not only the primary energy currency for cellular processes (like ion pumps and neurotransmitter transport) but also acts as a neurotransmitter itself, signaling through purinergic receptors. Guanine Triphosphate (GTP) is essential for the function of G-protein coupled receptors (GPCRs).
• DNA Methylation: This is the most common and fundamental epigenetic mechanism.
  • The Chemical Process: It involves the addition of a methyl group (-CH₃) to a DNA molecule. This modification does not change the underlying DNA sequence.
  • The Specific Site: In vertebrates, this process almost exclusively occurs at the 5th carbon position of the cytosine base, particularly when it is followed by a guanine base (a "CpG dinucleotide"). This chemical modification is carried out by enzymes called DNA methyltransferases.
  • The Neurochemical Consequence: Methylation typically acts to silence or repress gene transcription. By controlling which genes are "on" or "off," it powerfully regulates the synthesis of crucial neurochemical machinery, including neurotransmitter receptors, synthetic enzymes (e.g., GAD, Tyrosine Hydroxylase), and transporter proteins. Environmental factors can influence methylation patterns, providing a chemical link between experience and long-term changes in neuronal function.
  • Non-Epigenetic Modifications: It is important to distinguish this from processes like glycation, which is the non-enzymatic, haphazard attachment of sugar molecules to proteins or lipids and is not a regulated mechanism for gene control.

1.2. Important Metabolic Pathways & Enzyme Function

Enzymes are biological catalysts that facilitate virtually every chemical reaction in the neuron, from energy production to neurotransmitter synthesis and degradation. Understanding their roles is fundamental to neurochemistry and psychopharmacology.

1.2.1. The Krebs (TCA) Cycle and Neuropsychiatric Relevance

The Krebs cycle (or Tricarboxylic Acid Cycle) is a core metabolic pathway occurring in the mitochondria. Its primary function is to generate ATP, the energy currency essential for all neuronal functions, including maintaining ion gradients (Na+/K+ pump) and neurotransmitter transport.

• Thiamine (Vitamin B1) as a Co-factor: Several enzymes in this pathway require thiamine to function correctly.
• Clinical Relevance (Wernicke-Korsakoff Syndrome): In chronic alcoholism, thiamine deficiency is common. This impairs the function of thiamine-dependent enzymes, most notably α-ketoglutarate dehydrogenase. The resulting energy deficit disproportionately affects metabolically active and vulnerable brain regions like the mammillary bodies and thalamus, leading to the cell death and lesions that produce the amnesia and confabulation characteristic of Korsakoff's syndrome.

1.2.2. Alcohol Metabolism

The breakdown of ethanol is a two-step enzymatic process:

1. Ethanol → Acetaldehyde: Catalyzed by Alcohol Dehydrogenase (ADH). This is the rate-limiting step, meaning the overall speed of alcohol clearance is determined by the activity of this enzyme. Neonates have minimal ADH activity, making them highly vulnerable to alcohol toxicity.
2. Acetaldehyde → Acetate: Catalyzed by Aldehyde Dehydrogenase (ALDH).
• Pharmacological Relevance (Disulfiram): Disulfiram works by irreversibly inhibiting ALDH. If a person taking disulfiram consumes alcohol, the toxic metabolite acetaldehyde cannot be broken down. Its accumulation causes the highly unpleasant aversive reaction (flushing, nausea, tachycardia), which is the basis of its therapeutic use.

What is the rate-limiting enzyme for ethanol clearance?

A. Aldehyde dehydrogenase B. Alcohol dehydrogenase C. Catalase D. CYP2E1 E. ADH2

Explanation: The conversion of ethanol to acetaldehyde by alcohol dehydrogenase (ADH) is the primary rate-limiting step in alcohol metabolism.

Disulfiram’s aversive mechanism is through inhibition of:

A. Alcohol dehydrogenase B. Aldehyde dehydrogenase C. Cytochrome P450 D. Monoamine oxidase E. Acetaldehyde dehydrogenase

Explanation: Disulfiram irreversibly inhibits aldehyde dehydrogenase (ALDH), causing a toxic accumulation of acetaldehyde after alcohol ingestion, which produces the characteristic aversive reaction. (Note: option E is the same enzyme).

1.2.3. Enzyme Kinetics and Efficiency

• Diffusion-Limited Enzymes: Some enzymes are so efficient that their catalytic speed is limited only by the rate at which the substrate can physically diffuse into the active site.
• Acetylcholinesterase (AChE): This is the classic neurochemical example. It degrades acetylcholine in the synaptic cleft almost instantaneously (<1 millisecond). This extreme efficiency is crucial for the rapid, high-fidelity transmission required at the neuromuscular junction and in cholinergic pathways mediating attention.

Which enzyme's activity is primarily limited by the rate at which its substrate can diffuse to its active site?

A. Adenylate cyclase B. Aldehyde dehydrogenase C. Monoamine oxidase (MAO) D. Acetylcholinesterase E. Catechol-O-methyltransferase (COMT)

Explanation: Acetylcholinesterase (AChE) is a "catalytically perfect" or diffusion-limited enzyme. It operates so rapidly that the overall reaction rate is constrained only by how fast acetylcholine can reach it, ensuring the swift termination of cholinergic signals.

1.2.4. Inherited Enzyme Deficiencies

• Lesch-Nyhan Syndrome: This is a rare X-linked recessive disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). This enzyme is part of the purine salvage pathway. Its deficiency leads to a massive overproduction and accumulation of uric acid, resulting in severe neurological symptoms including dystonia, cognitive impairment, and characteristic self-mutilating behaviors (e.g., biting lips and fingers).

Lesch–Nyhan syndrome is caused by deficiency of which enzyme?

A. Xanthine oxidase B. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) C. Adenosine deaminase D. Purine nucleoside phosphorylase E. Uricase

Explanation: Lesch-Nyhan syndrome is a classic inborn error of purine metabolism caused by a deficiency in the HGPRT enzyme, leading to hyperuricemia and severe neurobehavioral consequences.

1.2.5. Important Enzymes in Neurotransmitter Synthesis & Degradation

These enzymes are central to neurochemistry and will be discussed in detail in later sections, but key examples include:

• Synthesis (Rate-Limiting): Tyrosine Hydroxylase is the rate-limiting enzyme for the synthesis of all catecholamines (dopamine, noradrenaline, adrenaline).
• Synthesis: Glutamate Decarboxylase (GAD) converts the excitatory neurotransmitter glutamate into the primary inhibitory neurotransmitter, GABA.
• Degradation: Monoamine Oxidase B (MAO-B) is the primary enzyme for degrading dopamine within the presynaptic terminal.

Which of the following enzymes is responsible for converting L-tyrosine to L-Dopa in the catecholamine synthesis pathway?

A. Dopamine beta-hydroxylase B. Phenylethanolamine N-methyltransferase C. Tyrosine hydroxylase D. Aromatic L-amino acid decarboxylase E. Monoamine oxidase

Explanation: Tyrosine hydroxylase is the crucial rate-limiting enzyme in the synthesis of all catecholamines, catalyzing the first step: the conversion of L-tyrosine to L-Dopa.

Glutamate decarboxylase catalyses synthesis of:

A. Glutamine B. GABA C. Glutamate D. Aspartate E. Glycine

Explanation: Glutamate decarboxylase (GAD) is the key synthetic enzyme that converts glutamate into GABA, the brain's principal inhibitory neurotransmitter.

Which enzyme degrades dopamine presynaptically?

A. MAO-A B. COMT C. MAO-B D. Acetylcholinesterase E. Choline acetyltransferase

Explanation: Monoamine oxidase B (MAO-B), located on the mitochondrial membrane within the presynaptic terminal, is the primary enzyme responsible for the intraneuronal degradation of dopamine.

1.3. Cellular Death Mechanisms

The life and death of neurons are tightly regulated processes. Dysregulation of these pathways is central to neurodevelopmental disorders, acute brain injury, and chronic neurodegeneration. From a neurochemical perspective, the key distinction is between programmed, non-inflammatory death and unregulated, inflammatory death.

• Apoptosis (Programmed Cell Death): This is an orderly, energy-dependent process of cellular self-destruction. It is a "clean" or "tidy" process that avoids triggering inflammation.
  • Key Features: Cell shrinkage, Condensation of chromatin (pyknosis), Membrane "blebbing" (the membrane bulges outwards), Formation of apoptotic bodies which are then cleared by phagocytic cells (like microglia) without spilling their contents.
  • Neurochemical Relevance: Apoptosis is essential for normal brain development, including the pruning of excess neurons and synapses. It is also implicated in the slow, progressive neuronal loss seen in some neurodegenerative diseases. Crucially, it is non-inflammatory.
• Necrosis (Unregulated Cell Death): This is a "messy" and chaotic form of cell death that occurs in response to acute injury, such as trauma, ischemia (stroke), or toxins.
  • Key Features: Cellular swelling (oncosis), Loss of membrane integrity and rupture (lysis), Release of intracellular contents (e.g., enzymes, ions) into the extracellular space.
  • Neurochemical Relevance: The spillage of cellular contents acts as a damage signal that triggers a robust inflammatory response, involving the release of pro-inflammatory cytokines from surrounding glial cells. This inflammation can cause secondary damage to neighbouring, otherwise healthy neurons. Excitotoxicity, a process where excessive glutamate leads to cell death, often results in necrosis.

Which cellular death process is characterized by cell shrinkage, chromatin condensation, and membrane blebbing without inflammation?

A. Apoptosis B. Necrosis C. Autophagy D. Pyroptosis E. Necroptosis

Explanation: Apoptosis is the definition of programmed cell death, distinguished by its orderly morphological changes (cell shrinkage, chromatin condensation, membrane blebbing) and, critically, the absence of an inflammatory response.

A neuron with surrounding inflammatory cytokines is most consistent with what cell death process?

A. Necrosis B. Apoptosis C. Autophagy D. Pyroptosis E. Entosis

Explanation: Necrosis is an unregulated form of cell death involving membrane rupture and the release of intracellular contents. This release triggers a local inflammatory cascade, characterized by the presence of inflammatory mediators like cytokines.

An experimental cell culture is observed where cells are dying, surrounded by significant inflammation and the presence of toxic markers in the extracellular environment. Select the term that best describes this cellular process.

A. Apoptosis B. Necrosis C. Entosis D. Excitotoxicity E. Autophagy

Explanation: The key features described are cell death accompanied by significant inflammation and the release of toxic markers. This pathological profile is the hallmark of necrosis, which is distinct from the non-inflammatory, programmed process of apoptosis.

1.4. Precursor Molecules & Biosynthesis

Neurotransmitters are not created from scratch; they are synthesized from precursor molecules through specific enzymatic pathways. The availability of these precursors can be a rate-limiting factor in neurotransmitter production.

1.4.1. The Tryptophan Pathway: Serotonin and Melatonin

• The Precursor: The synthesis of serotonin begins with L-tryptophan, an essential amino acid that must be obtained from the diet. Its transport across the blood-brain barrier is a critical, rate-limiting step.
• The Pathway:
  1. Tryptophan is converted to 5-Hydroxytryptophan (5-HTP) by the enzyme tryptophan hydroxylase.
  2. 5-HTP is then converted to Serotonin (5-HT) by the enzyme aromatic L-amino acid decarboxylase.
• Serotonin as a Precursor: Serotonin itself serves as the direct precursor for the synthesis of melatonin, the hormone crucial for regulating circadian rhythms and sleep-wake cycles. This synthesis occurs primarily in the pineal gland.

What is the essential amino acid precursor for the synthesis of serotonin?

A. Tyrosine B. L-DOPA C. L-tryptophan D. Glutamate E. Phenylalanine

Explanation: The entire serotonin synthesis pathway begins with the essential amino acid L-tryptophan, which is hydroxylated and then decarboxylated to form serotonin (5-hydroxytryptamine).

Serotonin (5-HT) serves as a direct precursor for the synthesis of which crucial monoamine, particularly known for its role in regulating sleep-wake cycles?

A. Dopamine B. Norepinephrine C. Epinephrine D. Melatonin E. Histamine

Explanation: Serotonin is enzymatically converted into melatonin, primarily within the pineal gland. This neurochemical link is fundamental to the relationship between the serotonergic system and the regulation of sleep and circadian rhythms.

1.4.2. The Tyrosine Pathway: The Catecholamines

• The Precursor: The synthesis of all catecholamines (dopamine, noradrenaline, and adrenaline) begins with the amino acid L-tyrosine.
• The Pathway:
  1. L-tyrosine undergoes hydroxylation to become L-DOPA. This step is catalyzed by the enzyme tyrosine hydroxylase, which is the rate-limiting enzyme for the entire catecholamine pathway.
  2. L-DOPA is then converted to Dopamine by the enzyme aromatic L-amino acid decarboxylase (sometimes called DOPA decarboxylase).
  3. Dopamine can then be further converted to noradrenaline, which can in turn be converted to adrenaline in relevant neurons.

Which molecule undergoes hydroxylation during the synthesis pathway of dopamine?

A. Tryptophan B. Serotonin C. L-tyrosine D. Norepinephrine E. Epinephrine

Explanation: The first and rate-limiting step in the synthesis of dopamine (and all catecholamines) is the hydroxylation of L-tyrosine to form L-DOPA, a reaction catalyzed by tyrosine hydroxylase.

1.4.3. Precursor Peptides: Pro-opiomelanocortin (POMC)

• The Concept: Unlike small-molecule neurotransmitters, many neuropeptides are synthesized as large, inactive precursor proteins called pro-peptides or pro-hormones. These are then cleaved by enzymes into smaller, biologically active peptides.
• POMC: Pro-opiomelanocortin is the classic example of a pro-peptide. It is a large protein that is processed to yield several crucial neuroactive molecules, including:
  • Adrenocorticotropic hormone (ACTH): Acts on the adrenal glands to stimulate the release of cortisol.
  • α-Melanocyte-stimulating hormone (α-MSH): Involved in appetite regulation.
  • β-endorphin: An endogenous opioid peptide involved in pain relief and reward.
• Important Distinction: POMC is NOT a precursor for other opioid peptides like enkephalins or other neuropeptides like Substance P.

Pro-opiomelanocortin (POMC) serves as a precursor for the synthesis of several hormones and peptides in the brain, including which of the following?

A. Adrenocorticotropic hormone (ACTH) B. Enkephalin C. Substance P D. Dopamine E. Serotonin

Explanation: POMC is a large pro-peptide that is enzymatically cleaved to produce several smaller active molecules, most notably ACTH, α-MSH, and the endogenous opioid β-endorphin.

Which of the following hormones is primarily released from the adrenal gland?

A. Adrenocorticotropic Hormone (ACTH) B. Cortisol C. Proopiomelanocortin (POMC) D. Thyroid-stimulating hormone (TSH) E. Growth hormone (GH)

Explanation: The synthesis pathway is as follows: POMC is cleaved in the pituitary to produce ACTH. ACTH is then released into the bloodstream and travels to the adrenal glands, where it stimulates the synthesis and release of cortisol.

Part 3: Receptor Families and Signal Transduction

Receptors are the protein targets for neurotransmitters and most psychotropic drugs. They are responsible for translating an extracellular chemical signal into an intracellular physiological response. They are broadly classified into three main families based on their structure and mechanism of action.

3.1. Ionotropic Receptors (Ligand-Gated Ion Channels)

These receptors mediate fast, direct synaptic transmission.

• Mechanism: The receptor itself is an ion channel. When a neurotransmitter (ligand) binds directly to the receptor, it causes an immediate conformational change, opening a pore in the center of the protein. This allows specific ions to flow across the cell membrane, rapidly changing the postsynaptic neuron's electrical potential.
• Analogy: A simple, spring-loaded gate. The neurotransmitter is the hand that pushes the gate open, allowing immediate passage.
• Structure: They are complex proteins made of multiple subunits (typically four or five) arranged around a central pore. Each individual subunit is a protein chain that typically spans the cell membrane four times.
• Speed: Very fast (milliseconds).

Important Examples in Psychiatry:

• Inhibitory (allow Cl⁻ influx): GABA-A receptor, Glycine receptor.
• Excitatory (allow Na⁺/Ca²⁺ influx): NMDA receptor, AMPA receptor, Nicotinic Acetylcholine receptor, 5-HT3 receptor (the only ionotropic serotonin receptor).

Many ionotropic neurotransmitter receptors, such as the nicotinic acetylcholine receptor, are composed of multiple subunits, with each subunit typically possessing how many transmembrane domains?

A. 1 B. 2 C. 3 D. 4 E. 7

Explanation: This is a key structural feature of ligand-gated ion channels. Each of the 4 or 5 subunits that form the channel has its own polypeptide chain that passes through the membrane four times. This is distinct from GPCRs, which have seven transmembrane domains in a single protein.

Diazepam predominantly potentiates which receptor type?

A. GABA-A inotropic B. GABA-B metabotropic C. NMDA D. GABA-A metabotropic E. Glycine

Explanation: Diazepam and other benzodiazepines are positive allosteric modulators of the GABA-A receptor, which is an ionotropic chloride channel. They enhance the fast inhibitory effects of GABA.

Which of the following receptor subtypes are ionotropic?

A. 5-HT₃ B. 5-HT₂A C. D₂ D. Muscarinic M₁ E. NMDA

Explanation: Both the 5-HT₃ receptor and the NMDA receptor are ligand-gated ion channels (ionotropic). 5-HT₃ is the only ionotropic serotonin receptor. D₂, 5-HT₂A, and Muscarinic M₁ receptors are all metabotropic (G-protein coupled).

3.2. Metabotropic Receptors (G-Protein Coupled Receptors - GPCRs)

These receptors mediate slower, indirect, and modulatory effects. The vast majority of neurotransmitter receptors fall into this category.

• Mechanism: The receptor is not an ion channel itself. Instead, it is coupled to an intracellular protein called a G-protein. When a neurotransmitter binds, the receptor activates the G-protein, which then initiates a cascade of intracellular events, often involving second messengers.
• Analogy: A doorbell. The neurotransmitter is the finger that presses the button (receptor). This sends an electrical signal (G-protein) inside the house, which then rings a bell (second messenger), alerting the occupants to act.
• Structure: GPCRs consist of a single long polypeptide chain that snakes across the cell membrane seven times. This is often called a "7-transmembrane" or "serpentine" structure.
• Speed: Slower (seconds to minutes) but effects can be more widespread and longer-lasting.

Important Examples in Psychiatry:

• All Dopamine receptors (D1-D5)
• All Muscarinic Acetylcholine receptors (M1-M5)
• All Adrenergic receptors (α and β)
• All Serotonin receptors EXCEPT 5-HT3
• GABA-B receptor
• All Opioid receptors (µ, δ, κ)
• Cannabinoid receptors (CB1 and CB2)

G-protein coupled receptors are characterized by how many transmembrane helices?

A. Five B. Six C. Seven D. Eight E. Twelve

Explanation: This is the defining structural feature of all GPCRs. The single protein chain crosses the membrane seven times, creating the structure necessary for extracellular ligand binding and intracellular G-protein coupling.

Which receptor is metabotropic?

A. 5-HT₂A B. AMPA C. GABAₐ D. NMDA E. Nicotinic ACh

Explanation: 5-HT₂A receptors are G-protein coupled. The other options (AMPA, GABA-A, NMDA, Nicotinic) are all classic examples of ionotropic, ligand-gated ion channels.

Cannabinoid CB₁ receptors belong to which receptor class?

A. Ionotropic ligand-gated channels B. Nuclear receptors C. Receptor tyrosine kinases D. Metabotropic G-protein-coupled receptors E. Enzyme-linked receptors

Explanation: Both CB₁ and CB₂ receptors are classic GPCRs that couple via Gi/o proteins to modulate neurotransmission, typically by inhibiting adenylyl cyclase and calcium channels.

3.3. Intracellular Second Messenger Systems

Second messengers are small intracellular molecules that are rapidly generated or mobilized in response to GPCR activation. They amplify and broadcast the initial signal throughout the neuron.

• The cAMP Pathway:
  • Activated by Gs (stimulatory) or Gi (inhibitory) G-proteins.
  • Gs stimulates the enzyme adenylyl cyclase, which converts ATP to cyclic AMP (cAMP).
  • Gi inhibits adenylyl cyclase, reducing cAMP levels.
  • cAMP goes on to activate other enzymes, like Protein Kinase A (PKA).
• The Phospholipase C (IP₃/DAG) Pathway:
  • Activated by Gq G-proteins.
  • Gq stimulates the enzyme phospholipase C (PLC).
  • PLC cleaves a membrane lipid (PIP₂) into two second messengers:
    1. Inositol Triphosphate (IP₃): Mobilizes Ca²⁺ from intracellular stores.
    2. Diacylglycerol (DAG): Activates Protein Kinase C (PKC).
• Lithium's Mechanism: A key mechanism of action for lithium is the inhibition of the inositol phosphate signaling pathway. By inhibiting enzymes that recycle inositol, lithium dampens the signaling of Gq-coupled receptors (like 5-HT2A and M1), which may contribute to its mood-stabilizing effects.

Which of the following is an intracellular second messenger system?

A. IP₃ (inositol triphosphate) B. Dopamine C. Serotonin D. GABA E. Glutamate

Explanation: IP₃ is a classic second messenger produced by the action of phospholipase C. The other options are all first messengers (neurotransmitters) that act extracellularly on receptors.

Which of the following is implicated in the mechanism of action of lithium?

A. Direct modulation of GABA-A receptors B. Inhibition of monoamine reuptake C. Blockade of dopamine D2 receptors D. Inositol phosphate signaling pathway E. Allosteric modulation of AMPA receptors

Explanation: Lithium's inhibition of inositol monophosphatase, a key enzyme in the recycling of inositol, is a well-established mechanism that dampens signaling through the IP₃/DAG second messenger pathway.

3.4. Nuclear Receptors

This is the third major class of receptors. They are located intracellularly and function as transcription factors to directly alter gene expression.

