Chapter 12. Introduction to the Pharmacology of Central Nervous System Drugs

Drugs acting in the central nervous system (CNS) were among the first to be discovered by primitive humans and are still the most widely used group of pharmacologic agents. In addition to their use in therapy, many drugs acting on the CNS are used without prescription to increase one’s sense of well-being.

The mechanisms by which various drugs act in the CNS have not always been clearly understood. Since the causes of many of the conditions for which these drugs are used (e.g., schizophrenia, anxiety) are themselves poorly understood, it is not surprising that in the past much of CNS pharmacology has been purely descriptive. However, dramatic advances in the methodology of CNS pharmacology now make it possible to study the action of a drug on individual cells and even on single ion channels within synapses. This information has provided the basis for several major developments in studies of the CNS.

First, it is clear that nearly all drugs with CNS effects act on specific receptors that modulate synaptic transmission, either directly by affecting the receptors themselves or indirectly through various second-messenger coupling systems, ion channels, or other mechanisms. Second, drugs are among the most important tools for studying all aspects of CNS physiology, from the mechanism of convulsions to the laying down of long-term memory. As will be described below, synthetic agonists that mimic natural transmitters (and in many cases are more selective than the endogenous substances) and antagonists are extremely useful in such studies. Third, unraveling the actions of drugs with known clinical efficacy has led to some of the most fruitful hypotheses regarding the mechanisms of disease. For example, information on the action of antipsychotic drugs on dopamine receptors has provided the basis for important hypotheses regarding the pathophysiology of schizophrenia. Studies of the effects of a variety of agonists and antagonists on gamma-aminobutyric acid (GABA) receptors have resulted in new concepts pertaining to the pathophysiology of several diseases, including anxiety and epilepsy.

This chapter provides an introduction to the functional organization of the CNS and its synaptic transmitters as a basis for understanding the actions of the drugs described in the following chapters.

Most drugs that act on the CNS appear to do so by changing ion flow through transmembrane channels of nerve cells. The membranes of nerve cells contain two types of ion channels defined on the basis of the mechanisms that control their gating (opening and closing) as voltage-gated and ligand-gated channels (Figure 12–1a and b). Voltage-gated channels respond to changes in the membrane potential of the cell. In nerve cells, voltage-gated sodium channels are concentrated near and on the axon and are responsible for the action potential which transmits the signal from cell body to nerve terminal. There are also many types of voltage-sensitive calcium and potassium channels on the cell body, dendrites, and initial segment, which act on a slower time scale and modulate the rate at which the neuron discharges. Ligand-gated channels, also called ionotropic receptors, are opened by the binding of neurotransmitters to the channel. The channel is formed of subunits, and the receptor is an integral part of the channel complex. These channels are insensitive or only weakly sensitive to membrane potential. Activation of these channels typically results in a brief (a few milliseconds to tens of milliseconds) opening of the channel. Ligand-gated channels are responsible for fast synaptic transmission typical of hierarchical pathways in the CNS (see below).

Research has now well established that the traditional view of completely separate voltage-gated and ligand-gated channels requires substantial modifications. Neurotransmitters also bind to G protein-coupled receptors (metabotropic receptors) that can modulate voltage-gated ion channels. Neurotransmitter-controlled ion channels are found on cell bodies and on both the presynaptic and postsynaptic sides of synapses. In neurotransmitter-controlled ion channels, coupling may occur by one of two mechanisms. First, control may occur through a receptor that is coupled to the ion channel through a portion of the G protein itself (Figure 12–1c). Two types of voltage-gated ion channels are involved in this type of signaling: calcium channels and potassium channels. When G proteins interact with calcium channels, they inhibit channel function. This mechanism accounts for the presynaptic inhibition that occurs when presynaptic metabotropic receptors are activated. In contrast, when these receptors are postsynaptic, they activate (cause the opening of) potassium channels, resulting in a slow postsynaptic inhibition. Second, control may be through a receptor coupled to a G protein that modulates the concentration of diffusible second messengers, such as cyclic adenosine monophosphate (cAMP), inositol trisphosphate (IP3), and diacylglycerol (DAG), which secondarily modulate ion channels (Figure 12–1d).

