CNS Introduction, and Sedative-Hypnotic and Anxiolytic Drugs

Chapter 7 CNS Introduction, and Sedative-Hypnotic and Anxiolytic Drugs

I. CNS Introduction: See Rapid Review Neuroscience, Chapters 4 to 6, for a review of principles needed to understand how drugs affect neurobiological processes.

A. Synaptic Transmission

1. Electrical synapses (Fig. 7-1)

a. Important mechanism for rapid cell communication

b. Minimal impact of drugs on this process

2. Chemical synapses (Fig. 7-2)

7-1 Electrical synapse. Ions diffuse through central pore of connexon (arrows). A, Gap junction forms between dendrites of two neurons. B, Gap junction. C, Connexon.

(From Nolte J: The Human Brain, 5th ed. Philadelphia, Mosby, 2002.)

7-2 Chemical synapse. A, Axon terminal forms chemical synapse on dendrite of another neuron. B, Two neurotransmitters (gray and orange dots) are released by presynaptic terminal. One (orange) has postsynaptic effect. The other (gray), by binding both to postsynaptic receptors and presynaptic autoreceptors, can affect both postsynaptic target and activities of the presynaptic terminal.

(From Nolte J: The Human Brain, 5th ed. Philadelphia, Mosby, 2002.)

Mechanisms of signal transduction processes at synapses is high yield for Board Exams.

a. Slower and more complex signaling process than via electrical synapses; important for actions of most CNS drugs

(1) Release of neurotransmitter from the presynaptic terminal requires calcium; enters through voltage-dependent calcium channels.

(2) Voltage-dependent calcium channels open when action potentials depolarize the terminal.

(3) Synaptic cleft

• Space between presynaptic axon terminal and postsynaptic membrane through which transmitter diffuses

(4) Postsynaptic responses depend on receptor subtype.

b. Direct gating

• Ligand-gated receptors

(1) Binding of neurotransmitter opens or closes an ion channel within the receptor.

(2) Activation results in a rapid change in postsynaptic membrane potential.

(3) Neurotransmitters that activate gated channels:

(a) Glutamate

Glutamate the most important excitatory amino acid in brain.

(b) Acetylcholine (ACh)

GABA the most important inhibitory amino acid in brain.

(d) Glycine

(e) Serotonin

c. Indirect gating

• Non-channel-linked receptors

(1) Binding of neurotransmitter activates second-messenger pathways by way of guanosine triphosphate-binding (G proteins).

(2) Signal transduction pathways activated by second messengers have multiple and lasting effects.

(3) Important signaling pathways

(a) Cyclic adenosine monophosphate (cAMP)

(b) Polyphosphoinositide products

Diacylglycerol (DAG)

Inositol-trisphosphate (IP₃)

Increased intracellular Ca²⁺ important for smooth muscle contraction, secretions, and transmitter release.

(d) K⁺ conductance (hyperpolarization)

(e) Cation conductance, mainly Na⁺ (depolarization)

(f) Cl^– conductance (hyperpolarization)

Learn how CNS drugs affect the chemical synapse as you study these drugs.

B. Important small-molecule neurotransmitters

1. Acetylcholine (ACh); review Fig. 3-2A for synthesis, storage, release and inactivation.

a. Activation of M₁ muscarinic receptors is excitatory.

(1) Decreases K⁺ conductance

(2) Increases IP₃ and DAG

b. Activation of M₂ muscarinic receptors is inhibitory.

(1) Increases K⁺ conductance

(2) Decreases cAMP

c. Activation of nicotinic receptors is excitatory.

• Increases cation conductance

Reduction in the activity of the cholinergic neurons occurs in Alzheimer’s disease; drugs are used to increase CNS cholinergic activity.

2. Dopamine (DA); Fig. 7-3

a. Activation of D₁ receptors is stimulatory.

• Increases cAMP

b. Activation of D₂ receptors is inhibitory.

(1) Presynaptic

• Decreases Ca²⁺ conductance

(2) Postsynaptic

(a) Increases K⁺ conductance

(b) Decreases cAMP

7-3 Chemistry and pharmacology of the dopamine (DA) synapse. Almost all antipsychotics bind to the D₂ receptor, and some bind to the D₁ receptor.

(From Hardman JG, Limbird LE: Goodman and Gilman’s The Pharmacologic Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001. Reproduced with permission of The McGraw-Hill Companies.)

Dopamine is responsible for reward, drive, and in various feelings such as euphoria, orgasm, anger, addiction, love, pleasure.

3. Norepinephrine (NE); Fig. 7-4; also review Fig. 3-2B for syntheses, storage release and inactivation

a. Activation of α₁ receptors is excitatory.