• Mechanism: Lipophilic (fat-soluble) ligands like corticosteroids (e.g., cortisol) and thyroid hormones can easily cross the cell membrane. They bind to their corresponding receptors in the cytoplasm or nucleus. This binding causes the receptor-ligand complex to move to the nucleus, bind to DNA, and change the rate at which specific genes are transcribed into proteins.

Part 4: Important Neurotransmitter & Neuropeptide Systems

4.1. Dopamine (DA)

Dopamine is a monoamine neurotransmitter that plays a critical role in motivation, reward, motor control, and executive function. Its dysregulation is implicated in psychosis, addiction, Parkinson's disease, and ADHD.

4.1.1. Synthesis, Metabolism, and Important Enzymes

Dopamine is a catecholamine, synthesized from the amino acid L-tyrosine.

• Synthesis Pathway:
  1. L-Tyrosine → L-DOPA: The precursor, L-tyrosine, is hydroxylated (an -OH group is added) to form L-DOPA. This is the rate-limiting step for all catecholamine synthesis and is catalyzed by the enzyme Tyrosine Hydroxylase.
  2. L-DOPA → Dopamine: L-DOPA is then rapidly decarboxylated (a -COOH group is removed) to form dopamine. This is catalyzed by aromatic L-amino acid decarboxylase (also known as DOPA decarboxylase).
• Degradation Pathway: Dopamine's action is terminated by reuptake into the presynaptic neuron via the Dopamine Transporter (DAT). Once inside the neuron, it is either repackaged into vesicles or degraded by two key enzymes:
  1. Monoamine Oxidase B (MAO-B): This enzyme is located on the outer membrane of mitochondria within the presynaptic terminal. It is the primary enzyme responsible for degrading dopamine inside the neuron.
  2. Catechol-O-Methyl Transferase (COMT): This enzyme is located primarily in the synaptic cleft and postsynaptic neuron. It is responsible for degrading dopamine that has not been taken back up into the presynaptic neuron.

Which enzyme is responsible for converting L-tyrosine to L-Dopa?

A. Dopamine beta-hydroxylase B. Phenylethanolamine N-methyltransferase C. Tyrosine hydroxylase D. Aromatic L-amino acid decarboxylase E. Monoamine oxidase

Explanation: Tyrosine hydroxylase is the crucial rate-limiting enzyme in the synthesis of all catecholamines, catalyzing the first step: the hydroxylation of L-tyrosine to form L-DOPA.

Which enzyme degrades dopamine presynaptically?

A. MAO-A B. COMT C. MAO-B D. Acetylcholinesterase E. Choline acetyltransferase

Explanation: MAO-B is located on the mitochondrial membrane within the presynaptic terminal and is the primary enzyme for the intraneuronal degradation of dopamine. COMT acts mainly postsynaptically.

4.1.2. Receptors

All dopamine receptors are metabotropic G-protein coupled receptors (GPCRs), meaning they have a 7-transmembrane structure. They are divided into two main families with opposing actions on the second messenger cAMP.

• D1-like Family (D₁ and D₅):
  • Coupled to a Gs (stimulatory) protein.
  • Action: Increases the activity of the enzyme adenylyl cyclase, leading to an increase in the second messenger cAMP.
  • Generally considered excitatory.
• D2-like Family (D₂, D₃, and D₄):
  • Coupled to a Gi (inhibitory) protein.
  • Action: Inhibits the activity of adenylyl cyclase, leading to a decrease in the second messenger cAMP.
  • Generally considered inhibitory. This family is the primary target for all antipsychotic medications.
  • Amisulpride is an antipsychotic noted for its high selectivity for D₂/D₃ receptors with minimal activity at other receptors.
• Receptor Abundance: There is some ambiguity in literature regarding which receptor is most abundant. D₁ receptors are the most widely distributed throughout the brain. However, D₂ receptors are highly concentrated in key areas like the striatum and are the most clinically relevant target for antipsychotics. For exam purposes, be aware of this nuance, but D₂ is the most important receptor in psychopharmacology.

Dopamine receptors, which are classified as metabotropic receptors, typically span the cell membrane how many times?

A. 3 times B. 4 times C. 5 times D. 7 times E. 9 times

Explanation: As members of the GPCR superfamily, all dopamine receptors consist of a single polypeptide chain that crosses the cell membrane seven times.

Which dopamine receptor subtype is most abundant in the human brain?

A. D₁ B. D₂ C. D₃ D. D₄ E. D₅

Explanation: D₂ receptors are highly expressed and predominate in the key dopaminergic pathways of the striatum, making them the most abundant subtype in these clinically relevant regions and the primary target for antipsychotic drugs. (Note: While some sources state D1 is most widespread, D2 is the correct answer in this exam context).

4.1.3. The Concept of Partial Agonism

A partial agonist is a drug that binds to and activates a receptor, but has only partial efficacy relative to a full agonist. In the dopamine system, this creates a unique "stabilizing" effect.

• Mechanism:
  • In a high-dopamine environment (e.g., mesolimbic pathway in psychosis), a partial agonist competes with the full agonist (dopamine) for the receptor. Because it produces a weaker signal, the net effect is a reduction in overall dopamine transmission (acting like an antagonist).
  • In a low-dopamine environment (e.g., mesocortical pathway), the partial agonist provides a baseline level of stimulation that is greater than zero, thus increasing net dopamine transmission (acting like an agonist).
• Important Examples: Aripiprazole, Brexpiprazole, and Cariprazine are the classic D₂ partial agonists. Cariprazine is noted to have a preference for D₃ over D₂ receptors.
• Clinical Application: This stabilizing effect is highly useful.
  • Hyperprolactinemia: Full D₂ antagonists (like risperidone) block dopamine in the tuberoinfundibular pathway, causing prolactin levels to rise. A partial agonist like aripiprazole provides enough dopaminergic tone to keep prolactin levels normal, making it an effective strategy to counter this side effect.
  • Schizophrenia & Depression: Aripiprazole is approved for both schizophrenia (reducing mesolimbic hyperactivity) and as an adjunctive treatment for depression (potentially boosting mesocortical/prefrontal dopamine).

Which of the following are partial D₂ agonists? (Select all that apply)

A. Aripiprazole B. Brexpiprazole C. Cariprazine D. Risperidone E. Haloperidol

Explanation: Aripiprazole, brexpiprazole, and cariprazine are the three main antipsychotics that function as partial agonists at the dopamine D₂ receptor. Risperidone and haloperidol are D₂ antagonists.

To counter risperidone-induced hyperprolactinemia, adding which antipsychotic is most effective?

A. Clozapine B. Olanzapine C. Quetiapine D. Aripiprazole E. Lurasidone

Explanation: Aripiprazole’s partial D₂ agonism provides a baseline level of stimulation in the tuberoinfundibular pathway, which is sufficient to inhibit prolactin release. When added to a D₂ antagonist like risperidone, it effectively normalizes prolactin levels.

4.1.4. Neurochemical Hypotheses of Schizophrenia

The original dopamine hypothesis proposed that psychosis was due to excessive dopamine. This has been refined to a more nuanced model.

• Mesolimbic Pathway: Hyperactivity (too much dopamine) in this pathway is thought to underlie the positive symptoms of schizophrenia (e.g., hallucinations, delusions).
• Mesocortical Pathway: Hypoactivity (too little dopamine) in this pathway, particularly projecting to the dorsolateral prefrontal cortex (DLPFC), is thought to underlie the negative and cognitive symptoms (e.g., anhedonia, executive dysfunction).

Which neurotransmitter deficit underlies cognitive symptoms in schizophrenia?

A. Acetylcholine B. Dopamine C. Norepinephrine D. Serotonin E. GABA

Explanation: The cognitive and negative symptoms of schizophrenia are specifically linked to a deficit or hypofunction of the mesocortical dopamine pathway projecting to the dorsolateral prefrontal cortex (DLPFC).

4.2. Noradrenaline (NA / Norepinephrine, NE)

Noradrenaline is a monoamine neurotransmitter and hormone belonging to the catecholamine family. It is the primary neurotransmitter of the sympathetic nervous system and plays a crucial role in the central nervous system in regulating arousal, vigilance, attention, mood, and the "fight-or-flight" stress response.

4.2.1. Synthesis and Metabolism

The synthesis of noradrenaline is a direct continuation of the dopamine pathway, occurring within noradrenergic neurons.

• Synthesis Pathway:
  1. L-Tyrosine → L-DOPA → Dopamine (as described previously).
  2. Dopamine → Noradrenaline: Inside synaptic vesicles, the enzyme dopamine β-hydroxylase adds a hydroxyl (-OH) group to dopamine, converting it into noradrenaline.
• Degradation Pathway: Like dopamine, noradrenaline's action is terminated by reuptake via the Noradrenaline Transporter (NET). Once inside the presynaptic neuron, it is degraded by:
  1. Monoamine Oxidase A (MAO-A): While MAO-B preferentially metabolizes dopamine, MAO-A shows a higher affinity for noradrenaline and serotonin.
  2. Catechol-O-Methyl Transferase (COMT): Acts on noradrenaline in the synaptic cleft.

4.2.2. Receptors

All noradrenergic receptors (adrenoceptors) are metabotropic G-protein coupled receptors (GPCRs). They are divided into two main classes, alpha (α) and beta (β), each with important subtypes.

• Alpha (α) Receptors:
  • α₁ Receptors: Gq-protein coupled (excitatory). They are primarily postsynaptic and mediate many of the excitatory and vasoconstrictive effects. Blockade by drugs like prazosin or many antipsychotics (e.g., clozapine, quetiapine) causes vasodilation, leading to the side effect of orthostatic hypotension.
  • α₂ Receptors: Gi-protein coupled (inhibitory). They are primarily presynaptic autoreceptors. When noradrenaline binds, it inhibits its own further release.
    • Agonists (e.g., clonidine, guanfacine) stimulate these receptors, reducing sympathetic outflow. This is their mechanism for treating hypertension and ADHD.
    • Antagonists (e.g., mirtazapine) block this negative feedback brake, increasing the release of noradrenaline and serotonin.
• Beta (β) Receptors (β₁, β₂, β₃):
  • Gs-protein coupled (stimulatory).
  • They are postsynaptic, mediating many of the metabolic and cardiac effects.
  • Beta-blockers (e.g., propranolol) are antagonists at these receptors, reducing the peripheral physical symptoms of anxiety (e.g., tachycardia, tremor).

Which ADHD medication can cause hypotension via α2 agonism?

A. Methylphenidate B. Amphetamine C. Atomoxetine D. Clonidine E. Lisdexamfetamine

Explanation: Clonidine (and guanfacine) are central α₂-adrenergic agonists. By stimulating these presynaptic autoreceptors in the brainstem, they reduce the overall sympathetic outflow, leading to a decrease in blood pressure and heart rate.

Postural hypotension caused by α₁-adrenergic blockade is most likely seen with:

A. Propranolol B. Prazosin C. Clonidine D. Fluoxetine E. Haloperidol

Explanation: Prazosin is a selective α₁-adrenergic antagonist. Its primary therapeutic use is for hypertension and PTSD-related nightmares, and its main side effect is orthostatic hypotension due to vasodilation. Many antipsychotics also have α₁-blocking properties, but prazosin is the classic example.

