Section III - Drugs Acting on the Central Nervous System docx

Section III Drugs Acting on the Central Nervous System Chapter 12 Neurotransmission and the Central Nervous System Overview Drugs that act upon the central nervous system (CNS) influence the lives of everyone, every day These agents are invaluable therapeutically because they can produce specific physiological and psychological effects Without general anesthetics, modern surgery would be impossible Drugs that affect the CNS can selectively relieve pain, reduce fever, suppress disordered movement, induce sleep or arousal, reduce the desire to eat, or allay the tendency to vomit Selectively acting drugs can be used to treat anxiety, mania, depression, or schizophrenia and so without altering consciousness (see Chapters 19: Drugs and the Treatment of Psychiatric Disorders: Depression and Anxiety Disorders and 20: Drugs and the Treatment of Psychiatric Disorders: Psychosis and Mania) The nonmedical self-administration of CNS-active drugs is a widespread practice Socially acceptable stimulants and antianxiety agents produce stability, relief, and even pleasure for many However, the excessive use of these and other drugs also can affect lives adversely when their uncontrolled, compulsive use leads to physical dependence on the drug or to toxic side effects, which may include lethal overdosage (see Chapter 24: Drug Addiction and Drug Abuse) The unique quality of drugs that affect the nervous system and behavior places investigators who study the CNS in the midst of an extraordinary scientific challenge—the attempt to understand the cellular and molecular basis for the enormously complex and varied functions of the human brain In this effort, pharmacologists have two major goals: to use drugs to elucidate the mechanisms that operate in the normal CNS and to develop appropriate drugs to correct pathophysiological events in the abnormal CNS Approaches to the elucidation of the sites and mechanisms of action of CNS drugs demand an understanding of the cellular and molecular biology of the brain Although knowledge of the anatomy, physiology, and chemistry of the nervous system is far from complete, the acceleration of interdisciplinary research on the CNS has led to remarkable progress This chapter introduces guidelines and fundamental principles for the comprehensive analysis of drugs that affect the CNS Specific therapeutic approaches to neurological and psychiatric disorders are discussed in the chapters that follow in this section (see Chapters 13: History and Principles of Anesthesiology, 14: General Anesthetics, 15: Local Anesthetics, 16: Therapeutic Gases: Oxygen, Carbon Dioxide, Nitric Oxide, and Helium, 17: Hypnotics and Sedatives, 18: Ethanol, 19: Drugs and the Treatment of Psychiatric Disorders: Depression and Anxiety Disorders, 20: Drugs and the Treatment of Psychiatric Disorders: Psychosis and Mania, 21: Drugs Effective in the Therapy of the Epilepsies, 22: Treatment of Central Nervous System Degenerative Disorders, 23: Opioid Analgesics, and 24: Drug Addiction and Drug Abuse) Organizational Principles of the Brain The brain is an assembly of interrelated neural systems that regulate their own and each other's activity in a dynamic, complex fashion Macrofunctions of Brain Regions The large anatomical divisions provide a superficial classification of the distribution of brain functions Cerebral Cortex The two cerebral hemispheres constitute the largest division of the brain Regions of the cortex are classified in several ways: (1) by the modality of information processed (e.g., sensory, including somatosensory, visual, auditory, and olfactory, as well as motor and associational); (2) by anatomical position (frontal, temporal, parietal, and occipital); and (3) by the geometrical relationship between cell types in the major cortical layers ("cytoarchitectonic" classifications) The cerebral cortex exhibits a relatively uniform laminar appearance within any given local region Columnar sets of approximately 100 vertically connected neurons are thought to form an elemental processing module The specialized functions of a cortical region arise from the interplay upon this basic module of connections among other regions of the cortex (corticocortical systems) and noncortical areas of the brain (subcortical systems) (seeMountcastle, 1997) Varying numbers of adjacent columnar modules may be functionally, but transiently, linked into larger informationprocessing ensembles The pathology of Alzheimer's disease, for example, destroys the integrity of the columnar modules and the corticocortical connections (seeMorrison and Hof, 1997; see also Chapter 22: Treatment of Central Nervous System Degenerative Disorders) These columnar ensembles serve to interconnect nested distributed systems in which sensory