An important consequence of the involvement of G proteins in receptor signaling is that, in contrast to the brief effect of transmitters on ionotropic receptors, the effects of metabotropic receptor activation can last tens of seconds to minutes. Metabotropic receptors predominate in the diffuse neuronal systems in the CNS.

Communication between neurons in the CNS occurs through chemical synapses in the vast majority of cases. An action potential in the presynaptic fiber propagates into the synaptic terminal and opens voltage-sensitive calcium channels in the membrane of the terminal. Calcium flows into the terminal, and the increase in intraterminal calcium concentration promotes the fusion of synaptic vesicles with the presynaptic membrane. The transmitter contained in the vesicles is released into the synaptic cleft and diffuses to the receptors on the postsynaptic membrane. Binding of the transmitter to its receptor causes a brief change in membrane conductance (permeability to ions) of the postsynaptic cell.

The binding of the neurotransmitter to the postsynaptic membrane can result in two types of postsynaptic potentials; excitatory or inhibitory. Excitatory postsynaptic potentials (EPSPs) are usually generated by the opening of sodium or calcium channels. In some synapses, 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 presynaptic metabotropic receptors.

Virtually all of the drugs that act in the CNS produce their effects by modifying some step in chemical synaptic transmission. Figure 12–2 illustrates some of the steps that can be altered. These transmitter-dependent actions can be divided into presynaptic and postsynaptic categories. Drugs acting on the synthesis, storage, metabolism, and release of neurotransmitters fall into the presynaptic category. Synaptic transmission can be depressed by blockade of transmitter synthesis or storage (Figure 12–2, Sites 2 and 3). For example, reserpine depletes the synapses of monoamines by interfering with intracellular storage. Blockade of transmitter catabolism (Figure 12–2, Site 4) can increase transmitter concentrations and has been reported to increase the amount of transmitter released per impulse. Drugs can also alter the release of transmitter (Figure 12–2, Site 5). For example, the stimulant amphetamine induces the release of catecholamines from adrenergic nerve endings and botulinum toxin blocks the release of acetylcholine. After a transmitter has been released into the synaptic cleft, its action is terminated either by uptake or degradation (Figure 12–2, Sites 6 and 7, respectively). For some neurotransmitters, there are uptake mechanisms into the synaptic terminal and also into surrounding neuroglia. Cocaine, for example, blocks the uptake of catecholamines at adrenergic synapses and thus potentiates the action of these amines. In contrast, no uptake mechanism has been found for any of the numerous CNS peptides, and it has yet to be demonstrated whether specific enzymatic degradation terminates the action of peptide transmitters. The transmitter acetylcholine is inactivated within the synapse by enzymatic degradation. Anticholinesterase drugs block the degradation of acetylcholine and thereby prolong its action.

In the postsynaptic region, the transmitter receptor provides the primary site of drug action (Figure 12–2, Site 8). Drugs can act either as neurotransmitter agonists, such as the opioids, which mimic the action of endogenous peptides such as enkephalin, or as neurotransmitter antagonists, acting to block receptor function. Receptor antagonism is a common mechanism of action for CNS drugs. Drugs can also act directly on the ion channel of ionotropic receptors. For example, barbiturates can enter and block the channel of many excitatory ionotropic receptors. In the case of metabotropic receptors, drugs can act at any of the steps downstream of the receptor. Perhaps the best example is provided by the methylxanthines (such as caffeine), which can modify neurotransmitter responses mediated through the second-messenger cAMP. At high concentrations, the methylxanthines elevate the level of cAMP by blocking its metabolism and thereby prolong its action in the postsynaptic cell.

The selectivity of CNS drug action is based almost entirely on the fact that different transmitters are used by different groups of neurons. Furthermore, these transmitters are often segregated into neuronal systems that subserve different CNS functions. Without such segregation, it would be impossible to selectively modify CNS function even if one had a drug that operated on a single neurotransmitter system.

Most of the neuronal systems in the CNS can be divided into two broad categories: hierarchical systems and nonspecific (diffuse) neuronal systems.

