Chapter 7: Acetylcholine Psychopharmacology Study Notes

Overview of the Cholinergic System and Curare

• Conceptual Background: The study of acetylcholine (ACh) often begins with historical anecdotes that illustrate its profound effects on the body. One notable story involves Frederick Prescott and Scott Smith (Anderson, 2010), who experimented with curare.
• Curare: A paralyzing agent that acts on the cholinergic system. The effects of such substances highlight the critical role of ACh in muscle movement and the neuromuscular junction.
• Acetylcholine (ACh): Identified as a primary neurotransmitter in both the peripheral nervous system (PNS) and the central nervous system (CNS).
• Cholinergic System: Refers to the network of neurons that use acetylcholine as their primary signaling molecule.

Acetylcholine Synthesis, Storage, and Inactivation

• Synthesis Process:
  • Precursors: The synthesis of ACh requires two primary precursors:
    • Choline: Obtained primarily through the diet.
    • Acetyl coenzyme A (acetyl CoA): A metabolic product found in cells.
  • Enzyme: The synthesis is catalyzed by the enzyme Choline acetyltransferase (ChAT).
• Storage:
  • Vesicular ACh Transporter (VAChT): This protein is responsible for loading ACh into synaptic vesicles for release.
  • Pharmacological Intervention: The drug vesamicol blocks VAChT, leading to a depletion of ACh in the nerve terminal.
• Inactivation and Cleanup:
  • Breakdown: ACh is broken down in the synaptic cleft by the enzyme Acetylcholinesterase (AChE).
  • Reuptake: The breakdown product, choline, is taken back into the presynaptic neuron via the Choline transporter for reuse in synthesis.
• Receptor Types: ACh acts upon two main classes of receptors:
  • Nicotinic (nACh): Ionotropic receptors.
  • Muscarinic (mACh): Metabotropic receptors.

The Neuromuscular Junction (NMJ) and E-C Coupling

• Setting the Stage: The events at the NMJ provide the necessary excitation for Excitation-Contraction (E-C) coupling. Released ACh binds to receptor proteins on the sarcolemma, triggering an action potential (AP) in the muscle fiber.
• Steps in E-C Coupling:
  1. Propagation: The action potential propagates along the sarcolemma and down the T tubules.
  2. Calcium Release: Transmission of the AP along the T tubules of the triads causes voltage-sensitive tubule proteins to change shape. This opens calcium ($Ca^{2+}$) release channels in the terminal cisterns of the sarcoplasmic reticulum (SR), allowing $Ca^{2+}$ to flow into the cytosol.
  3. Troponin Binding: Calcium binds to troponin, which then removes the blocking action of tropomyosin. This shape change exposes the active binding sites for myosin on the thin actin filaments.
  4. Contraction: Myosin binds to actin, forming cross-bridges. Contraction (cross-bridge cycling) begins, marking the end of the E-C coupling phase.
• The Aftermath (Relaxation):
  • When the muscle AP ceases, voltage-sensitive tubule proteins return to their original shape, closing SR calcium channels.
  • $Ca^{2+}$ levels in the sarcoplasm fall as it is continually pumped back into the SR via active transport.
  • Without $Ca^{2+}$, tropomyosin's blocking action is restored, inhibiting myosin-actin interaction and resulting in relaxation.

Pathologies and Toxins of the Cholinergic System

• Botulism Toxin:
  • Derived from the bacterium Clostridium botulinum.
  • Acts as a deadly poison by inhibiting the release of ACh.
  • Applications: Used therapeutically for specific "on-label" medical conditions, "off-label" applications, and cosmetic procedures (e.g., Botox).
• Myasthenia Gravis:
  • An autoimmune disorder characterized by the destruction of ACh receptors at the NMJ, leading to severe muscle weakness.
• Alzheimer’s Disease Treatment:
  • Acetylcholinesterase inhibitors (AChE inhibitors) like donepezil (brand name Aricept) are used to increase ACh levels in the brain to mitigate cognitive decline.
• AChE Inhibition (Reversible vs. Irreversible):
  • Irreversible Inhibition: Caused by organophosphorous compounds, including nerve gases like sarin and soman.
  • Environmental/Historical Impact: These compounds are linked to toxic exposures and conditions like Gulf War syndrome.

Organization of the Cholinergic System

• Peripheral Nervous System (PNS):
  • Found at the neuromuscular junction (motor control).
  • Autonomic Nervous System (ANS):
    • Parasympathetic Branch: Uses ACh at both the preganglionic neuron (synapsing at the ganglion) and the ganglionic neuron (synapsing on the target organ).
    • Sympathetic Branch: Uses ACh at the preganglionic neuron; however, the ganglionic neuron typically releases norepinephrine onto the target organ.
• Central Nervous System (CNS):
  • Basal Forebrain Cholinergic System (BFCS): Originates in areas like the medial septum, diagonal band nuclei, and nucleus basalis, projecting to the neocortex, hippocampus, and amygdala.
  • Dorsolateral Pons: Includes the laterodorsal and pedunculopontine tegmental nuclei, projecting to the thalamus, midbrain, and brainstem.
  • Striatum: Contains cholinergic interneurons that regulate motor behavior in the caudate-putamen and nucleus accumbens.

Cholinergic Receptors: Detailed Characteristics

• Nicotinic Receptors (nACh):
  • Type: Ionotropic (fast-acting ion channels).
  • Locations: NMJ, ganglionic neurons (both sympathetic and parasympathetic), and the CNS.
  • CNS Function: Often presynaptic, where they enhance the release of other neurotransmitters.
  • Structure: Composed of multiple subunits and configurations.
  • Dynamics: Continuous exposure leads to a desensitized state; they require a period without the agonist for resensitization. Excessive activation can lead to a depolarization block.
• Muscarinic Receptors (mACh):
  • Type: Metabotropic (G-protein coupled).
  • Subtypes: Five distinct types ($M_1$ through $M_5$).
  • Brain Locations: High concentrations in the cortex and hippocampus (cognitive functions), striatum (motor functions), thalamus, and basal forebrain.
  • Peripheral Locations: Found in cardiac muscles of the heart, smooth muscles of various organs, and pancreatic beta cells.
• Role of $M_5$ Receptors in Reward:
  • $M_5$ receptors in the Ventral Tegmental Area (VTA) excite dopamine (DA) receptors, modulating drug reward.
  • Research Evidence (Berizzi et al., 2018): Using male iP rats (genetically selected for ethanol consumption), researchers found that the $M_5$ receptor negative allosteric modulator ML375 ($30\,mg/kg$) significantly reduced voluntary ethanol consumption but had no effect on sucrose (sugar) reinforcement.

Summary Table of Cholinergic Drugs and Toxins

Cognitive Function and Supplements

• Cognitive Impact:
  • Antimuscarinic agents are known to produce amnesia.
  • ACh is vital for attentional processes and the facilitation of sensory cues.
  • Alzheimer’s Disease: Involves the significant loss of cholinergic neurons among other neuronal losses.
• Dietary Supplements (e.g., NeuroQ): Many products claim to enhance ACh function. Evaluation of ingredients includes: