Introduction to Central Nervous System Pharmacology

Overview

The central nervous system (CNS) consists of the brain and spinal cord. Sensory information arrives to the CNS from the special senses and peripheral nerves and is integrated with memories and internal drive states to generate cognitive, emotional, and motor (behavioral) responses. This processing occurs because of the complex interplay of neurotransmitters and neuromodulators acting on their receptors to excite or inhibit CNS neurons. In persons with brain disorders, structural or functional disturbances of CNS processing produce aberrant cognitive, emotional, or motor responses. Brain disorders are seen in association with a variety of disease processes, including degenerative, ischemic, and psychological disturbances.

Most CNS drugs correct an imbalance in neurotransmitters or their receptors. Drugs are used to relieve the symptoms of brain dysfunction, but they usually do not correct the underlying disorder. Although short-term drug treatment may be effective in relieving acute symptoms such as pain and insomnia, drug therapy for many brain disorders is a lifelong process.

After reviewing pertinent concepts of CNS function and neurotransmission, this chapter explains the general mechanisms by which drugs alter CNS activities and processes.

Neurotransmission in the Central Nervous System

Principles of Neurotransmission

In the past century, great debates raged about the nature of neuronal communication in the CNS. The early physiologists believed that neurons communicated by electrical signals directly passing from neuron to neuron in a hard-wired fashion much like wires in a telegraph relay. The early pharmacologists argued for chemical transmission, with substances released into the synapse between communicating neurons. Modern research shows that both were right to some degree because most neuronal communication occurs by chemical neurotransmitters serving as messengers that enable neurons to communicate with one another. However, there is also evidence of direct voltage signaling between neurons at electrotonic or gap junctions.

The details of chemical neurotransmission undergo constant refinement as new mechanisms and neurotransmitters are discovered. An early statement by Sir Henry Dale, known as Dale’s principle, suggested that each neuron contained only one type of neurotransmitter. This principle was revised with the finding that neurons may release more than one neurotransmitter, as is the case with co-transmitters (see later). It was also thought that neurotransmitter action was limited to the single synapse where released. The neuroanatomic demonstration of diffuse neuronal systems with fine, widespread projections throughout the CNS, such as norepinephrine and serotonergic fibers arising from brain stem nuclei, led to the concept of the chemical soup or chemical milieu model of neurotransmission. Newer methods using in vitro brain slice preparations and other techniques show that neurotransmitters can diffuse far from the synapse and affect other neurons at other synapses. Identification of neuroactive substances both intrinsic and extrinsic to the CNS that exert generalized effects on neurons strengthened the concept of action at a distance. A neuromodulator is a general term for any substance that exerts an effect on neurotransmission among a set of neurons in the brain.

The action of drugs on the CNS is similar to the chemical milieu model of neurotransmission, because drug molecules are widely distributed throughout the brain and can simultaneously interact with receptors on neurons in several different neuronal tracts. This lack of specificity can lead to therapeutic effects and adverse effects at the same time. For this reason, the development of agents that are more selective for specific receptor types and subtypes is a useful approach to improving the therapeutic index of CNS drugs.

Neurotransmitter Synthesis and Metabolism

Neurotransmitters are synthesized in neuronal cell bodies or terminals, and they are stored in neuronal vesicles until they are released into a synapse (Fig. 18-1). The release of neurotransmitters is activated by membrane depolarization and calcium influx into the cell. Calcium evokes the interaction of storage vesicle proteins (synaptobrevin and synaptotagmin) and membrane-docking proteins (syntaxin and neurexin) and leads to vesicle fusion with the membrane and exocytosis of the neurotransmitter.

FIGURE 18-1 Central nervous system (CNS) neurotransmission and sites of drug action. CNS drugs act primarily by affecting the synthesis, storage, release, reuptake, or degradation of neurotransmitters *(NT)* or by activating receptors. *NTs* are synthesized from precursors accumulated or synthesized in the neurons. The *NTs* are stored in vesicles whose membranes contain proteins involved in NT release (synaptobrevin and synaptotagmin). The *NTs* are released when an action potential–mediated calcium influx initiates interaction of synaptobrevin and synaptotagmin with neuronal membrane-docking proteins (syntaxin and neurexin). This leads to docking and exocytosis. Synaptic *NTs* can activate presynaptic (R₃) or postsynaptic receptors (R₁, R₂). The action of *NTs* is terminated by reuptake into the presynaptic neuron or by enzymatic degradation.

