Brody's Human Pharmacology: With STUDENT CONSULT

Chapter 27 Introduction to the Central Nervous System

Drugs acting on the central nervous system (CNS) are among the most widely used of all drugs. Humankind has experienced the effects of mind-altering drugs throughout history, and many compounds with specific and useful effects on brain and behavior have been discovered. Drugs used for therapeutic purposes have improved the quality of life dramatically for people with diverse illnesses, whereas illicit drugs have altered the lives of many others, often in detrimental ways.

Discovery of the general anesthetics was essential for the development of surgery, and continued advances in the development of anesthetics, sedatives, narcotics, and muscle relaxants have made possible the complex microsurgical procedures in use today. Discovery of the typical antipsychotics and tricyclic antidepressants in the 1950s and the introduction of the atypical antipsychotics and new classes of antidepressants within the past 20 years have revolutionized psychiatry and enabled many individuals afflicted with these mind-paralyzing diseases to begin to lead productive lives and contribute to society. Similarly, the introduction of 3,4-dihydroxy-phenylalanine (l-DOPA) for the treatment of Parkinson’s disease in 1970 was a milestone in neurology and allowed many people who had been immobilized for years the ability to move and interact with their environment. Other advances led to the development of drugs to reduce pain or fever, relieve seizures and other movement disorders associated with neurological diseases, and alleviate the incapacitating effects associated with psychiatric illnesses, including bipolar disorder and anxiety. Major neuropsychiatric disorders and the classes of drugs available for treatment are summarized in Table 27-1.

TABLE 27–1 Major Neuropsychiatric Disorders and Classes of Drugs Used for Treatment

Disorder or Indication

Drug Group/Class

Neurodegenerative Disorders

Parkinson’s disease

Dopamine A-enhancing compounds

Alzheimer’s disease

Acetylcholinesterase inhibitors

NMDA receptor antagonists

Psychiatric Disorders

Psychotic disorders (schizophrenia)

Typical and atypical antipsychotics

Major depression


Bipolar disorder

Mood stabilizers, anticonvulsants, atypical antipsychotics



Sleep disorders

Anxiolytics and sleep-promoting drugs

Anorexia nervosa and bulimia nervosa

Antidepressants, antipsychotics


Corticosteroids, progestational agents


Appetite suppressants, fat absorption inhibitors

Neurological Disorders



The nonmedical use of drugs affecting the CNS has also increased dramatically. Alcohol, hallucinogens, caffeine, nicotine, and other compounds were used historically to alter mood and behavior and are still in common use. In addition, many stimulants, depressants, and antianxiety agents intended for medical use are obtained illicitly and used for their mood-altering effects. Although the short-term effects of these drugs may be exciting or pleasurable, excessive use often leads to physical dependence or toxic effects that result in long-term alterations in the brain. This dependence is a major problem in adolescents, because the use of illicit drugs by this age group has increased significantly over the past 20 years, and very little is known about the long-term effects of these compounds on the developing brain.





Blood-brain barrier


Central nervous system


Carbon monoxide






γ-Aminobutyric acid












Nitric oxide

Although tremendous advances have been made, our knowledge of the brain and how it functions is incomplete, as is an understanding of the molecular entities underlying psychiatric disorders and the molecular targets through which drugs alter brain function. In addition, although many compounds have been developed with beneficial therapeutic effects for countless patients, many patients do not respond to any available medications, underscoring the need for further research and development.

Understanding the actions of drugs on the CNS and their rational use for the treatment of brain diseases requires knowledge of the organization and component parts of the brain. Most drugs interact with specific proteins at defined chemical synapses associated with specific neurotransmitter pathways. These interactions are responsible for the primary therapeutic actions of drugs and many of their unwanted side effects.

To induce CNS effects, drugs must obviously be able to reach their targets in the brain. Because the brain is protected from many harmful and foreign blood-borne substances by the blood-brain barrier (BBB), the entry of many drugs is restricted. Therefore it is important to understand the characteristics of drugs that enable them to enter the CNS. This chapter covers basic aspects of CNS function, with a focus on the cellular and molecular processes and neurotransmitters thought to underlie CNS disorders. The mechanisms through which drugs act to alleviate the symptoms of these disorders are emphasized.


