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TARGETS OF CNS DRUG ACTION

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Most drugs that act on the central nervous system (CNS) appear to do so by changing ion flow through transmembrane channels of nerve cells.

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A. Types of Ion Channels
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Ion channels of neuronal membranes are of 2 major types: voltage gated and ligand gated (Figure 21–1). Voltage-gated ion channels respond to changes in membrane potential. They are concentrated on the axons of nerve cells and include the sodium channels responsible for action potential propagation. Cell bodies and dendrites also have voltage-sensitive ion channels for potassium and calcium. Ligand-gated ion channels, also called ionotropic receptors, respond to chemical neurotransmitters that bind to receptor subunits present in their macromolecular structure. Neurotransmitters also bind to G protein-coupled receptors (metabotropic receptors) that can modulate voltage-gated ion channels. Neurotransmitter-coupled ion channels are found on cell bodies and on both the presynaptic and postsynaptic sides of synapses.

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FIGURE 21–1

Types of ion channels and neurotransmitter receptors in the CNS: A shows a voltage-gated ion channel in which the voltage sensor controls the gating (broken arrow). B shows a ligand-gated ion channel in which binding of the neurotransmitter to the ionotropic channel receptor controls the gating. C shows a metabotropic receptor coupled to a G protein that can interact directly with an ion channel. D shows a receptor coupled to a G protein that activates an enzyme; the activated enzyme generates a diffusible second messenger, for example, cAMP, which interacts to modulate an ion channel. (Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 21–2.)

Graphic Jump Location
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B. Types of Receptor-Channel Coupling
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In the case of ligand-gated ion channels, activation (or inactivation) is initiated by the interaction between chemical neurotransmitters and their receptors (Figure 21–1). Coupling may be through a receptor that acts directly on the channel protein (panel B), through a receptor that is coupled to the ion channel through a G protein (C), or through a receptor coupled to a G protein that modulates the formation of diffusible second messengers, including cyclic adenosine monophosphate (cAMP), inositol trisphosphate (IP3), and diacylglycerol (DAG), which secondarily modulate ion channels (D).

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C. Role of the Ion Current Carried by the Channel
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Excitatory postsynaptic potentials (EPSPs) are usually generated by the opening of sodium or calcium channels. In some synapses, similar depolarizing potentials result from the closing of potassium channels. Inhibitory postsynaptic potentials (IPSPs) are usually generated by the opening of potassium or chloride channels. For example, activation of postsynaptic metabotropic receptors increases the efflux of potassium. Presynaptic inhibition can occur via a decrease in calcium influx elicited by activation of metabotropic receptors.

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SITES & MECHANISMS OF DRUG ACTION

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