Hierarchical Systems

These systems include all of the pathways directly involved in sensory perception and motor control. The pathways are generally clearly delineated anatomically and contain large myelinated, rapidly conducting fibers. The information is typically phasic (i.e., dependent on the frequency of action potential firing), and the information is processed sequentially at each successive relay nucleus on its way to its destination. A lesion at any link will incapacitate the system. Within each nucleus and in the cortex, there are two types of cells: relay or projection neurons and local circuit neurons (Figure 12–3a). Projection neurons form interconnecting pathways transmitting signals over long distances. The cell bodies are relatively large and their axons are long. These neurons are excitatory, and their synaptic influences, which involve ionotropic receptors, are very short-lived. The excitatory transmitters released from these cells are glutamate and aspartate.

Local circuit neurons are typically smaller than projection neurons, and their axons arborize in the immediate vicinity of the cell body. The vast majority of these neurons are inhibitory, and they release either GABA or glycine. They synapse primarily on the cell body of the projection neurons but can also synapse on the dendrites of projection neurons as well as with each other. A special class of local circuit neurons in the spinal cord forms axoaxonic synapses on the terminals of sensory axons (Figure 12–3b). Two common types of pathways for these neurons include recurrent feedback pathways and feed-forward pathways (Figure 12–3a). Although there is a great variety of synaptic connections in these hierarchical systems, the fact that a limited number of transmitters are utilized by these neurons indicates that any major pharmacologic manipulation of this system will have a profound effect on the overall excitability of the CNS.

Nonspecific or Diffuse Neuronal Systems

Diffuse systems are broadly distributed, with neurons frequently sending processes to many different areas. These systems differ in fundamental ways from the hierarchical systems. The axons of these neurons are very fine and contain unmyelinated, slowly conducting fibers. The axons branch repeatedly and diverge into many areas. Branches from the same neuron can innervate several functionally different parts of the CNS. The axons commonly have periodic enlargements (varicosities) that contain transmitter vesicles. The transmitters in diffuse systems are often amines (norepinephrine, dopamine, 5-hydroxytryptamine [serotonin]) or peptides that exert actions on metabotropic receptors and, therefore, initiate long-lasting synaptic effects. Based on all of these observations, it is clear that the diffuse systems cannot convey specific topographic or highly transient types of information; rather large areas of the CNS must be affected at the same time and in a rather uniform way. These systems have been implicated in such global functions as sleeping and waking, attention, appetite, and emotional states.

To be accepted as a neurotransmitter, a candidate chemical must (1) be present in higher concentration in the synaptic area than in other areas (i.e., must be localized in appropriate areas), (2) be released by electrical or chemical stimulation via a calcium-dependent mechanism, and (3) produce the same sort of postsynaptic response that is seen with physiologic activation of the synapse (i.e., must exhibit synaptic mimicry). Table 12–1 lists the most important chemicals currently accepted as neurotransmitters in the CNS.

Acetylcholine

Approximately 5% of brain neurons have receptors for acetylcholine (ACh). Most CNS responses to ACh are mediated by a large family of G protein-coupled muscarinic M1 receptors that lead to slow excitation when activated. The ionic mechanism of slow excitation involves a decrease in membrane permeability to potassium. At a few sites, ACh causes slow inhibition of the neuron by activating the M2 subtype of receptor, which opens potassium channels. Nicotinic receptors are present in the CNS but are less common than muscarinic receptors. A number of pathways contain acetylcholine, including neurons in the neostriatum, the medial septal nucleus, and the reticular formation. Cholinergic pathways appear to play an important role in cognitive functions, especially memory. Presenile dementia of the Alzheimer type is reportedly associated with a profound loss of cholinergic neurons. However, the specificity of this loss has been questioned since the levels of other putative transmitters, for example, somatostatin, are also decreased. Drugs affecting the activity of cholinergic systems in the brain include the acetylcholinesterase inhibitors used in Alzheimer’s disease (e.g., donepezil, rivastigmine) and the muscarinic blocking agents used in parkinsonism (e.g., benztropine).