Cell Types: Neurons and Glia

The CNS is composed of two predominant cell types, neurons and glia, each of which has many morphologically and functionally diverse subclasses. Glial cells outnumber neurons and contain many neurotransmitter receptors and transporters. For many years these cells were thought to play a supportive role, but recent studies indicate that glial cells play a key role in CNS function. There are three types of glial cells: astrocytes, oligodendrocytes, and microglia (Fig. 27-1). Astrocytes physically separate neurons and multineuronal pathways, assist in repairing nerve injury, and modulate the metabolic and ionic microenvironment. These cells express ion channels and neurotransmitter transport proteins and play an active role in modulating synapse function. Oligodendrocytes form the myelin sheath around axons and play a critical role in maintaining transmission down axons. Interestingly, polymorphisms in the genes encoding several myelin proteins have been identified in tissues from patients with both schizophrenia and bipolar disorder and may contribute to the underlying etiology of these disorders. Microglia proliferate after injury or degeneration, move to sites of injury, and transform into large macrophages (phagocytes) to remove cellular debris. These antigen-presenting cells with innate immune function also appear to play a role in endocrine development.


FIGURE 27–1 Types of cells in the CNS: Selected examples.

Neurons are the major cells involved in intercellular communication because of their ability to conduct impulses and transmit information. They are structurally different from other cells, with four distinct features (Fig. 27-2):

• Dendrites

• A perikaryon (cell body or soma)

• An axon

• A nerve (or axon) terminal


FIGURE 27–2 Structural components of nerve cells.

The perikaryon contains most of the organelles necessary for maintenance and function, including the nucleus, rough endoplasmic reticulum, ribosomes, Golgi apparatus, mitochondria, lysosomes, and cytoskeletal elements. Dendrites are relatively short afferent processes with similar cytoplasmic contents. The number of dendrites varies greatly between cell types, and many dendrites possess multiple spines protruding from their surface. Both dendrites and perikarya contain surface receptors to receive signals from nearby neurons. Incoming signals from the dendrites are relayed to the cell body, which transmits information to the nerve terminal via the axon.

The axon contains neurofilaments and microtubules, which play an important role in maintaining cell shape, growth, and intracellular transport. The movement of organelles, peptide neurotransmitters, and cytoskeletal components from their sites of synthesis in the cell body to the axon terminal (anterograde) and back to the cell body (retrograde) is called axonal transport. The main function of the axon is propagation of the action potential. The axon maintains ionic concentrations of Na+ and K+ to ensure a transmembrane potential of –65 mV. In response to an appropriate stimulus, ion channels open and allow Na+ influx, causing depolarization toward the Na+ equilibrium potential (+30 mV). This causes opening of neighboring channels, resulting in unidirectional propagation of the action potential. When it reaches the nerve terminal, depolarization causes release of chemical messengers to transmit information to nearby cells.

Nerve terminals contain all components required for synthesis, release, reuptake, and packaging of small molecule neurotransmitters into synaptic vesicles, as well as mitochondria and structural elements. They may also contain structures classically thought to be restricted to the perikaryon, such as ribosomes and machinery for protein synthesis, and proteolytic enzymes important in the final processing of peptide neurotransmitters.

Neurons are often shaped according to their function. Unipolar or pseudounipolar neurons have a single axon, which bifurcates close to the cell body, with one end typically extending centrally and the other peripherally (see Fig. 27-1). Unipolar neurons tend to serve sensory functions. Bipolar neurons have two extensions and are associated with the retina, vestibular cochlear system, and olfactory epithelium; they are commonly interneurons. Finally, multipolar neurons have many processes but only one axon extending from the cell body. These are the most numerous neurons and include spinal motor, pyramidal, and Purkinje neurons.

Neurons may also be classified by the neurotransmitter they release and the response they produce. For example, neurons that release γ-aminobutyric acid (GABA) generally hyperpolarize postsynaptic cells; thus GABAergic neurons are generally inhibitory. In contrast, neurons that release glutamate depolarize postsynaptic cells and are excitatory.

The Synapse

Effective transfer and integration of information in the CNS requires passage of information between neurons or other target cells. The nerve terminal is usually separated from adjacent cells by a gap of 20 nm or more; therefore signals must cross this gap. This is accomplished by specialized areas of communication, referred to as synapses. The synapse is the junction between a nerve terminal and a postsynaptic specialization on an adjacent cell where information is received.

Most neurotransmission involves communication between nerve terminals and dendrites or perikarya on the postsynaptic cell, called axodendritic or axosomatic synapses, respectively. However, other areas of the neuron may also be involved in both sending and receiving information. Neurotransmitter receptors are often spread diffusely over the dendrites, perikarya, and nerve terminals but are also commonly found on glial cells, where they likely serve a functional role. In addition, transmitters can be stored in and released from dendrites. Thus transmitters released from nerve terminals may interact with receptors on other axons at axoaxonic synapses; transmitters released from dendrites can interact with receptors on either “postsynaptic” dendrites or perikarya, referred to as dendrodendritic ordendrosomatic synapses, respectively (Fig. 27-3).


FIGURE 27–3 Types of synaptic connections in the CNS.

In addition, released neurotransmitters may diffuse from the synapse to act at receptors in extrasynaptic regions or on other neurons or glia distant from the site of release. This process is referred to asvolume transmission (Fig. 27-4). Although the significance of volume transmission is not well understood, it may play an important role in the actions of neurotransmitters in brain regions where primary inactivation mechanisms are absent or dysfunctional.


FIGURE 27–4 Volume transmission in the CNS. Released transmitter can activate receptors on an adjacent postsynaptic neuron at a site close to the release site (A) or at an extrajunctional site (B), on a postsynaptic neuron distant to the release site (C), or on a glial cell distant from the site of release (D).

The Life Cycle of Neurotransmitters

Neurotransmitters are any chemical messengers released from neurons. They represent a highly diverse group of compounds including amines, amino acids, peptides, nucleotides, gases, and growth factors (Table 27-2). Most classical neurotransmitters, first identified in peripheral neurons, play a major role in central transmission including acetylcholine (ACh), dopamine (DA), norepinephrine (NE), epinephrine (Epi), and serotonin (5-HT). Recently it has become clear that histamine is also an important neurotransmitter in the brain. The amino acid neurotransmitters include the excitatory compounds glutamate and aspartate and the inhibitory compounds GABA and glycine. All of these molecules are synthesized in nerve terminals and are generally stored in and released from small vesicles (Fig. 27-5). In addition to these small molecules, it is now clear that many peptides function as neurotransmitters. Peptide neurotransmitters are cleaved from larger precursors by proteolytic enzymes and packaged into large vesicles in neuronal perikarya. The most recent and surprising group of neurotransmitters identified are often referred to as unconventional neurotransmitters and include the gases nitric oxide (NO) and carbon monoxide (CO), along with several growth factors including brain-derived neurotrophic factor and nerve growth factor. The gaseous neurotransmitters are synthesized and released upon demand and thus are not stored in vesicles. The growth factors are stored in vesicles and released constitutively from both perikarya and dendrites.

TABLE 27–2 Representative Neurotransmitters in the CNS




Primary amines

Quaternary amines






Indoleamines and related compounds



Amino acids





γ-Aminobutynic Acid


Nucleotides and nucleosides


Adenosine triphosphate








Neuropeptide Y



Substance P

Vasoactive intestinal peptide




Nitric oxide

Carbon monoxide

Growth factors


Brain-derived neurotrophic factor

Nerve growth factor


FIGURE 27–5 Life cycle of a neurotransmitter.

For many years it was assumed that a single neuron synthesized and released only one neurotransmitter. We know now that many classical neurotransmitters coexist with peptide neurotransmitters in neurons, and both are released in response to depolarization. ACh coexists with enkephalin, vasoactive intestinal peptide, and substance P, whereas DA coexists with cholecystokinin and enkephalin. In some cases both substances cause physiological effects on postsynaptic cells, suggesting the possibility of multiple signals carrying independent, complementary, or mutually reinforcing messages.

Because many centrally acting drugs act by altering the synthesis, storage, release, or inactivation of specific neurotransmitters, it is critical to understand these processes. For neurons to fire rapidly and repetitively, they must maintain sufficient supplies of neurotransmitter. Most neurons synthesize neurotransmitters locally in the nerve terminal (with the exception of peptides) and have complex mechanisms for regulating this process. Synthesis is usually controlled by either the amount and activity of synthetic enzymes or the availability of substrates and cofactors. For example, ACh synthesis is regulated primarily by substrate availability (see Chapters 9 and Chapters 10), whereas DA, NE, and Epi syntheses are regulated primarily by the activity of the synthetic enzyme tyrosine hydroxylase, and that of 5-HT by tryptophan hydroxylase (see Chapters 9 and Chapters 11).