Propranolol exerts its therapeutic effects primarily through which mechanism?

A. Selective alpha-1 adrenergic receptor antagonism B. Non-selective beta-1 and beta-2 adrenergic receptor blockade C. Dopamine D2 receptor agonism D. Serotonin 5HT1A receptor agonism E. Angiotensin-converting enzyme (ACE) inhibition

Explanation: Propranolol is a non-selective beta-blocker, meaning it antagonizes both β₁ and β₂ adrenoceptors. This action blocks the effects of adrenaline and noradrenaline, reducing heart rate, blood pressure, and tremor.

4.2.3. Pharmacological Modulation

The noradrenergic system is a key target for many antidepressants and ADHD medications.

• Reuptake Inhibition:
  • SNRIs (Serotonin-Noradrenaline Reuptake Inhibitors): Drugs like venlafaxine and duloxetine block both SERT and the Noradrenaline Transporter (NET), increasing synaptic levels of both neurotransmitters. The noradrenergic effect of venlafaxine is particularly prominent at higher doses and is responsible for its dose-dependent risk of hypertension.
  • NRIs (Noradrenaline Reuptake Inhibitors): Drugs like reboxetine and atomoxetine are selective for NET. Atomoxetine's efficacy in ADHD is thought to stem from its ability to increase noradrenaline (and indirectly, dopamine) levels in the prefrontal cortex.
  • TCAs (Tricyclic Antidepressants): Most TCAs (e.g., imipramine, amitriptyline) are potent inhibitors of both serotonin and noradrenaline reuptake.
• Receptor Modulation:
  • Mirtazapine: As mentioned, its primary antidepressant mechanism is α₂-autoreceptor antagonism, which disinhibits and increases the release of both noradrenaline and serotonin.

Venlafaxine’s most concerning dose-related side effect is:

A. Hypotension B. Bradycardia C. Hypertension D. QT prolongation E. Agranulocytosis

Explanation: At lower doses, venlafaxine primarily inhibits serotonin reuptake. As the dose increases, its inhibition of noradrenaline reuptake becomes more significant, leading to increased noradrenergic tone and a dose-dependent risk of hypertension.

Atomoxetine acts by:

A. Dopamine reuptake inhibition B. Serotonin release C. Noradrenaline reuptake inhibition D. GABA agonism E. NMDA antagonism

Explanation: Atomoxetine is a selective noradrenaline reuptake inhibitor (NRI). By blocking NET, it increases the availability of noradrenaline in the synapse, particularly in the prefrontal cortex, which is its mechanism of action for treating ADHD.

4.3. Serotonin (5-Hydroxytryptamine, 5-HT)

Serotonin is a monoamine neurotransmitter that plays a vast and multifaceted role in regulating mood, anxiety, sleep, appetite, cognition, and perception. Its extensive receptor family allows for highly diverse and sometimes opposing effects, making it a primary target for a wide range of psychotropic medications.

4.3.1. Synthesis and Metabolism

• Synthesis Pathway:
  1. L-Tryptophan → 5-HTP: The synthesis begins with the essential amino acid L-tryptophan, which must be obtained from the diet. The enzyme tryptophan hydroxylase converts it to 5-HTP. The availability of tryptophan is the primary rate-limiting step for serotonin synthesis.
  2. 5-HTP → Serotonin (5-HT): 5-HTP is then converted to serotonin by the enzyme aromatic L-amino acid decarboxylase.
• Degradation Pathway: Serotonin's action is terminated by reuptake into the presynaptic neuron via the Serotonin Transporter (SERT). Once inside the neuron, it is degraded primarily by Monoamine Oxidase A (MAO-A).

The biochemical precursor of serotonin is:

A. Tyrosine B. Phenylalanine C. L-tryptophan D. 5-HTP E. Melatonin

Explanation: The entire synthesis pathway for serotonin begins with the essential amino acid L-tryptophan. 5-HTP is an intermediate in this pathway, not the initial precursor.

4.3.2. Receptor Subtypes and Functions

The serotonin system is incredibly complex, with at least 14 distinct receptor subtypes. All are metabotropic (GPCRs) except for the 5-HT3 receptor. Understanding the function of key subtypes is crucial for the MRCPsych exam.

• 5-HT1A Receptors: Gi-coupled (inhibitory). Stimulation is associated with antidepressant and anxiolytic effects. Presynaptic 5-HT1A autoreceptors act as a brake on serotonin release. Buspirone is a 5-HT1A partial agonist.
• 5-HT2A Receptors: Gq-coupled (excitatory). Stimulation is associated with anxiety, insomnia, sexual dysfunction, and the hallucinogenic effects of drugs like LSD. Antagonism is a key mechanism of atypical antipsychotics. ECT is known to cause a reduction (downregulation) in 5-HT2 receptor density.
• 5-HT2C Receptors: Gq-coupled (excitatory). Antagonism is strongly linked to the weight gain seen with antipsychotics like olanzapine and antidepressants like mirtazapine.
• 5-HT3 Receptors: The only ionotropic serotonin receptor. Stimulation is associated with nausea and vomiting. Antagonism is the mechanism of anti-emetic drugs like ondansetron.

The psychedelic psilocybin acts primarily as an agonist at which receptor?

A. 5-HT1A B. 5-HT2A C. D2 D. NMDA E. GABA-A

Explanation: The psychoactive and hallucinogenic effects of classic psychedelics like psilocybin and LSD are mediated primarily by their agonist activity at the 5-HT2A receptor.

A recognized neurochemical finding post-ECT is:

A. Increase in presynaptic serotonin 5HT1A receptors. B. Global increase in glutamate levels. C. Reduction in serotonin 5HT2 receptor density. D. Decrease in dopaminergic neurotransmission. E. Significant increase in cortisol levels.

Explanation: A consistent finding after a course of ECT is the downregulation (reduction in density) of postsynaptic 5-HT2 receptors, which is thought to be one of the neurochemical changes underlying its powerful antidepressant effect.

Which statement regarding serotonin receptor modulation is TRUE?

A. Stimulation of 5-HT1A receptors primarily leads to anorgasmia. B. 5-HT2A receptor stimulation is associated with therapeutic effects of antidepressants. C. Antagonism of 5-HT2C receptors is a known cause of weight gain. D. Activation of 5-HT3 receptors typically results in an antiemetic effect. E. 5-HT1A receptors, when stimulated, enhance serotonin release.

Explanation: Blockade of 5-HT2C receptors is a key mechanism contributing to increased appetite and weight gain with drugs like mirtazapine and olanzapine. In contrast, 5-HT2A stimulation causes sexual dysfunction, 5-HT1A stimulation is therapeutic, and 5-HT3 antagonism (not activation) is antiemetic.

4.3.3. Pharmacological Modulation

The serotonin system is the most common target for antidepressant medications.

• Reuptake Inhibition (SERT Blockade):
  • SSRIs: e.g., fluoxetine, sertraline, citalopram. These drugs block SERT, increasing the amount and duration of serotonin in the synaptic cleft.
  • Sertraline is unique among SSRIs for also having a moderate inhibitory effect on the Dopamine Transporter (DAT).
  • Fluoxetine is notable for its 5-HT2C antagonist properties.
• Multi-modal Agents:
  • Vortioxetine: Has a complex mechanism, acting as a SERT inhibitor, 5-HT1A agonist, and an antagonist at 5-HT3, 5-HT7, and 5-HT1D receptors.
  • Trazodone (SARI): Combines weak SERT inhibition with potent 5-HT2A antagonism.

Which SSRI has measurable DAT inhibitory activity?

A. Fluoxetine B. Sertraline C. Citalopram D. Escitalopram E. Paroxetine

Explanation: While all SSRIs primarily target the serotonin transporter, sertraline is distinguished by its additional, clinically relevant affinity for and inhibition of the dopamine transporter (DAT).

4.4. Acetylcholine (ACh)

Acetylcholine is a small-molecule neurotransmitter that plays a vital role in both the central and peripheral nervous systems. In the CNS, it is crucial for learning, memory, attention, and arousal. Its depletion is a key feature of Alzheimer's disease.

4.4.1. Synthesis and Metabolism

The synthesis and degradation of acetylcholine are rapid and highly efficient.

• Synthesis:
  • Precursors: Choline and Acetyl Coenzyme A (Acetyl-CoA). Choline transport into the neuron is the rate-limiting step.
  • Enzyme: Choline Acetyltransferase (ChAT) catalyzes the reaction.
• Degradation:
  • Unlike monoamines, ACh action is not terminated by reuptake.
  • Instead, it is rapidly broken down in the synaptic cleft by the enzyme Acetylcholinesterase (AChE), a diffusion-limited enzyme.
  • The resulting choline is transported back into the presynaptic neuron for recycling.

Which neurotransmitter is rapidly degraded in the synaptic cleft by a dedicated esterase?

A. Acetylcholine B. Dopamine C. Serotonin D. GABA E. Glutamate

Explanation: Acetylcholine is unique among these neurotransmitters in that its synaptic action is terminated by enzymatic degradation in the cleft by acetylcholinesterase (an esterase). The others primarily rely on reuptake transporters.

4.4.2. Receptors

Acetylcholine acts on two major families of receptors.

• Nicotinic Receptors (nAChRs):
  • Type: Ionotropic (ligand-gated cation channels).
  • Mechanism: Cause rapid depolarization (excitation).
  • Pharmacology: Bupropion is a nicotinic receptor antagonist, contributing to its efficacy as a smoking cessation aid.
• Muscarinic Receptors (mAChRs):
  • Type: Metabotropic (GPCRs).
  • Pharmacology:
    • Antagonists (Anticholinergics): Many TCAs (e.g., amitriptyline) and antipsychotics (e.g., clozapine) block muscarinic receptors, causing side effects like dry mouth, blurred vision, constipation, and cognitive impairment.
    • M4 Agonism: The hypersalivation seen with clozapine is a paradoxical effect mediated by its agonist activity at the M4 receptor subtype.

Hypersalivation is a known side effect of clozapine. This effect is primarily mediated by which mechanism?

A. D2 receptor blockade B. 5HT2A receptor antagonism C. M4 muscarinic receptor agonism D. H1 histamine receptor antagonism E. Alpha-1 adrenergic blockade

Explanation: While clozapine is a potent antagonist at many muscarinic receptors (causing dry mouth), its paradoxical effect of hypersalivation is attributed to its agonist activity at the M4 subtype, particularly in salivary glands.

4.4.3. Clinical Relevance: The Cholinergic Hypothesis of Alzheimer's Disease

• The Hypothesis: A core pathological feature of Alzheimer's disease is the severe loss of cholinergic neurons originating in the basal forebrain (e.g., Nucleus Basalis of Meynert). This cholinergic deficit is strongly correlated with the decline in memory and attention.
• Therapeutic Strategy: The primary treatment is to boost cholinergic function by inhibiting the enzyme that breaks down acetylcholine.
• Acetylcholinesterase Inhibitors (AChEIs): Drugs like donepezil, rivastigmine, and galantamine are reversible inhibitors of AChE, increasing the amount of acetylcholine in the synaptic cleft.

Which drug inhibits acetylcholinesterase?

A. Memantine B. Donepezil C. Galantamine D. Rivastigmine E. Ketamine

Explanation: Galantamine, donepezil, and rivastigmine are all acetylcholinesterase inhibitors used to treat the cognitive symptoms of Alzheimer's disease. Memantine is an NMDA antagonist.

4.5. Gamma-Aminobutyric Acid (GABA)

GABA is the principal inhibitory neurotransmitter in the mature central nervous system. Its primary function is to reduce neuronal excitability. It plays a crucial role in anxiety, sedation, sleep, and seizure control and is the target of benzodiazepines, Z-drugs, and barbiturates.

4.5.1. Synthesis and Metabolism

GABA is synthesized directly from the brain's main excitatory neurotransmitter, glutamate, creating a delicate balance between excitation and inhibition.

• Synthesis:
  • Precursor: Glutamate.
  • Enzyme: Glutamate Decarboxylase (GAD) catalyzes the conversion of glutamate to GABA.
• Degradation: GABA is metabolized by the enzyme GABA transaminase.

Glutamate decarboxylase catalyses the synthesis of:

A. Glutamine B. GABA C. Glutamate D. Aspartate E. Glycine

Explanation: Glutamate decarboxylase (GAD) is the key synthetic enzyme that converts the excitatory neurotransmitter glutamate into the main inhibitory neurotransmitter, GABA.

4.5.2. Receptors

GABA acts on two major classes of receptors with distinct structures and mechanisms.

• GABA-A Receptors:
  • Type: Ionotropic (ligand-gated chloride channel).
  • Mechanism: When GABA binds, the channel opens, allowing chloride ions (Cl⁻) to flow into the neuron, causing rapid inhibition.
  • Allosteric Modulation:
    • Benzodiazepines (e.g., Diazepam) are positive allosteric modulators that increase the frequency of channel opening.
    • Z-drugs (e.g., Zolpidem, Zopiclone) are selective for receptors containing the α1 subunit, which mediates sedation.
    • Barbiturates bind to a different site and increase the duration of channel opening.
• GABA-B Receptors:
  • Type: Metabotropic (Gi-coupled GPCR).
  • Mechanism: Produces slower, more prolonged inhibition.
  • Pharmacology: Gamma-hydroxybutyrate (GHB) is an agonist at GABA-B receptors.

Diazepam predominantly potentiates which receptor type?

A. GABA-A inotropic B. GABA-B metabotropic C. NMDA D. GABA-A metabotropic E. Glycine

Explanation: Diazepam is a classic benzodiazepine that enhances the inhibitory effects of GABA by acting as a positive allosteric modulator on the GABA-A receptor, which is an ionotropic chloride channel.

Zopiclone exerts its hypnotic effect via which GABA-A subunit?

A. α1 B. α2 C. α3 D. β2 E. γ2

Explanation: The "Z-drugs" (Zopiclone, Zolpidem) preferentially bind to the benzodiazepine site on GABA-A receptors that contain the α1 subunit. This subunit is primarily responsible for mediating sedation and amnesia.

Gamma-hydroxybutyrate (GHB) acts as a ligand for which receptor?

A. GABAA receptor B. GABAB receptor C. NMDA receptor D. Alpha-1 adrenergic receptor E. Serotonin 5HT1A receptor

Explanation: GHB is a CNS depressant that exerts its effects through agonism at the metabotropic GABA-B receptor.

4.5.3. Clinical and Pharmacological Relevance

• Flumazenil: This drug is a competitive antagonist at the benzodiazepine binding site on the GABA-A receptor. It is used as an antidote to reverse overdose with benzodiazepines and Z-drugs.
• GABAergic Neurons: Medium spiny neurons are the principal output neurons of the striatum (e.g., caudate nucleus) and are primarily GABAergic.
• Important Distinction (Gabapentinoids): Drugs like Pregabalin and Gabapentin, despite their names, do not act directly on GABA receptors. Their mechanism is binding to the α2δ subunit of voltage-gated calcium channels, reducing the release of excitatory neurotransmitters like glutamate.

Which drug’s overdose can be specifically reversed by flumazenil?

A. Barbiturates B. Z-drugs (e.g., zopiclone) C. Baclofen D. Ethanol E. Propofol

Explanation: Flumazenil is a benzodiazepine-site antagonist that competitively blocks the binding of both benzodiazepines and related Z-drugs, reversing their sedative and respiratory depressant effects. It does not work for barbiturates or alcohol.

In the caudate nucleus, which neuronal cell aids GABAergic transmission?

A. Purkinje cell B. Medium spiny neuron C. Granule cell D. Pyramidal cell E. Chandelier cell

Explanation: Medium spiny neurons are the main GABAergic projection neurons in the striatum (which includes the caudate), forming the primary output of this brain region.

Pregabalin exerts its therapeutic effect by binding to:

A. GABA-A receptors B. α2δ subunit of voltage-gated calcium channels C. NMDA receptors D. Dopamine transporters E. Serotonin receptors

Explanation: This is a crucial point of distinction. Pregabalin is not a GABAergic agent. It binds to the α2δ subunit of presynaptic voltage-gated calcium channels, modulating their function to reduce the release of several neurotransmitters, including glutamate.

4.6. Glutamate

Glutamate is the most abundant neurotransmitter in the brain and the principal fast excitatory neurotransmitter. It is critically involved in nearly all aspects of normal brain function, including learning, memory, and synaptic plasticity. However, excessive glutamatergic activity can be neurotoxic.

4.6.1. Synthesis and the Glutamate-Glutamine Cycle

Glutamate does not readily cross the blood-brain barrier and must be synthesized within the brain. The glutamate-glutamine cycle is the primary mechanism for replenishing neuronal glutamate stores while preventing its toxic accumulation in the synapse.

• Synthesis: Glutamate can be synthesized from glucose via the Krebs cycle. A key immediate step is the conversion of glutamine to glutamate by the enzyme glutaminase within the presynaptic neuron.
• The Cycle:
  1. Glutamate is released from presynaptic neurons.
  2. Its action is terminated by rapid uptake into surrounding astrocytes.
  3. Inside the astrocyte, the enzyme glutamine synthetase converts glutamate into glutamine.
  4. Glutamine is then transported back to the neuron to be converted back into glutamate.

Which neurotransmitter mediates the fastest excitatory transmission in the CNS?

A. GABA B. Dopamine C. Glutamate D. Serotonin E. Acetylcholine

Explanation: Glutamate, acting at ionotropic receptors like AMPA and NMDA, produces rapid excitatory postsynaptic potentials, making it the primary mediator of fast excitatory neurotransmission in the brain.

4.6.2. Receptors

Glutamate receptors are divided into ionotropic (fast) and metabotropic (slow) classes.

• Ionotropic Glutamate Receptors:
  • AMPA Receptors: Mediate the vast majority of fast excitatory neurotransmission. They are simple glutamate-gated sodium (Na⁺) channels.
  • NMDA Receptors: Crucial for synaptic plasticity. They are glutamate-gated calcium (Ca²⁺) channels and have several special properties:
    1. Co-agonist Requirement: Require binding of both glutamate and a co-agonist (glycine or D-serine).
    2. Voltage-Dependence: At rest, the channel is blocked by a magnesium ion (Mg²⁺). The channel only opens when the neuron is already partially depolarized, which repels the Mg²⁺ ion.

Pharmacology of the NMDA Receptor

The unique properties of the NMDA receptor make it a key drug target.

• Antagonists:
  • Ketamine and Phencyclidine (PCP) block the channel pore. Their psychotomimetic effects form the basis of the glutamate hypothesis of schizophrenia.
  • Memantine is a low-affinity antagonist used in Alzheimer's disease to reduce excitotoxicity.
  • Kynurenic Acid is an endogenous antagonist at the glycine co-agonist site.
• Agonists:
  • D-cycloserine is a partial agonist at the glycine co-agonist site, investigated as a cognitive enhancer.

NMDA receptors are:

A. G-protein coupled B. Glutamate-gated Ca²⁺ channels C. Voltage-gated Na⁺ channels D. Chloride channels E. K⁺ leak channels

Explanation: NMDA receptors are ionotropic receptors that, when activated, are primarily permeable to calcium ions (Ca²⁺). This influx of calcium is the key trigger for downstream signaling cascades involved in synaptic plasticity.

Glycine and D-serine both act as co-agonists at which receptor?

A. Dopamine receptors B. NMDA receptors C. GABA receptors D. Adrenergic receptors E. Acetylcholine receptors

Explanation: A unique feature of the NMDA receptor is its requirement for a co-agonist to bind at the glycine modulatory site in addition to glutamate binding at its own site for the channel to open. Glycine and D-serine fulfill this co-agonist role.

Which animal model is used to study schizophrenia via NMDA receptor antagonism?

A. Maternal immune activation in rodents B. Chronic restraint stress in rodents C. NMDA antagonist ketamine administration D. Circadian rhythm disruption in mice E. Olfactory bulbectomy in rats

Explanation: The administration of subanesthetic doses of NMDA antagonists like ketamine or PCP reliably induces both positive and negative symptoms of schizophrenia in healthy humans and animal models. This provides strong support for the glutamate hypothesis of the disorder.

Which endogenous compound antagonizes the glycine co-agonist site on the NMDA receptor?

A. Kynurenic acid B. D-serine C. Glycine D. Glutamate E. Aspartate

Explanation: Kynurenic acid is a metabolite of the tryptophan pathway that acts as an endogenous antagonist at the glycine site of the NMDA receptor, thereby modulating glutamatergic neurotransmission.

4.7. Endocannabinoids

The endocannabinoid system is a unique neuromodulatory system that plays a crucial role in regulating neurotransmitter release, synaptic plasticity, appetite, pain, mood, and memory. Unlike classical neurotransmitters, endocannabinoids are synthesized "on-demand" and act as retrograde messengers.

4.7.1. Important Ligands and Receptors

• Endogenous Ligands (Endocannabinoids): These are lipid-based signaling molecules. The two most well-studied are:
  1. Anandamide (from the Sanskrit word for "bliss")
  2. 2-Arachidonoylglycerol (2-AG)
• Exogenous Ligands: The primary psychoactive component of cannabis, Δ⁹-tetrahydrocannabinol (THC), is an exogenous agonist.
• Receptors: Both are metabotropic GPCRs.
  1. CB1 Receptors: One of the most abundant GPCRs in the brain, highly concentrated on presynaptic terminals. When activated, they inhibit the release of neurotransmitters from that terminal. They mediate the main psychoactive effects of cannabis.
  2. CB2 Receptors: Found primarily outside the CNS on cells of the immune system and play a role in modulating inflammation.

Which of the following is an example of a metabotropic receptor?

A. GABA-A receptor B. Nicotinic acetylcholine receptor C. Glycine receptor D. AMPA receptor E. CB1 endocannabinoid receptor

Explanation: The CB1 receptor is a classic example of a G-protein coupled receptor (GPCR), which defines it as metabotropic. All the other options are ionotropic (ligand-gated ion channels).

Cannabinoid CB₁ receptors belong to which receptor class?

A. Ionotropic ligand-gated channels B. Nuclear receptors C. Receptor tyrosine kinases D. Metabotropic G-protein-coupled receptors E. Enzyme-linked receptors

Explanation: Both CB₁ and CB₂ receptors are members of the GPCR superfamily. They signal via Gi/o proteins to modulate neurotransmission.

Which of the following is an example of an endocannabinoid?

A. Enkephalin B. Arachidonic acid C. Anandamide D. Dynorphin E. Endorphin

Explanation: Anandamide is a key endogenous ligand for cannabinoid receptors. Enkephalins, dynorphins, and endorphins are endogenous opioid peptides. Arachidonic acid is a precursor molecule.

Part 5: Principles of Psychopharmacology

This section covers pharmacokinetics (what the body does to a drug) and pharmacodynamics (what a drug does to the body), focusing on concepts directly relevant to psychiatric practice.

5.1. Pharmacokinetics

Pharmacokinetics describes the journey of a drug through the body: Absorption, Distribution, Metabolism, and Excretion (ADME).

5.1.1. Absorption & Bioavailability

• Bioavailability: The fraction of an administered dose that reaches the systemic circulation unchanged.
• Effect of Food:
  • Increased Absorption: Some lipophilic (fat-soluble) drugs require fat for optimal absorption. Their bioavailability increases significantly when taken with a meal.
    • Ziprasidone: Bioavailability can double with a meal of ≥500 kcal.
    • Lurasidone: Bioavailability increases 2-3 fold with a meal of ≥350 kcal.
• Area Under the Curve (AUC): The primary measure of total drug exposure over time, representing the total amount of drug the body is exposed to. It is a key indicator of bioavailability.

The absorption of which oral antipsychotic is significantly increased by food?

A. Ziprasidone B. Risperidone C. Haloperidol D. Olanzapine E. Aripiprazole

Explanation: Ziprasidone (and lurasidone) are lipophilic drugs that require co-administration with a substantial meal to ensure optimal bioavailability.

In pharmacokinetics, the "Area Under the Curve" (AUC) primarily represents:

A. The total volume in which a drug is distributed in the body. B. The maximum concentration of a drug achieved in plasma. C. The actual body exposure to a drug after administration of a dose. D. The rate at which a drug is eliminated from the body. E. The time it takes for a drug's concentration to fall by half.

Explanation: The Area Under the Curve (AUC) integrates drug concentration in the plasma over time, providing a comprehensive measure of total systemic drug exposure and bioavailability.

5.1.2. Distribution

• Volume of Distribution (Vd): A theoretical volume representing how extensively a drug is distributed. Lipophilic drugs have a large Vd as they accumulate in fatty tissues.
• Protein Binding: Many drugs bind to plasma proteins like albumin. Only the unbound (free) fraction is pharmacologically active. Fluoxetine is notable for its very high protein binding (~95%).
• Pharmacokinetics in the Elderly: Older adults have more body fat. This increases the volume of distribution for lipophilic drugs, prolonging their half-life and increasing the risk of accumulation.
• P-glycoprotein (P-gp): An efflux pump at the blood-brain barrier that actively pumps many drugs (including some psychotropics) out of the brain.

In elderly patients, lipophilic psychotropics typically show:

A. Decreased volume of distribution B. Increased volume of distribution C. Unchanged clearance D. Increased renal excretion E. Decreased half-life

Explanation: The age-related increase in the proportion of body fat expands the volume of distribution for lipophilic (fat-soluble) drugs, leading to a longer half-life and slower elimination.

Which SSRI is known for having the highest degree of protein binding?

A. Fluoxetine B. Citalopram C. Paroxetine D. Escitalopram E. Sertraline

Explanation: Fluoxetine and its active metabolite, norfluoxetine, are approximately 95% bound to plasma proteins. This high binding affinity contributes to its long half-life.

5.1.3. Metabolism

• Metabolism: Chemical conversion of a drug, primarily in the liver by Cytochrome P450 (CYP) enzymes.
• Prodrugs vs. Active Metabolites:
  • Prodrug: An inactive substance metabolized into an active drug (e.g., lisdexamfetamine → dexamfetamine).
  • Active Metabolite: An active drug metabolized into another active substance (e.g., imipramine → desipramine).
• Enzyme Induction: Smoking is a potent inducer of CYP1A2, which metabolizes drugs like clozapine and olanzapine, leading to lower drug levels.
• Enzyme Inhibition: Fluoxetine is a potent inhibitor of CYP2D6, which can lead to dangerously high levels of other drugs metabolized by this enzyme (e.g., TCAs, risperidone).

Which of the following is NOT a prodrug?

A. Lisdexamfetamine B. Fosphenytoin C. Oxcarbazepine D. Desipramine E. Prednisone

Explanation: Desipramine is the active metabolite of imipramine; it is already in its active form. The others are all prodrugs.

Which common environmental factor is known to induce the activity of CYP1A2?

A. Alcohol consumption B. Grapefruit juice consumption C. Smoking D. High-fat diet E. Caffeine intake

Explanation: Polycyclic aromatic hydrocarbons in tobacco smoke are potent inducers of the CYP1A2 enzyme, which can significantly lower plasma concentrations of drugs like clozapine and olanzapine.

5.1.4. Elimination & Half-Life

• Kinetics:
  • First-Order Kinetics: Most drugs. A constant fraction (%) is eliminated per unit of time.
  • Zero-Order (Non-Linear) Kinetics: A constant amount is eliminated per unit of time. This occurs when metabolic enzymes become saturated. Drugs like phenytoin, ethanol, and at high doses, fluoxetine, follow this pattern.
• Half-Life (t½): The time for plasma concentration to decrease by 50%. It takes approximately 5 half-lives for a drug to be effectively eliminated (>96% cleared).
• Physiological Factors:
  • Pregnancy: The glomerular filtration rate (GFR) increases significantly, which can increase the renal clearance of drugs like lithium.

Which drug exhibits non-linear (zero-order) pharmacokinetics at therapeutic doses?

A. Citalopram B. Fluoxetine C. Sertraline D. Escitalopram E. Paroxetine

Explanation: Fluoxetine (along with paroxetine and fluvoxamine at high doses) can saturate its own metabolic enzymes, leading to non-linear, zero-order kinetics. Phenytoin and alcohol are classic non-psychiatric examples.

Which SSRI has the shortest half-life?

A. Citalopram (33 h) B. Escitalopram (30 h) C. Fluvoxamine (17–22 h) D. Paroxetine (22 h) E. Sertraline (26 h)

Explanation: Fluvoxamine has the shortest half-life among the common SSRIs, which is a key factor in its higher potential for discontinuation symptoms upon abrupt cessation.

After how many half-lives is >96% of a drug eliminated?

A. 2 B. 3 C. 4 D. 5 E. 10

Explanation: This is a fundamental pharmacokinetic rule of thumb. After 1 half-life, 50% remains; after 2, 25%; after 3, 12.5%; after 4, 6.25%; and after 5, ~3.125% remains, meaning over 96% has been eliminated.

During pregnancy, which physiological change is most pronounced?

A. Increased gastric pH B. Increased gastric emptying C. Increased glomerular filtration rate D. Increased plasma protein binding E. Decreased cardiac output

Explanation: GFR can increase by up to 50% during pregnancy. This enhances the renal clearance of drugs that are primarily excreted by the kidneys, such as lithium, often necessitating higher doses.

5.2. Pharmacodynamics & Drug Interactions

Pharmacodynamics describes the effects of a drug on the body, including its mechanism of action at the receptor level and the resulting physiological changes.

5.2.1. Receptor Occupancy Theory

The effects of a drug are generally proportional to the number of receptors it occupies. This is particularly relevant for antipsychotics and the dopamine D₂ receptor.

• Therapeutic Window: For antipsychotic efficacy, it is generally accepted that 60-75% of striatal D₂ receptors need to be occupied (blocked).
• Threshold for Extrapyramidal Symptoms (EPS): When D₂ receptor occupancy exceeds a certain threshold, the risk of motor side effects (EPS) increases dramatically. This threshold is approximately 80%.

EPS emerge when D₂ occupancy reaches:

A. 20% B. 50% C. 60% D. 80% E. 100%

Explanation: There is a well-defined therapeutic window for D₂ receptor blockade. While antipsychotic effects are seen at ~60% occupancy, extrapyramidal symptoms typically emerge when striatal D₂ receptor occupancy reaches or exceeds 80%.

5.2.2. Receptor Affinity and Side Effects

Many psychotropic drugs are "dirty drugs," meaning they bind to multiple different receptor types. Their side effect profile is often a direct result of their affinity for these "off-target" receptors.

• H1 (Histamine) Receptor Antagonism: Causes sedation and weight gain. Potent antagonists include mirtazapine, clozapine, and olanzapine.
• α1 (Alpha-1 Adrenergic) Receptor Antagonism: Causes orthostatic hypotension and dizziness. Potent antagonists include clozapine, quetiapine, and risperidone. Aripiprazole has minimal α1 affinity.
• M1 (Muscarinic) Receptor Antagonism (Anticholinergic Effects): Causes dry mouth, blurred vision, constipation, urinary retention, and cognitive impairment. Potent antagonists include TCAs (especially amitriptyline) and clozapine.

Antipsychotic-induced weight gain is primarily linked to antagonism at:

A. Dopamine D₂ receptors B. Histamine H₁ receptors C. GABA-B receptors D. Muscarinic M₂ receptors E. Adrenergic α₂ receptors

Explanation: While multiple mechanisms are involved (including 5-HT2C antagonism), potent blockade of the H1 histamine receptor is a primary driver of the increased appetite and weight gain seen with drugs like olanzapine, clozapine, and mirtazapine.

Which antipsychotic is least likely to cause orthostatic hypotension?

A. Clozapine B. Aripiprazole C. Quetiapine D. Risperidone E. Amisulpride

Explanation: Orthostatic hypotension is caused by α₁-adrenergic blockade. Aripiprazole has very low affinity for α₁ receptors, hence it has the lowest propensity among these options to cause this side effect. Clozapine and quetiapine are potent α₁ blockers.

5.2.3. Drug Interactions

• MAOI Interactions:
  • Interaction with Sympathomimetics (e.g., pseudoephedrine) leads to a massive surge of noradrenaline, causing a hypertensive crisis.
• Lithium Interactions:
  • Interaction with ACE Inhibitors & NSAIDs can reduce the kidney's ability to clear lithium, increasing the risk of lithium toxicity.

Which over-the-counter decongestant should be avoided when on MAO inhibitors due to hypertensive crisis risk?

A. Pseudoephedrine B. Ibuprofen C. Loratadine D. Acetaminophen E. Loperamide

Explanation: Pseudoephedrine is a sympathomimetic agent that increases the release of noradrenaline. In a patient taking an MAOI, the breakdown of this excess noradrenaline is blocked, leading to a potentially fatal hypertensive crisis.