After exocytosis, the neurotransmitter may activate presynaptic and postsynaptic receptors. A neurotransmitter’s action is then terminated either by its reuptake into the presynaptic neuron or by its degradation to inactive compounds, with degradation catalyzed by enzymes located on presynaptic and postsynaptic neuronal membranes or within the cytoplasm.

Neurotransmitters can also diffuse from the synapse of their origin to affect neurons in the surrounding vicinity. In this way, different neurotransmitters released from different types of neurons form a chemical milieu, as described previously. The net influence of the chemical milieu on neurotransmission depends on the concentrations of the excitatory and inhibitory neurotransmitters acting at a particular synapse.

Excitatory and Inhibitory Neurotransmission

CNS neurotransmitters can evoke either an excitatory or an inhibitory synaptic membrane potential and trigger effects at presynaptic and postsynaptic sites on target neurons. If an excitatory postsynaptic membrane potential reaches firing threshold, an action potential is conducted along the dendritic and axonal membrane and evokes the release of a neurotransmitter from the nerve terminal. An inhibitory postsynaptic membrane potential hyperpolarizes the neuronal membrane and inhibits the firing of action potentials. Depending on whether a presynaptic membrane potential is excitatory or inhibitory, it will increase or decrease the release of a neurotransmitter from the neuron. Presynaptic receptors, also called autoreceptors, can also be coupled with cyclic adenosine monophosphate (cAMP) or other second messengers that modulate neurotransmitter release.

As shown in Box 18-1, the interaction of multiple neurotransmitters at a particular site in a neuronal tract enables the complex interplay of various neuronal systems and contributes to the wide range of functional expression exhibited in the CNS. For example, inhibition of the release of an inhibitory neurotransmitter will actually increase neurotransmission in the target neuron. Similarly, drugs can act in complex ways to affect neurotransmission. Ethanol (ethyl alcohol), for instance, can diminish the inhibitory influence of the cerebral cortex on certain human behaviors and thereby increase drug-induced behaviors, a phenomenon called behavioral disinhibition. Ethanol and other CNS depressants, initially or at low doses, exert their effects on the smaller and more numerous inhibitory neurons, creating disinhibition via excitation owing to removal of inhibitory neurotransmitters. At higher doses, larger excitatory neurons are inhibited and profound depression of CNS activity can occur.

Box 18-1 Patterns of Neurotransmission in the Central Nervous System

A, B, C, D, E, and F are neurons in a tract that projects from left to right. Neurons B, D, and E release excitatory neurotransmitters (+). Neurons A and F release inhibitory neurotransmitters (−). The net effect of neuronal interactions on neurotransmission from B to C is shown in the accompanying table. Each interaction presupposes that the other neurons are quiescent at that time. Other, more complex interactions are possible.

Interaction	Effect on Neurotransmission (B → C)
A → B	Decreased
D → A → B	Greatly decreased
F → A → B	Increased
E → B	Increased

Fast versus Slow Signals

Neurotransmitters in the CNS can be characterized as slow or fast, depending on the receptors that are activated and the persistence of signal transduction pathways. The best examples of fast neurotransmitters are γ-aminobutyric acid (GABA) and glutamate acting at ligand-gated ion channels. Binding of these amino acid neurotransmitters directly to subunits of the ion channel protein directly initiates ion flow with a signal that lasts for only a few milliseconds. Examples of slow neurotransmitters are norepinephrine and serotonin acting at G protein–coupled receptors. These activated G protein–coupled receptor proteins initiate a slower, multistep process with alterations in second messengers and membrane effects that can last from many milliseconds to as long as a second. A slow (long-acting) signal can influence the overall tone of a neuron because it can modulate the signals of several other fast neurotransmitters acting on the same neuron. For this reason, slow neurotransmitters can also be called neuromodulators.