After synthesis, neurotransmitters are concentrated in vesicles by carrier proteins through an energy-dependent process. This mechanism transports neurotransmitters into vesicles at concentrations 10 to 100 times higher than in the cytoplasm. Two families of vesicular transporters have been identified, one that transports monoamines and the other that transports amino acids. Vesicular storage protects neurotransmitters from catabolism by intracellular enzymes and maintains a ready supply of neurotransmitters for release. Although nonvesicular release of some neurotransmitters has been proposed, this appears to be rare under normal circumstances.

The arrival of an action potential causes the nerve terminal membrane to depolarize, resulting in release of neurotransmitter into the synaptic cleft. This process is initiated by opening voltage-dependent Ca++ channels in the membrane, enabling Ca++ to enter the cell. Ca++ influx leads to a complex sequence of events resulting in translocation and fusion of vesicles with the plasma membrane, releasing their contents into the synaptic cleft by exocytosis (Fig. 27-5).

After receptor activation, neurotransmitters must be inactivated to terminate their actions and allow for further information transfer. Rapid enzymatic hydrolysis of ACh terminates its action (see Chapters 9 and Chapters 10), while the actions of biogenic amines are terminated primarily by reuptake into presynaptic terminals by specific energy-dependent transporters (see Chapters 9 and Chapters 11). The amino acid neurotransmitters are taken up primarily by astrocytes, and recent data suggest that biogenic amines may also be taken up by these cells, a process that may play an important role in some disease states and in the action of the antidepressant agents. Inside the terminal, neurotransmitters can be repackaged into vesicles and rereleased. All inactivation processes are important targets for drug action.

The action of any transmitter may also be terminated by simple diffusion or nonspecific (energy-independent) absorption into surrounding tissues. These processes are effective and more important in terminating the actions of peptides and gaseous neurotransmitters than in inactivating classical small molecule neurotransmitters.

Neurotransmitter Receptors

As discussed in Chapter 1, receptors are sensors by which cells detect incoming messages. Many different types of receptors can coexist on cells, including receptors for different transmitters and multiple subtypes for a single transmitter. The response of a particular neuron to a neurotransmitter depends as much on the type of receptors present as on the type of transmitter released. Because each transmitter can activate a receptor family composed of different receptor subtypes associated with distinct signal transduction mechanisms, a single transmitter may cause completely different effects on different cells (see Chapter 1). The function of the neuron is to integrate these multiple messages, from a single transmitter or from multiple transmitters, to control the impulse activity of its own axon.


An understanding of the effects and side effects of drugs affecting the CNS requires a basic understanding of CNS organization. This organization can be viewed from anatomical, functional, or chemical perspectives.

Anatomical and Functional Organization

The gross anatomy of the brain includes the cerebrum or cerebral hemispheres; subcortical structures including the thalamus and hypothalamus (the diencephalon); the midbrain; and the hindbrain, composed of the pons, medulla, and cerebellum (Fig. 27-6).


FIGURE 27–6 Gross anatomical structures in the brain.

The cerebrum, or cerebral cortex, is the largest part of the human brain and is divided into apparently symmetrical left and right hemispheres, which have different functions. The right hemisphere is associated with creativity and the left with logic and reasoning. The cerebral cortex processes most sensory, motor, and associational information and integrates many somatic and vegetative functions.

The cerebral cortex contains four regions, the frontal, parietal, occipital, and temporal lobes (Fig. 27-7). The frontal lobe extends anterior from the central sulcus and contains the motor and prefrontal cortices. It is associated with higher cognitive functions and long-term memory storage; the posterior portion is the primary motor cortex and controls fine movements. The parietal lobe, between the occipital lobe and central sulcus, is associated with sensorimotor integration and processes information from touch, muscle stretch receptors, and joint receptors. This area contains the primary somatosensory cortex. The temporal lobe is located laterally in each hemisphere and is the primary cortical target for information originating in the ears and vestibular organs; it is involved in vision and language. The occipital lobe is located in the posterior cortex and is involved in visual processing. It is the main target for axons from thalamic nuclei that receive inputs from the visual pathways and contains the primary visual cortex.


FIGURE 27–7 Regions of the cerebrum.

The thalamus and hypothalamus are part of the diencephalon. The thalamus has both sensory and motor functions. Sensory information enters the thalamus and is transmitted to the cortex. The hypothalamus is involved in homeostasis, emotion, thirst, hunger, circadian rhythms, and control of the autonomic nervous system. It also controls the pituitary gland. The limbic system, often referred to as the “emotional brain,” consists of several structures beneath the cerebral cortex that integrate emotional state with motor and visceral activities. The hippocampus is involved in learning and memory; the amygdala in memory, emotion, and fear; and the ventral tegmental area/nucleus accumbens septi in addiction.

The medulla, pons, and often midbrain are referred to as the brainstem and are involved in vision, hearing, and body movement. The medulla regulates vital functions such as breathing and heart rate, while the pons is involved in motor control and sensory analysis and is important in consciousness and sleep. The cerebellum is associated with the regulation and coordination of movement, posture, and balance. The cerebellum and brainstem relay information from the cerebral hemispheres and limbic system to the spinal cord for integration of essential reflexes. The spinal cord receives, sends, and integrates sensory and motor information.

Chemical Organization

The effects of drugs are determined primarily by the type and activity of cells in which their molecular targets are located and the types of neural circuits in which those cells participate. Thus an understanding of the chemical organization of the brain is particularly useful in pharmacology. CNS diseases often affect neurons containing specific neurotransmitters, and drugs often activate or inhibit synthesis, storage, release, or inactivation of these neurotransmitters. Many neurotransmitter systems arise from relatively small populations of neurons localized in discrete nuclei in the brain that project widely through the brain and spinal cord.

Dopaminergic Systems

Neurons synthesizing DA have their cell bodies primarily in two brain regions, the midbrain, containing the substantia nigra and adjacent ventral tegmental area, and the hypothalamus (Fig. 27-8). Nigrostriatal DA neurons project to the striatum (caudate nucleus and putamen) and are involved in control of posture and movement; these neurons degenerate in Parkinson’s disease. The ventral tegmental neurons extend to the cortex and limbic system, referred to as the mesocortical and mesolimbic pathways, respectively, and are important for complex target-oriented behaviors, including psychotic behaviors. Those neurons projecting from the ventral tegmental area to the nucleus accumbens septi are believed to be involved in addiction. DA is also synthesized by much shorter neurons originating in the arcuate and periventricular nuclei of the hypothalamus that extend to the intermediate lobe of the pituitary and into the median eminence, known as the tuberoinfundibular pathway. These neurons regulate pituitary function and decrease prolactin secretion. Drugs used for the treatment of Parkinson’s disease (see Chapter 28) stimulate these DA systems, whereas drugs used for the treatment of psychotic disorders such as schizophrenia (see Chapter 29) block them.


FIGURE 27–8 Dopaminergic pathways in the brain.

Cholinergic Systems

Three primary groups of cholinergic neurons are found in the brain, those originating in ventral areas of the forebrain (nucleus basalis and nuclei of the diagonal band and medial septum), the pons, and the striatum (Fig. 27-9). Neurons from the nucleus basalis project to large areas of the cerebral cortex, while septal and diagonal band neurons project largely to the hippocampus. These pathways are important in learning and memory and degenerate in Alzheimer’s disease. Thus treatment of this disorder involves the use of acetylcholinesterase inhibitors in attempts to alleviate this cholinergic deficit (see Chapter 28). Neurons originating in the pons project to the thalamus and basal forebrain and have descending pathways to the reticular formation, cerebellum, vestibular nuclei, and cranial nerve nuclei; they are involved in arousal and REM sleep. Finally, there are small cholinergic interneurons in the striatum that are inhibited by nigrostriatal DA neurons, forming the basis for the use of muscarinic receptor antagonists in treating Parkinson’s disease (see Chapter 28).


FIGURE 27–9 Cholinergic pathways in the brain.

Serotonergic Systems

Serotonergic neurons originate primarily in the raphe nucleus and have widespread projections (Fig. 27-10). Neurons from the rostral raphe project to the limbic system, thalamus, striatum, and cerebral cortex, whereas caudal raphe neurons descend to the spinal cord. Serotonergic pathways have broad influences throughout the brain and are important for sensory processing and homeostasis. They play a role in psychotic behaviors (see Chapter 29), depression and obsessive-compulsive disorder (see Chapter 30), and eating behavior (see Chapter 33) and are major targets for drugs used to treat these diseases.


FIGURE 27–10 Serotonergic pathways in the brain.