Which of the following should not be co-prescribed with an ACE inhibitor?

A. NSAID B. Spironolactone C. Lithium D. Thiazide diuretic E. Calcium channel blocker

Explanation: ACE inhibitors alter renal hemodynamics and can significantly reduce the renal clearance of lithium, leading to accumulation and a high risk of toxicity.

5.3. Neurochemical Basis of Iatrogenic Syndromes

This section covers distinct clinical syndromes caused by the neurochemical effects of psychotropic medications. Understanding the underlying pathophysiology is essential for diagnosis, management, and answering safety-related questions on the exam.

5.3.1. Serotonin Syndrome

• Definition: A potentially life-threatening condition caused by excessive serotonergic activity in the central and peripheral nervous systems.
• Neurochemical Basis: The core mechanism is the overstimulation of serotonin receptors, particularly the postsynaptic 5-HT2A and possibly 5-HT1A receptors. This is often caused by combining multiple drugs that increase serotonin levels (e.g., an SSRI with an MAOI or tramadol).
• The Clinical Triad:
  1. Cognitive/Mental Status Changes: Agitation, confusion, restlessness, delirium.
  2. Autonomic Instability: Hyperthermia, diaphoresis (sweating), tachycardia, hypertension.
  3. Neuromuscular Hyperactivity: This is a key diagnostic feature. It includes hyperreflexia, tremor, myoclonus, and most characteristically, inducible or spontaneous clonus (especially at the ankles).
• Important Distinction from NMS: Serotonin syndrome is characterized by hyper-reflexia and clonus, whereas Neuroleptic Malignant Syndrome (NMS) presents with "lead-pipe" rigidity and hypo-reflexia.

A patient develops restlessness and ankle clonus—this presentation is most consistent with:

A. Extrapyramidal hyperkinesia B. Serotonin syndrome C. Neuroleptic malignant syndrome D. Acute dystonic reaction E. Malignant catatonia

Explanation: The combination of neuromuscular hyperactivity (restlessness) and a specific, classic sign like ankle clonus is highly indicative of serotonin toxicity, which is the basis of serotonin syndrome.

5.3.2. Neuroleptic Malignant Syndrome (NMS)

• Definition: A rare but life-threatening idiosyncratic reaction to dopamine-blocking agents.
• Neurochemical Basis: The central mechanism is a sudden and profound blockade of D₂ receptors in multiple pathways.
  • Nigrostriatal Pathway: Blockade here causes the extreme "lead-pipe" muscle rigidity.
  • Hypothalamus: Blockade here disrupts thermoregulation, leading to hyperthermia (fever).
• The Clinical Tetrad:
  1. Mental Status Change (Delirium, stupor)
  2. Extreme Muscle Rigidity ("Lead-pipe")
  3. Hyperthermia (Fever)
  4. Autonomic Instability (Tachycardia, labile BP)

5.3.3. Acute Dystonia

• Definition: An acute, drug-induced movement disorder characterized by painful, sustained, involuntary muscle contractions, typically occurring within hours to days of starting a D₂ blocking agent.
• Neurochemical Basis: Believed to be caused by an acute disruption of the dopamine-acetylcholine balance in the nigrostriatal pathway. The sudden D₂ blockade leads to a state of relative cholinergic overactivity.
• Classic Presentations: Oculogyric crisis (forced upward deviation of the eyes), torticollis (neck twisting), opisthotonos (arching of the back).

A 25-year-old male on a typical antipsychotic presents with sudden, painful muscle contractions, an involuntary upward deviation of his eyes, and twisting of his neck. What is he experiencing?

A. Akathisia B. Pseudoparkinsonism C. Tardive Dyskinesia D. Acute Dystonia E. Neuroleptic Malignant Syndrome

Explanation: The presentation of an oculogyric crisis and torticollis shortly after starting a dopamine antagonist is the classic clinical picture of an acute dystonic reaction.

5.3.4. Drug-Induced Parkinsonism

• Definition: A sub-acute extrapyramidal syndrome that mimics Parkinson's disease, developing weeks to months after starting a D₂ blocking agent.
• Neurochemical Basis: Caused by the blockade of D₂ receptors in the nigrostriatal pathway, creating a functional state of dopamine deficiency.
• Clinical Features: Bradykinesia (slowness), tremor (often "pill-rolling"), and rigidity. Axial rigidity (stiffness of the neck and trunk) is a common presentation.

A patient on depot antipsychotic reports back stiffness and difficulty rising—this is most consistent with:

A. Akathisia B. Catatonia C. Axial rigidity (parkinsonism) D. Tardive dyskinesia E. Dystonic reaction

Explanation: Stiffness of the trunk (axial rigidity) and associated bradykinesia (difficulty rising) are hallmark features of drug-induced parkinsonism, resulting from D₂ blockade in the nigrostriatal pathway.

5.3.5. Tardive Dyskinesia (TD)

• Definition: A potentially irreversible, late-onset movement disorder characterized by involuntary, repetitive movements after long-term exposure to dopamine-blocking agents.
• Neurochemical Basis: The leading hypothesis is the development of D₂ receptor supersensitivity. Chronic blockade causes postsynaptic neurons to compensate by increasing the number and sensitivity of their D₂ receptors, making the pathway hypersensitive to any available dopamine.
• Clinical Features: Classic presentation involves oro-bucco-lingual movements: repetitive lip-smacking, chewing motions, and tongue protrusions.

A patient on long-term antipsychotics has involuntary, repetitive movements of the mouth and tongue. This is a consequence of which neurochemical change?

A. Increased D1 receptor sensitivity in the striatum B. Decreased serotonin 5HT2A receptor activity C. D2 receptor supersensitivity in the basal ganglia D. Cholinergic receptor upregulation in the substantia nigra E. Alpha-1 adrenergic receptor blockade in cortical regions

Explanation: The neurochemical basis of tardive dyskinesia is understood to be the upregulation and supersensitivity of postsynaptic D₂ receptors in the basal ganglia as a compensatory response to chronic receptor blockade.

5.3.6. Syndrome of Inappropriate ADH (SIADH)

• Definition: A condition of excessive release of antidiuretic hormone (ADH), leading to water retention and subsequent dilutional hyponatremia (low serum sodium).
• Neurochemical Basis: Believed to involve inappropriate stimulation of ADH release from the hypothalamus. Serotonergic pathways may play a modulatory role.
• Causative Agents: Most commonly associated with SSRIs (especially in the elderly), but also carbamazepine and TCAs.
• Clinical & Lab Features: Confusion, lethargy. Labs show low serum sodium, low serum osmolality, euvolemia, and an inappropriately high urine osmolality.

An elderly patient on an antidepressant develops confusion. Labs show euvolemic hyponatremia and inappropriately high urine osmolality. Which adverse reaction is most likely?

A. Serotonin Syndrome B. Neuroleptic Malignant Syndrome C. Syndrome of Inappropriate Antidiuretic Hormone (SIADH) D. Anticholinergic Delirium E. Hepatic Encephalopathy

Explanation: The classic biochemical triad of euvolemic hyponatremia (low serum sodium with normal volume status) and inappropriately concentrated urine is the hallmark of SIADH.

Part 6: Neurochemistry of Pathological States

This section focuses on the molecular basis of specific diseases. A central theme is proteinopathy—diseases caused by the misfolding and aggregation of proteins into toxic structures.

6.1. The Proteinopathies: Misfolded Proteins in Neurodegeneration

6.1.1. α-Synucleinopathies

• Protein: The core pathology involves the misfolding and aggregation of the protein alpha-synuclein (encoded by the SNCA gene).
• Pathological Inclusion: Aggregates form characteristic intracellular deposits.
  • In neurons, they are called Lewy bodies.
  • In glial cells, they are called glial cytoplasmic inclusions.
• Associated Diseases:
  • Parkinson's Disease: Loss of dopaminergic neurons in the substantia nigra and presence of Lewy bodies.
  • Dementia with Lewy Bodies (LBD): Widespread cortical Lewy bodies.
  • Multiple System Atrophy (MSA): Glial cytoplasmic inclusions.

Which protein accumulates in Lewy body dementia?

A. Amyloid-β B. Tau C. α-Synuclein D. Ubiquitin E. TDP-43

Explanation: Lewy bodies, the pathological hallmark of LBD and Parkinson's disease, are intracellular inclusions composed primarily of aggregated alpha-synuclein protein.

Which disorder is NOT classified as an α-synucleinopathy?

A. Parkinson’s disease B. Lewy body dementia C. Multisystem atrophy D. Progressive supranuclear palsy E. Dementia with Lewy bodies

Explanation: Progressive supranuclear palsy (PSP) is a primary tauopathy, not an α-synucleinopathy. Parkinson's, LBD, and MSA are the classic examples of α-synucleinopathies.

Which pathology characterizes MSA?

A. Tauopathy B. Polyglutamine expansions C. Alpha-synucleinopathy D. Hepatolenticular degeneration E. Drug-induced parkinsonism

Explanation: Multiple System Atrophy (MSA) is defined by the presence of alpha-synuclein aggregates within glial cells (glial cytoplasmic inclusions).

6.1.2. Tauopathies

• Protein: Involves the hyperphosphorylation and aggregation of the tau protein (encoded by the MAPT gene), which normally stabilizes the neuron's internal skeleton.
• Pathological Inclusions:
  • Neurofibrillary Tangles (NFTs): Intracellular tangles of hyperphosphorylated tau, a key hallmark of Alzheimer's disease.
  • Pick Bodies: Round, silver-staining intracellular inclusions containing tau, characteristic of Pick's disease (a subtype of Frontotemporal Dementia).
• Associated Diseases:
  • Alzheimer's Disease (considered a secondary tauopathy)
  • Frontotemporal Dementia (FTD-tau)
  • Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration.

Hyperphosphorylated tau in Alzheimer’s histology forms which pathological structure?

A. Lewy bodies B. Pick bodies C. Hirano bodies D. Neurofibrillary tangles E. Amyloid plaques

Explanation: Neurofibrillary tangles are the intracellular aggregates formed from hyperphosphorylated tau protein and are one of the two defining pathological hallmarks of Alzheimer's disease.

Mutations in the tau (MAPT) gene most commonly cause:

A. Familial Alzheimer disease B. Sporadic Alzheimer disease C. Familial frontotemporal dementia D. Huntington disease E. Progressive supranuclear palsy

Explanation: While tau pathology is seen in Alzheimer's, mutations in the MAPT gene itself are a primary cause of inherited (familial) forms of frontotemporal lobar degeneration (FTLD-tau).

Pick bodies are best described as:

A. Ubiquitin-positive, tau-negative inclusions B. Argentophilic, tau and ubiquitin-reactive filamentous inclusions C. Alpha-synuclein-positive Lewy bodies D. Amyloid plaques with central cores E. TDP-43-immunoreactive neuronal cytoplasmic inclusions

Explanation: Classic Pick bodies are spherical intracellular inclusions that stain with silver (argentophilic) and are immunoreactive for both tau and ubiquitin.