Dopamine

The major pathways containing dopamine are the projections linking the substantia nigra in the basal ganglia to the neostriatum; the ventral tegmental region to limbic structures, particularly the limbic cortex; the medullary-periventricular; the incertohypothalamic; and the tuberoinfundibular tracts. All dopamine receptors are metabotropic. Dopamine exerts slow inhibitory actions at synapses in specific neuronal systems via G protein-coupled activation of potassium channels. The D2 receptor is the main dopamine subtype in basal ganglia neurons, and it is widely distributed at the supraspinal level. In addition to the two receptors listed in Table 12–1, three other dopamine receptor subtypes have been identified (D3, D4, and D5). Drugs affecting the activity of dopaminergic pathways include antipsychotics (e.g., chlorpromazine), CNS stimulants (e.g., amphetamine), and antiparkinsonism drugs (e.g., levodopa).

Norepinephrine

Noradrenergic neuron cell bodies are mainly located in the brain stem (locus ceruleus) and the lateral tegmental area of the pons (reticular formation). These neurons diverge to provide most regions of the CNS with diffuse noradrenergic input. All noradrenergic receptor subtypes are metabotropic. Inhibitory effects are caused by activation of α2 receptors, which leads to an increase in potassium conductance. Excitatory effects are produced by both direct and indirect mechanisms. The direct mechanism involves the blockade of a potassium conductance that normally slows neuronal discharge. Depending on the type of neuron, this effect is mediated by either α1 or β receptors. The indirect mechanism involves disinhibition; that is, inhibitory local circuit neurons are inhibited. Facilitation of excitatory synaptic transmission is in accordance with many of the behavioral processes thought to involve noradrenergic pathways (e.g., attention and arousal). CNS stimulants, monoamine oxidase inhibitors, and tricyclic antidepressants have important effects on the activity of noradrenergic pathways.

Serotonin

Most serotonin (5-hydroxytryptamine, 5-HT) pathways originate from cell bodies in the raphe or midline regions of the pons and upper brain stem; these pathways contain unmyelinated fibers that innervate most regions of the CNS. Multiple 5-HT receptor subtypes have been identified and, with the exception of the 5-HT3 subtype, all are metabotropic. In most areas of the central nervous system, 5-HT has a strong inhibitory action. This action is mediated by 5-HT1A receptors and is associated with membrane hyperpolarization caused by an increase in potassium conductance. In fact, 5-HT1A receptors and GABAB receptors are both associated with the same family of potassium channels. The ionotropic 5-HT3 receptor exerts a rapid excitatory action at a very limited number of sites in the CNS. Both excitatory and inhibitory actions can occur on the same neuron if appropriate receptors are present. Most of the agents used in the treatment of major depressive disorders affect serotonergic pathways (e.g., tricyclic antidepressants [TCAs], selective serotonin reuptake inhibitors [SSRIs]). The actions of some CNS stimulants and newer antipsychoticdrugs may also be mediated via effects on serotonergic transmission. Reserpine, which may cause severe depression of mood, depletes vesicular stores of both serotonin and norepinephrine in CNS neurons. Other proposed regulatory functions of 5-HT–containing neurons include sleep, temperature, appetite, and neuroendocrine control.

Glutamic Acid (Glutamate)

Most neurons in the brain are excited by glutamic acid. This excitation is caused by the activation of both ionotropic and metabotropic receptors. The ionotropic receptors can be further divided into three subtypes on the basis of drugs that selectively activate them: kainate (KA), α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA), and N-methyl-d-aspartate (NMDA). The AMPA- and KA-activated channels are often referred to as non-NMDA channels and are permeable to sodium and potassium. The NMDA-activated channel is highly permeable to sodium, potassium, and calcium ions. NMDA receptors appear to play a role in synaptic plasticity related to learning and memory. Memantine is an NMDA antagonist used for treatment of Alzheimer’s dementia. Excessive activation of NMDA receptors after neuronal injury may be responsible for cell death. Although clinical trials have been disappointing, the blockade of NMDA receptors has been shown to attenuate the neuronal damage caused by anoxia in experimental animals. Glutamate metabotropic receptor activation can result in G protein-coupled activation of phospholipase C or inhibition of adenylyl cyclase. Depending on the type of synapse, these receptors can initiate a slow postsynaptic excitation or a presynaptic inhibition.