Noradrenergic Systems

Neurons synthesizing NE have their cell bodies primarily in the locus coeruleus in the pons and project anteriorly to large areas of the cerebral cortex, thalamus, hypothalamus, and olfactory bulb (Fig. 27-11). Other noradrenergic neurons originate in the midbrain (lateral tegmental region) and have ascending pathways to the limbic system and descending projections to the cerebellum and spinal cord, with fibers passing in the ventrolateral column. Noradrenergic pathways are involved in controlling responses to external sensory and motor stimuli, arousal and attention, and learning and memory and may be important in major depression (see Chapter 30). Midbrain neurons also play important roles in control of autonomic and neuroendocrine function.


FIGURE 27–11 Noradrenergic pathways in the brain.

Histaminergic Systems

All known histaminergic neurons originate in magnocellular neurons in the posterior hypothalamus, referred to as the tuberomammillary nucleus (Fig. 27-12). These neurons form long ascending connections to many telencephalic areas, including all areas of the cerebral cortex, the limbic system, caudate putamen, nucleus accumbens septi and globus pallidus. Also, long descending neurons project to mesencephalic and brainstem structures including cranial nerve nuclei, the substantia nigra, locus coeruleus, mesopontine tegmentum, dorsal raphe, cerebellum, and spinal cord. Histaminergic neurons play a major role in arousal, in coupling neuronal activity with cerebral metabolism, and in neuroendocrine regulation.


FIGURE 27–12 Histaminergic pathways in the brain.

Amino Acid Neurotransmitter Systems

Amino acid neurotransmitters are not restricted to specific pathways but are widespread throughout the brain and spinal cord. GABAergic neurons play a major inhibitory role in most brain regions and are important in anxiety and insomnia. Drugs for treating these disorders function to increase GABAergic activity (see Chapter 31). Glutamate is also widely distributed in the brain and functions opposite to GABA; that is, it is primarily excitatory. Recently, antagonists of specific glutamate N-methyl-D-aspartate (NMDA) receptors have been introduced for the treatment of Alzheimer’s disease, although the underlying rationale is somewhat unclear (see Chapter 28).

A summary of major neurotransmitter pathways and the specific brain disorders in which they play important roles is presented in Table 27-3.

TABLE 27–3 Neurotransmitter Pathway/Disorder Summary



The Blood-Brain Barrier

As mentioned, drugs acting on the brain must be able to gain access to their targets. Because of its unique importance, the brain is “protected” by a specialized system of capillary endothelial cells known as the BBB. Unlike peripheral capillaries that allow relatively free exchange of substances between cells, the BBB limits transport through both physical (tight junctions) and metabolic (enzymes) barriers (seeFig. 2-6). The primary BBB is formed by firmly connected endothelial cells with tight junctions lining cerebral capillaries. The secondary BBB surrounds the cerebral capillaries and is composed of glial cells.

There are several areas of the brain where the BBB is relatively weak, allowing substances to cross. These circumventricular organs include the pineal gland, area postrema, subfornical organ, vascular organ of the lamina terminalis, and median eminence.

Factors that influence the ability of drugs to cross the BBB include size, flexibility and molecular conformation, lipophilicity and charge, enzymatic stability, affinity for transport carriers, and plasma protein binding. In general, large polar molecules do not pass easily through the BBB, whereas small, lipid-soluble molecules such as barbiturates cross easily. Most charged molecules cross slowly, if at all. It is clear that the BBB is the rate-limiting factor for drug entry into the CNS.

The BBB is not formed fully at birth, and drugs that may have restricted access in the adult may enter the newborn brain readily. Similarly, the BBB can be compromised in conditions such as hypertension, inflammation, trauma, and infection. Exposure to microwaves or radiation has also been reported to open the BBB.

Although the action of many CNS-active drugs is based on their ability to cross the BBB, it may also be advantageous for a drug to be restricted from entering the brain. For example, l-DOPA, used for the treatment of Parkinson’s disease, must enter the brain to be effective. When administered alone, only 1% to 3% of the dose reaches the brain; the rest is metabolized by plasma DOPA decarboxylase to DA, which cannot cross the BBB. Thus l-DOPA is administered in combination with carbidopa, which inhibits DOPA decarboxylase and does not itself cross the BBB, thereby increasing the amount of l-DOPA available in the circulation to enter the brain (see Chapter 28).

