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 |
| 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 |
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
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.
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):
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.
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).
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.
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
| Category | Subcategory | Neurotransmitter |
|---|---|---|
| Primary amines | Quaternary amines | Acetylcholine |
| Catecholamines | ||
| Indoleamines and related compounds | ||
| Amino acids | Excitatory | |
| Inhibitory |