associations are rapidly modifiable as information is processed (seeMountcastle, 1997; Tononi and Edelman, 1998) Cortical areas termed association areas receive and somehow process information from primary cortical sensory regions to produce higher cortical functions such as abstract thought, memory, and consciousness The cerebral cortices also provide supervisory integration of the autonomic nervous system, and they may integrate somatic and vegetative functions, including those of the cardiovascular and gastrointestinal systems Limbic System The "limbic system" is an archaic term for an assembly of brain regions (hippocampal formation, amygdaloid complex, septum, olfactory nuclei, basal ganglia, and selected nuclei of the diencephalon) grouped around the subcortical borders of the underlying brain core to which a variety of complex emotional and motivational functions have been attributed Modern neuroscience avoids this term, because the components of the limbic system neither function consistently as a system nor are the boundaries of such a system precisely defined Parts of the limbic system also participate individually in functions that are capable of more precise definition Thus, the basal ganglia or neostriatum (the caudate nucleus, putamen, globus pallidus, and lentiform nucleus) form an essential regulatory segment of the so-called extrapyramidal motor system This system complements the function of the pyramidal (or voluntary) motor system Damage to the extrapyramidal system depresses the ability to initiate voluntary movements and causes disorders characterized by involuntary movements, such as the tremors and rigidity of Parkinson's disease or the uncontrollable limb movements of Huntington's chorea (seeChapter 22: Treatment of Central Nervous System Degenerative Disorders) Similarly, the hippocampus may be crucial to the formation of recent memory, since this function is lost in patients with extensive bilateral damage to the hippocampus Memory also is disrupted with Alzheimer's disease, which destroys the intrinsic structure of the hippocampus as well as parts of the frontal cortex (see also Squire, 1998) Diencephalon The thalamus lies in the center of the brain, beneath the cortex and basal ganglia and above the hypothalamus The neurons of the thalamus are arranged into distinct clusters, or nuclei, which are either paired or midline structures These nuclei act as relays between the incoming sensory pathways and the cortex, between the discrete regions of the thalamus and the hypothalamus, and between the basal ganglia and the association regions of the cerebral cortex The thalamic nuclei and the basal ganglia also exert regulatory control over visceral functions; aphagia and adipsia, as well as general sensory neglect, follow damage to the corpus striatum or to selected circuits ending there (seeJones, 1998) The hypothalamus is the principal integrating region for the entire autonomic nervous system, and, among other functions, it regulates body temperature, water balance, intermediary metabolism, blood pressure, sexual and circadian cycles, secretion of the adenohypophysis, sleep, and emotion Recent advances in the cytophysiological and chemical dissection of the hypothalamus have clarified the connections and possible functions of individual hypothalamic nuclei (Swanson, 1999) Midbrain and Brainstem The mesencephalon, pons, and medulla oblongata connect the cerebral hemispheres and thalamushypothalamus to the spinal cord These "bridge portions" of the CNS contain most of the nuclei of the cranial nerves, as well as the major inflow and outflow tracts from the cortices and spinal cord These regions contain the reticular activating system, an important but incompletely characterized region of gray matter linking peripheral sensory and motor events with higher levels of nervous integration The major monoamine-containing neurons of the brain (see below) are found here Together, these regions represent the points of central integration for coordination of essential reflexive acts, such as swallowing and vomiting, and those that involve the cardiovascular and respiratory systems; these areas also include the primary receptive regions for most visceral afferent sensory information The reticular activating system is essential for the regulation of sleep, wakefulness, and level of arousal as well as for coordination of eye movements The fiber systems projecting from the reticular formation have been called "nonspecific," because the targets to which they project are relatively more diffuse in distribution than those of many other neurons (e.g., specific thalamocortical projection) However, the chemically homogeneous components of the reticular system innervate targets in a coherent, functional manner despite their broad distribution (seeFoote and Aston-Jones, 1995; Usher et al., 1999) Cerebellum The cerebellum arises from the posterior pons behind the cerebral hemispheres It is also highly laminated and redundant in its detailed cytological organization The lobules and folia of the cerebellum project onto specific deep cerebellar nuclei, which in turn make relatively selective projections to the motor cortex (by way of the thalamus) and to the brainstem nuclei concerned with vestibular (position-stabilization) function In addition to maintaining the proper tone of antigravity musculature and providing continuous feedback during volitional movements of the trunk and extremities, the cerebellum also may regulate visceral function (e.g., heart rate, so as to maintain blood flow despite changes in posture) In addition, the cerebellum has been shown in recent studies to play a significant role in learning and memory (seeMiddleton and Strick, 1998) Spinal Cord The spinal cord extends from the caudal end of the medulla oblongata to the lower lumbar vertebrae Within this mass of nerve cells and tracts, the sensory information from skin, muscles, joints, and viscera is locally coordinated with motoneurons and with primary sensory relay cells that project to and receive signals from higher levels The spinal cord is divided into anatomical segments (cervical, thoracic, lumbar, and sacral) that correspond to divisions of the peripheral nerves and spinal column Ascending and descending tracts of the spinal cord are located within the white matter at the perimeter of the cord, while intersegmental connections and synaptic contacts are concentrated within the H-shaped internal mass of gray matter Sensory information flows into the dorsal cord, and motor commands exit via the ventral portion The preganglionic neurons of the autonomic nervous system (seeChapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems) are found in the intermediolateral columns of the gray matter Autonomic reflexes (e.g., changes in skin vasculature with alteration of temperature) easily can be elicited within local segments of the spinal cord, as shown by the maintenance of these reflexes after the cord is severed Microanatomy of the Brain Neurons operate either within layered structures (such as the olfactory bulb, cerebral cortex, hippocampal formation, and cerebellum) or in clustered groupings (the defined collections of central neurons that aggregate into nuclei) The specific connections between neurons within or across the macrodivisions of the brain are essential to the brain's functions It is through their patterns of neuronal circuitry that individual neurons form functional ensembles to regulate the flow of information within and between the regions of the brain Cellular Organization of the Brain Present understanding of the cellular organization of the CNS can be viewed simplistically according to three main patterns of neuronal connectivity (seeShepherd, 1998) Long-hierarchical neuronal connections typically are found in the primary sensory and motor pathways Here the transmission of information is highly sequential, and interconnected neurons are related to each other in a hierarchical fashion Primary receptors (in the retina, inner ear, olfactory epithelium, tongue, or skin) transmit first to primary relay cells, then to secondary relay cells, and finally to the primary sensory fields of the cerebral cortex For motor output systems, the reverse sequence exists with impulses descending hierarchically from motor cortex to spinal motoneuron This hierarchical scheme of organization provides a precise flow of information, but such organization suffers the disadvantage that destruction of any link incapacitates the entire system Local-circuit neurons establish their connections mainly within their immediate vicinity Such local-circuit neurons frequently are small and may have very few processes They are believed to regulate (i.e., expand or constrain) the flow of information through their small spatial domain Given their short axons, they may function without generating action potentials, which are essential for the long-distance transmission between hierarchically connected neurons The neurotransmitters for many local-circuit neurons in most brain regions have been inferred through pharmacological tests (see below) Single-source divergent circuitry is utilized by certain neuronal systems of the hypothalamus, pons, and medulla From their clustered anatomical location, these neurons extend multiple-branched and divergent connections to many target cells, almost all of which lie outside the brain region in which the neurons are located Neurons with divergent circuitry can be conceived of as special local- circuit neurons whose spatial domains are one to two orders of magnitude larger than those of the classical