Target Molecules

Most centrally acting drugs produce their effects by modifying cellular and molecular events involved in synaptic transmission. The distribution of these targets determines which cells are affected by a particular drug and is the primary determinant of the specificity of drug action. Drugs acting on the CNS can be classified into several major groups, based on the distribution of their specific target molecules. Drugs that act on molecules expressed by all types of cells (DNA, lipids, and structural proteins) have “general” actions. Other drugs act on molecules that are expressed specifically in neurons and not other cell types. These drugs are neuron-specific and interact with the transporters and channels that maintain the electrical properties of neurons.

Many drugs interact specifically with the macromolecules involved in the synthesis, storage, release, receptor interaction, and inactivation processes associated with particular neurotransmitters. The targets for these transmitter-specific drugs are expressed only by neurons synthesizing or responding to specific neurotransmitters; consequently, these drugs have more discrete and limited actions. The targets for transmitter-specific drugs can be any of the macromolecules involved in the life cycle of specific transmitter molecules (Fig. 27-13).


FIGURE 27–13 Sites of drug action in the CNS.

Last, some drugs mimic or interfere with specific signal transduction systems shared by a variety of different receptors. Such signal-specific drugs affect responses to activation of various receptors that use the same pathway for initiating signals. Although all of these drug groups are found in clinical practice, the transmitter-specific drugs represent the largest class. Because the distribution of their target molecules is more limited than that of the general, neuron-specific, or even signal-specific classes, administration of these compounds often results in a greater specificity of drug action and is reflected clinically by a lower incidence of unwanted side effects.

It is important to remember that all drugs have multiple actions. No drug causes only a single effect, because few, if any, drugs bind to only a single target. At higher concentrations most drugs can interact with a wide variety of molecules, often resulting in cellular alterations. Some drugs have potent actions on so many different processes in the CNS that it is difficult to identify their primary targets. Although some drugs may cause their therapeutic effects by combinations of specific actions, others may exert their primary effects through their interaction with a single cellular target. The window of selectivity of any particular drug will dramatically influence its incidence of unwanted side effects.

Levels of Neuronal Activity

Drug actions on neuronal systems in the CNS are largely dependent on the level of their tonic activity. In the absence of synaptic input, neurons can exist in either of two states. They can be quiescent by maintaining a constant and uniform hyperpolarization of their cell membrane, or they can initiate action potentials at uniform intervals by spontaneous graded depolarizations. A system with intrinsic spontaneous activity has different characteristics than those of a quiescent system. Although both can be activated, only a spontaneously active system can be inhibited. Drugs that inhibit neuronal function (CNS depressants) may have quite different effects depending on the activity of the neuronal system involved. Systems with tonic activity (either intrinsic or externally driven) are inhibited by CNS depressants, whereas quiescent systems are unaffected.

The activity of a tonically active neural network can be increased or decreased by excitatory or inhibitory control systems, respectively. This type of bidirectional regulation implies that the effect of a drug cannot be predicted solely on the basis of its effect on isolated neurons. A drug that reduces neuronal firing can activate a neural system by reducing a tonically active inhibitory input. Conversely, a drug that increases neuronal firing can inhibit a neural system by activating an inhibitory input (Fig. 27-14). Thus in some circumstances a “depressant” drug may cause excitation and a “stimulant” drug may cause sedation. A well-known example is the stimulant phase that is observed frequently after ingestion of ethanol (see Chapter 32), a general neuronal depressant. The initial stimulation is attributable to the depression of an inhibitory control system, which occurs only at low concentrations of ethanol. Higher concentrations cause a uniform depression of nerve activity. A similar “stage of excitement” can be observed during induction of general anesthesia, which is also caused by the removal of tonically active inhibitory control systems (see Chapter 35).


FIGURE 27–14 Hierarchical control systems in the CNS. A, Neuronal output can be increased by increasing tonic excitatory control or decreasing tonic inhibitory control. B, Output can be reduced by decreasing tonic excitatory control or increasing tonic inhibitory control.

Normal physiological variations in neuronal activity can also alter the effects of centrally acting drugs. For example, anesthetics are generally less effective in hyperexcitable patients, and stimulants are less effective in more sedate patients. This is attributable to the presence of varying levels of excitatory and inhibitory control systems, which alter sensitivity to drugs. Other stimulant and depressant drugs administered concurrently also alter responses to centrally acting drugs. Depressants are generally additive with other depressants, and stimulants are additive with stimulants. For example, ethanol potentiates the depression caused by barbiturates, and the result can be fatal. However, the interactions between stimulant and depressant drugs are more variable. Stimulant drugs usually antagonize the effects of depressant drugs, and vice versa. Because such antagonism is caused by activating or inhibiting competing control systems and not by neutralizing the effect of the drugs on their target molecules, concurrently administered stimulants and depressants typically do not completely cancel the effects of each other.