Neurotransmitters and Receptors

Important neurotransmitters in the CNS include acetylcholine and several amino acids, biogenic amines, and neuropeptides. Table 18-1 lists the names, receptors, mechanisms of signal transduction, and functions of the major neurotransmitters.

TABLE 18-1

Major Neurotransmitters and Their Receptors in the Central Nervous System

NEUROTRANSMITTER	RECEPTORS	SIGNAL TRANSDUCTION	FUNCTION
Acetylcholine	Muscarinic
	M₁, M₃, M₅	↑IP₃, ↑DAG, ↑iCa²⁺	Excitatory; role in arousal and consciousness, memory consolidation
	M₂, M₄	↓cAMP, ↑gK⁺, ↓gCa²⁺	Inhibitory; autoreceptor and heteroreceptor, decreases NT release
	Nicotinic	↑gNa⁺, ↑gCa²⁺	Excitatory; increases NT release, role in nicotine dependence
Amino Acids
GABA	GABA_A	↑gCl⁻	Inhibitory (major); ligand-gated ion channel site of action of sedative-hypnotics, alcohol, general anesthetics
	GABA_B	↓cAMP, ↑gK⁺, ↓gCa²⁺	Inhibitory; modulates motor neuron excitability
Glutamate	NMDA, AMPA, KA	↑gNa⁺, ↑gCa²⁺	Excitatory (major); roles in LTP (memory), excitotoxicity of neurons
	mGlu₁, mGlu₅	↑IP₃, ↑DAG, ↑iCa²⁺	Excitatory; memory consolidation, neuronal excitation
	mGlu₂-mGlu₄, mGlu₆-mGlu₈	↓cAMP, ↑gK⁺, ↓gCa²⁺	Inhibitory; role in thalamic sensory processing
Glycine	Strychnine-sensitive	↑gCl⁻	Inhibitory; highest levels in spinal cord
	Strychnine-insensitive	Co-agonist at NMDA receptor	Excitatory; obligate coagonist for function of NMDA receptor
Biogenic Amines
Dopamine	D₁, D₅	↑cAMP, ↑PKA	Excitatory; basal ganglia function, memory and performance
	D₂, D₃, D₄	↓cAMP, ↑gK⁺, ↓gCa²⁺	Inhibitory; decreases dopamine release, reduces firing of neurons
Norepinephrine	α₁	↑IP₃, ↑DAG, ↑iCa²⁺	Excitatory; autonomic nuclei in brain stem
	α₂	↓cAMP, ↑gK⁺, ↓gCa²⁺	Inhibitory; sympathetic outflow from CNS; decreases pain transmission
	β₁, β₂	↑cAMP, ↑PKA	Excitatory; cortex, limbic system, nucleus accumbens
Serotonin (5-HT)*	5-HT₁	↓cAMP, ↑gK⁺, ↓gCa²⁺	Inhibitory; role in anxiety and depression
	5-HT₂	↑IP₃, ↑DAG, ↑iCa²⁺	Excitatory; widespread distribution, role in antipsychotic action
	5-HT₃	↑gNa⁺, ↑gCa²⁺	Excitatory; mediate fast neuronal transmission in neocortex; presynaptic modulation of NT release
	5-HT₄	↑cAMP, ↑PKA	Excitatory; role in cognitive processes, anxiety
Histamine	H₁	↑IP₃, ↑DAG, ↑iCa²⁺	Excitatory; increases NT release, role in arousal, anxiety
	H₂	↑cAMP, ↑PKA	Excitatory; located in hippocampus, amygdala, and basal ganglia
	H₃	↓cAMP, ↑gK⁺, ↓gCa²⁺	Inhibitory; autoreceptor and heteroreceptor, decreases NT release
Neuropeptides
Opioid peptides	Mu, delta, kappa	↓cAMP, ↑gK⁺, ↓gCa²⁺	Inhibitory; analgesic role in sensory processing, role in drug dependence for opioids and other substances
Tachykinins	NK₁, NK₂, NK₃	↑IP₃, ↑DAG, ↑iCa²⁺	Excitatory; role in pain processing, autonomic regulation