GABA and Glycine

GABA is the primary neurotransmitter mediating IPSPs in neurons in the brain; it is also important in the spinal cord. The GABAA receptor is located on chloride ion channels and the binding of GABA opens the channel, hyperpolarizing the cell. GABAB receptors are coupled to G proteins that either activate potassium channels or inhibit calcium channels. Fast IPSPs are blocked by GABAA receptor antagonists, and slow IPSPs are blocked by GABAB receptor antagonists. A large majority of the local circuit neurons synthesize GABA, including neurons located in the dorsal horn of the spinal cord. Drugs that influence GABAA receptors include sedative-hypnotics (e.g., benzodiazepines, barbiturates) and some anticonvulsants (e.g., gabapentin, vigabatrin). GABAB receptors are activated by the drug baclofen, a very useful drug for the treatment of muscle spasticity (e.g., in cerebral palsy). Glycine receptors, which are more numerous in the gray matter of the spinal cord than in the brain, are blocked by strychnine, a spinal convulsant. Research evidence generally supports that glycine is released from spinal cord inhibitory local circuit neurons involved in postsynaptic inhibition.

Peptide Transmitters

Many peptides have been identified in the CNS, and some meet most or all of the criteria for acceptance as neurotransmitters. These peptides include opioid peptides (enkephalins, endorphins, dynorphins), neurotensin, substance P, somatostatin, cholecystokinin, vasoactive intestinal polypeptide, neuropeptide Y, and thyrotropin-releasing hormone. As in the peripheral autonomic nervous system, peptides often coexist with a conventional nonpeptide transmitter in the same neuron. The best defined peptide transmitters are the opioid peptides (beta-endorphin, met- and leu-enkephalin, and dynorphin), which are distributed at all levels of the neuraxis. The most important therapeutic actions of opioid analgesics (e.g., morphine) are mediated by receptors for these endogenous peptides. Substance P is a mediator of slow EPSPs in neurons involved in nociceptive sensory pathways in the spinal cord and brain stem. Peptide transmitters differ from nonpeptide transmitters in that (1) the peptides are synthesized in the cell body and transported to the nerve ending via axonal transport, and (2) no reuptake or specific enzyme mechanisms have been identified for terminating their actions.

Endocannabinoids

The primary psychoactive ingredient in marijuana or cannabis, Δ9-tetrahydrocannabinol (Δ9-THC), affects the brain mainly by activating a specific cannabinoid receptor, CB1. Several brain lipid derivatives (e.g., 2-arachidonyl-glycerol and anandamide) are the endogenous ligands for CB1 receptors. These ligands are not stored, as are classic neurotransmitters, but instead are rapidly synthesized in response to depolarization and consequent calcium influx. Endogenous cannabinoids are released postsynaptically after membrane depolarization but act presynaptically (retrograde transmission) to decrease transmitter release. Cannabinoids may affect memory, cognition, and pain perception by this mechanism.

Nitric Oxide

The gaseous substance nitric oxide (NO) is synthesized in many tissues in response to a variety of stimuli. The CNS contains a substantial amount of nitric oxide synthase (NOS) within certain classes of neurons. Neuronal NOS is an enzyme activated by calcium-calmodulin, and activation of NMDAreceptors, which increases intracellular calcium, resulting in the generation of NO. While a physiologic role for nitric oxide has been clearly established for vascular and erectile smooth muscle, its role in synaptic transmission and synaptic plasticity remains controversial.

Drugs acting in the CNS are the most widely used group of pharmacologic agents. These drugs can provide a wide range of therapeutic benefit, but, because of the organization of the CNS, they can also produce a wide range of adverse drug reactions. Drugs acting in the CNS can have effects (both positive and negative) at all three levels of the International Classification of Functioning, Disability and Health (ICF) Model of Disability: body function and structure, activity, and participation. For example, a benzodiazepine (e.g., diazepam), useful as a sleeping (hypnotic) agent and skeletal muscle relaxant, can impair motor function because of its GABAergic influence. This can have an effect on muscle activation, the ability to carry out basic motor functions, and the ability to participate in the responsibilities of life situations. On the other hand, a dopamine antagonist (e.g., clozapine) when used to treat schizophrenia, can have profound positive effects on an individual’s ability to participate in his or her own responsibilities in life situations.