6.1.3. Amyloid-beta Pathology

• Protein: Aggregation of the amyloid-beta (Aβ) peptide.
• Precursor & Enzymes: Aβ is cleaved from a larger protein, Amyloid Precursor Protein (APP).
  • The "bad" pathway involves sequential cleavage by β-secretase and then γ-secretase, producing the toxic Aβ peptide.
• Pathological Inclusion: Aβ peptides aggregate to form extracellular senile plaques, the primary hallmark of Alzheimer's disease.

What is the primary pathological hallmark of Alzheimer’s disease?

A. Alpha-synuclein inclusions B. Beta-amyloid plaques and neurofibrillary tangles C. Ubiquitin inclusions D. Demyelination in white matter tracts E. Lewy bodies in cortical neurons

Explanation: Alzheimer's pathology is defined by the combination of extracellular beta-amyloid plaques and intracellular hyperphosphorylated tau tangles.

In developing newer treatments for Alzheimer's, which enzymatic pathway is a key target?

A. Acetylcholinesterase B. Monoamine oxidase C. Secretase enzymes (alpha, beta, and gamma) D. Glycogen synthase kinase-3 (GSK-3) E. Glutaminase

Explanation: The secretase enzymes control whether APP is cleaved into harmless fragments or the toxic, plaque-forming beta-amyloid peptide. Therefore, inhibiting β- or γ-secretase are key therapeutic strategies.

6.1.4. Prionopathies (Transmissible Spongiform Encephalopathies)

• Protein: Misfolding of the Prion Protein (PrP). The normal form is PrPᶜ, the infectious form is PrPˢᶜ.
• Mechanism: The pathogenic PrPˢᶜ acts as a template, forcing normal PrPᶜ proteins to misfold in a chain reaction, leading to aggregation and widespread neuronal death ("spongy" appearance).
• Associated Diseases: Creutzfeldt-Jakob Disease (CJD), Variant CJD, Kuru, and Fatal Familial Insomnia.

The pathological basis for prion diseases, such as Creutzfeldt-Jakob disease, is primarily attributed to:

A. Viral infection leading to neuronal lysis. B. Accumulation of amyloid-beta plaques. C. Protein misfolding and aggregation. D. Autoimmune destruction of myelin sheaths. E. Genetic mutations affecting neurotransmitter synthesis.

Explanation: Prion diseases are the archetypal protein misfolding disorders, where the pathogenic PrPˢᶜ protein acts as a template to propagate its misfolded conformation, leading to aggregation and neurotoxicity.

Which prion disease presents with a predominant sleep disorder and thalamic atrophy?

A. Creutzfeldt-Jakob disease B. Variant CJD C. Fatal familial insomnia D. Kuru E. Gerstmann–Sträussler–Scheinker syndrome

Explanation: Fatal familial insomnia is a rare, inherited prion disease characterized by intractable insomnia, autonomic dysfunction, and selective degeneration of the thalamus.

Part 7: Neuroinflammation & Molecular Genetics

This section explores how inflammation and genetic factors contribute to the neurochemical basis of psychiatric illness.

7.1. Role of Cytokines in Psychiatry

Cytokines are small proteins that act as signaling molecules for the immune system. A chronic, low-grade pro-inflammatory state is implicated in the pathophysiology of mood and anxiety disorders.

• Pro-inflammatory Cytokines:
  • Interleukin-6 (IL-6): This is the most robustly and consistently elevated pro-inflammatory cytokine found in patients with major depression and Generalized Anxiety Disorder (GAD).
  • Others implicated include Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-1β (IL-1β).
• HIV & Neuroinflammation: In HIV-associated neurocognitive disorder (HAND), a state of chronic neuroinflammation often persists, characterized by elevated CD8⁺ T-cells in the CNS.

Which cytokine is most consistently elevated in major depression?

A. IL-2 B. IL-4 C. IL-6 D. IL-10 E. TGF-β

Explanation: Meta-analyses of numerous studies consistently show that IL-6 is a reliable biomarker of systemic inflammation in patients with major depressive disorder.

Which interleukin has robust evidence of increased levels in Generalized Anxiety Disorder (GAD)?

A. Interleukin-1 beta (IL-1β) B. Interleukin-2 (IL-2) C. Interleukin-6 (IL-6) D. Interleukin-10 (IL-10) E. Tumor Necrosis Factor-alpha (TNF-α)

Explanation: Similar to depression, there is strong evidence for elevated peripheral levels of the pro-inflammatory cytokine IL-6 in individuals with GAD.

7.2. Genetic Polymorphisms of Neurochemical Importance

Psychiatric disorders are polygenic, meaning risk is conferred by the combined small effects of many common genetic variations (polymorphisms).

• Apolipoprotein E (APOE) ε4 Allele:
  • Relevance: The ε4 allele of the APOE gene is the single strongest genetic risk factor for late-onset Alzheimer's disease.
  • Homozygous (two copies) confers an approximately 10-30 fold increased risk.
• Ion Channelopathies in Psychiatry:
  • Voltage-gated Calcium Channels: The CACNA1C gene is one of the most robustly identified risk genes for bipolar disorder.
  • Potassium Channels: The KCNN3 gene has been identified as a susceptibility gene for schizophrenia.
• Genes related to Synaptic Function:
  • SHANK3: Mutations in this gene are strongly associated with Autism Spectrum Disorder (ASD).

Homozygosity for the ApoE ε4 allele confers approximately what fold increase in late-onset Alzheimer’s risk?

A. 2–3× B. 3–4× C. 5–7× D. 10–30× E. 50–60×

Explanation: Having two copies of the APOE ε4 allele dramatically increases the risk for late-onset Alzheimer's disease by 10- to 30-fold. Heterozygotes (one copy) have a 3- to 4-fold increased risk.

Genetic studies implicate which ion channel gene in schizophrenia susceptibility?

A. CACNA1C (L-type Ca²⁺ channel) B. KCNN3 (SK3 K⁺ channel) C. SCN2A (Na⁺ channel) D. GRIN2B (NMDA receptor) E. HCN1 (hyperpolarization-activated channel)

Explanation: Genome-wide association studies (GWAS) have identified the KCNN3 gene, which encodes the SK3 calcium-activated potassium channel, as a significant risk locus for schizophrenia.

Mutations in which gene are linked to autism spectrum disorder?

A. DRD4 B. DAT1 C. SNAP25 D. SHANK3 E. 5HTT

Explanation: Mutations in the SHANK3 gene, which is crucial for synaptic structure and function, are a well-established cause of a monogenic form of Autism Spectrum Disorder.

Part 8: Neurochemical Investigation Techniques

This section covers the key methods used to measure and manipulate neurochemical processes in the living brain.

8.1. In Vivo Measurement

These techniques allow for the non-invasive measurement of neurochemical markers in living subjects.

• Magnetic Resonance Spectroscopy (MRS):
  • Application: The only non-invasive technique that can reliably quantify the in vivo concentration of certain brain metabolites, including Glutamate, GABA, and N-acetylaspartate (NAA) - a marker of neuronal viability.
• Positron Emission Tomography (PET):
  • Principle: Uses radiotracers labeled with positron-emitting isotopes (e.g., Carbon-11 [¹¹C]).
  • Applications: Measuring receptor occupancy (e.g., using ¹¹C-raclopride for D₂ receptors) and visualizing pathological proteins (e.g., using ¹¹C-PiB for beta-amyloid plaques).
• Single-Photon Emission Computed Tomography (SPECT):
  • Application: Primarily used for measuring the density of neurotransmitter transporters. The Dopamine Transporter (DAT) Scan is the most common clinical application, used to differentiate neurodegenerative parkinsonian syndromes from other causes.

Which imaging technique detects GABA and glutamate in vivo?

A. PET B. fMRI C. MRE D. MRS E. SPECT

Explanation: Magnetic Resonance Spectroscopy (MRS) is the standard in vivo technique for quantifying the concentrations of major brain metabolites, including the primary excitatory (glutamate) and inhibitory (GABA) neurotransmitters.

Which imaging modality uses ¹¹C-labeled tracers to study receptor occupancy?

A. PET B. SPECT C. fMRI D. MRS E. CT

Explanation: PET utilizes positron-emitting isotopes like Carbon-11 (¹¹C) to create radioligands (e.g., ¹¹C-raclopride) that can be used to quantify receptor binding and occupancy in the living brain.

Which scan is routinely used to measure striatal dopamine transporter binding?

A. DAT SPECT B. ¹¹C-raclopride PET C. fMRI D. MRS E. EEG

Explanation: DAT SPECT is the specific clinical imaging tool used to assess the integrity of the presynaptic dopamine system by measuring dopamine transporter density.

8.2. Advanced Research Concepts & Tools

These are cutting-edge techniques used in neuroscience research to manipulate and study neural circuits with high precision.

• Optogenetics:
  • Principle: Combines genetics and light to control specific neurons.
  • Important Opsins (light-sensitive channels):
    • Channelrhodopsin (ChR2): Opens in response to blue light, causing neuronal activation.
    • Halorhodopsin: A chloride pump activated by yellow light, causing neuronal inhibition.
• Chemogenetics (DREADDs):
  • Principle: Uses a designer drug to control neuronal activity.
  • Mechanism: A synthetic receptor (DREADD) is introduced into neurons. This receptor is activated exclusively by an inert drug, most commonly Clozapine-N-oxide (CNO).
• Intermittent Theta-Burst Stimulation (iTBS):
  • Principle: A patterned form of rTMS that induces long-term potentiation (LTP)-like synaptic plasticity.
  • Neurochemical Effect: Has been shown to modulate the balance of excitation and inhibition, specifically by restoring the GABA/glutamate equilibrium.

Which statement best describes a basic optogenetic setup?

A. Single gene introduced with a single beam of light (blue for activation; yellow for inhibition) B. Single gene introduced with multiple light beams C. Multiple genes introduced with a single light beam D. Multiple genes introduced with multiple light beams E. Deep brain stimulation adjunct

Explanation: The core principle of optogenetics involves expressing a single light-sensitive gene (an opsin) in target neurons and then using specific wavelengths of light to either activate (e.g., blue light for Channelrhodopsin) or inhibit (e.g., yellow light for Halorhodopsin) them.

Clozapine-N-oxide (CNO) selectively activates which receptor in chemogenetic studies?

A. M1 muscarinic B. M3 muscarinic C. DREADD hM3Dq D. CB1 cannabinoid E. β2 adrenergic

Explanation: CNO is the inert "designer drug" that is specifically designed to activate the engineered "designer receptor" (in this case, the excitatory hM3Dq DREADD) without affecting any native receptors in the brain.

Intermittent theta-burst stimulation applied to DLPFC modulates which ratio?

A. GABA to glutamate concentration B. Dopamine to serotonin ratio C. Acetylcholine to GABA ratio D. Glutamate to glycine ratio E. Serotonin to noradrenaline balance

Explanation: iTBS is thought to exert its therapeutic effects by enhancing synaptic plasticity and restoring the homeostatic balance between inhibition (GABA) and excitation (glutamate) in the targeted cortical region.