Introduction to the Central Nervous System

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Chapter 27 Introduction to the Central Nervous System

Abbreviations
ACh	Acetylcholine
BBB	Blood-brain barrier
CNS	Central nervous system
CO	Carbon monoxide
DA	Dopamine
Epi	Epinephrine
GABA	γ-Aminobutyric acid
Glu	Glutamate
5-HT	Serotonin
l-DOPA	3,4-dihydroxy-phenylalanine
NE	Norepinephrine
NMDA	N-methyl-D-aspartate
NO	Nitric oxide

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
Alzheimer’s disease	NMDA receptor antagonists
Psychiatric Disorders
Psychotic disorders (schizophrenia)	Typical and atypical antipsychotics
Major depression	Antidepressants
Bipolar disorder	Mood stabilizers, anticonvulsants, atypical antipsychotics
Anxiety	Anxiolytics
Sleep disorders	Anxiolytics and sleep-promoting drugs
Anorexia nervosa and bulimia nervosa	Antidepressants, antipsychotics
Anorexia/cachexia	Corticosteroids, progestational agents
Obesity	Appetite suppressants, fat absorption inhibitors
Neurological Disorders
Seizures	Anticonvulsants

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.

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.

NEUROTRANSMISSION IN THE CENTRAL NERVOUS SYSTEM

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 or dendrosomatic 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 as volume 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