Adaptive Responses

Adaptive mechanisms exist in all cells to control signaling. Adaptation can occur at several levels, predominantly at the receptors themselves. Two mechanisms are involved, sensitization and desensitization. As discussed in Chapter 1, sensitization is a process whereby a cell becomes more responsive to a given concentration of compound, whereas desensitization is a process whereby a cell becomes less responsive. Receptor sensitization and desensitization play a major role in the action of drugs in the CNS, in terms of both therapeutic effects and side effects induced.

Chronic activation of receptors, as occurs typically after long-term agonist administration, decreases the density of receptors in the postsynaptic cell membrane, whereas chronic decreases in synaptic activation, as a result of long-term antagonist administration, increases receptor density (see Fig. 1-16). Such changes occur slowly and are only slowly reversible, because increasing receptor density requires synthesis of new receptors, and reversing such an increase requires degrading these new receptors. Thus changing receptor density usually represents a long-term (days to weeks) adaptive response to changes in synaptic input.

Postsynaptic cells can also regulate the efficiency with which receptor activation is coupled to changes in cell physiology. These changes usually occur at the level of the coupling of a receptor to channel opening or second-messenger production and can be extremely rapid in onset. Often, a change in coupling efficiency results from increases or decreases in covalent modifications of the receptors, G proteins, channels, or enzymes responsible for signal transduction (see Chapter 1).

Adaptive responses to long-term drug administration are thought to underlie many desired therapeutic effects and unwanted side effects. For example, the therapeutic effects of antidepressants take several weeks to develop, corresponding to the time it takes for adrenergic and serotonergic receptor systems to adapt to the enhanced levels of the biogenic amines (see Chapter 30). Similarly, evidence suggests that antipsychotic-induced tardive dyskinesia may result from the up regulation of a subtype of DA receptors caused by chronic receptor antagonism (see Chapter 29).

Overall, it is clear that determining the mechanisms by which drugs affect CNS function is challenging. Clearly the mechanisms by which psychoactive drugs exert their effects at a molecular level are only beginning to be understood. Manipulating brain chemistry and physiology with specific drugs and observing the effects on integrated behavioral parameters is one of the few approaches available currently for relating the function of brain cells with complex integrated behaviors. Such information will be useful in the future for the rational design of drugs for the treatment of various CNS diseases. It will also be satisfying to understand more about the genesis and control of human thought and emotion. Although understanding the actions of drugs on the CNS poses a great challenge, it also promises great rewards.


Anonymous. Drugs for psychiatric disorders. Treat Guidel Med Lett. 2006;4:35-46.

Cooper et al. 2003 Cooper JR, Bloom FE, Roth RH. The biochemical basis of neuropharmacology, ed 8. New York: Oxford University Press, 2003.


1. The mechanism of action of which of the following neurotransmitters is terminated by enzymatic degradation?

A. ACh



D. Serotonin

E. Epi

2. Which of the following is true concerning the synthesis and storage of biogenic amine neurotransmitters?

A. They are stored in and released from vesicles in nerve terminals.

B. They are synthesized in perikarya.

C. Their concentration in the presynaptic cytosol is greater than in the vesicles.

D. They are passively transported into vesicles.

E. They are transported down axons by anterograde transport.

3. Which of the following represents an adaptive response to the long-term use of agonists?

A. Increased synthesis of receptors

B. Decreased degradation of receptors

C. Decreased density of postsynaptic receptors

D. Increased density of postsynaptic receptors

E. None of the above

4. Which types of neurons originate primarily in the substantia nigra and hypothalamus?

A. Noradrenergic

B. Serotoninergic

C. Dopaminergic

D. GABAergic

E. Histaminergic

5. What characteristics increase the likelihood that a drug will penetrate the blood-brain barrier and enter the CNS?

A. Negative charge

B. High degree of lipophilicity

C. High molecular weight

D. Positive charge

E. High degree of binding to plasma proteins

6. Why does ethanol, a CNS depressant, cause an initial phase of excitation following ingestion?

A. It activates excitatory glutamate receptors.

B. It inhibits GABAergic inhibition.

C. It reduces activity of a tonically active inhibitory system.

D. It blocks serotonin reuptake.

E. It is metabolized to aspartate, an excitatory compound.