intraregional interneurons rather than as sequential elements within any known hierarchical system For example, neurons of the locus ceruleus project from the pons to the cerebellum, spinal cord, thalamus, and several cortical zones, whose function is only subtly disrupted when the adrenergic fibers are destroyed experimentally Abundant data suggest that these systems could mediate linkages between regions that may require temporary integration (seeFoote and Aston-Jones, 1995; Aston-Jones et al., 1999) The neurotransmitters for some of these connections are well known (see below), while others remain to be identified Cell Biology of Neurons Neurons are classified in many different ways, according to function ( sensory, motor, or interneuron ), location, or identity of the transmitter they synthesize and release Microscopic analysis focuses on their general shape and, in particular, the number of extensions from the cell body Most neurons have one axon to carry signals to functionally interconnected target cells Other processes, termed dendrites, extend from the nerve cell body to receive synaptic contacts from other neurons; these dendrites may branch in extremely complex patterns Neurons exhibit the cytological characteristics of highly active secretory cells with large nuclei; large amounts of smooth and rough endoplasmic reticulum; and frequent clusters of specialized smooth endoplasmic reticulum (Golgi apparatus), in which secretory products of the cell are packaged into membrane-bound organelles for transport out of the cell body proper to the axon or dendrites (Figure 12–1) Neurons and their cellular extensions are rich in microtubules—elongated tubules approximately 24 nm in diameter Their functions may be to support the elongated axons and dendrites and to assist in the reciprocal transport of essential macromolecules and organelles between the cell body and the distant axon or dendrites Figure 12–1 Drug-Sensitive Sites in Synaptic Transmission Schematic view of the drug-sensitive sites in prototypical synaptic complexes In the center, a postsynaptic neuron receives a somatic synapse (shown greatly oversized) from an axonic terminal; an axoaxonic terminal is shown in contact with this presynaptic nerve terminal Drug-sensitive sites include: (1) microtubules responsible for bidirectional transport of macromolecules between the neuronal cell body and distal processes; (2) electrically conductive membranes; (3) sites for the synthesis and storage of transmitters; (4) sites for the active uptake of transmitters by nerve terminals or glia; (5) sites for the release of transmitter; (6) postsynaptic receptors, cytoplasmic organelles, and postsynaptic proteins for expression of synaptic activity and for long-term mediation of altered physiological states; and (7) presynaptic receptors on adjacent presynaptic processes and (8) on nerve terminals (autoreceptors) Around the central neuron are schematic illustrations of the more common synaptic relationships in the CNS (Modified from Bodian, 1972, and Cooper et al., 1996, with permission.) The sites of interneuronal communication in the CNS are termed synapses (see below) Although synapses are functionally analogous to "junctions" in the somatic motor and autonomic nervous systems, the central junctions are characterized morphologically by various additional forms of paramembranous deposits of specific proteins (essential for transmitter release, response, and catabolism; seeLiu and Edwards, 1997; Geppert and Südhof, 1998) These specialized sites are presumed to be the active zone for transmitter release and response The paramembranous proteins constitute a specialized junctional adherence zone, termed the synaptolemma(seeBodian, 1972) Like peripheral "junctions," central synapses also are denoted by accumulations of tiny (500 to 1500 Å) organelles, termed synaptic vesicles The proteins of these vesicles have been shown to have specific roles in transmitter storage, vesicle docking onto presynaptic membranes, voltage- and Ca2+-dependent secretion (seeChapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems), and recycling and restorage of released transmitter (seeAugustine et al., 1999) Synaptic Relationships Synaptic arrangements in the CNS fall into a wide variety of morphological and functional forms that are specific for the cells involved Many spatial arrangements are possible within these highly individualized synaptic relationships (seeFigure 12–1) The most common arrangement, typical of the hierarchical pathways, is the axodendritic or axosomatic synapse in which the axons of the cell of origin make their functional contact with the dendrites or cell body of the target In other cases, functional contacts may occur more rarely between adjacent cell bodies (somasomatic) or overlapping dendrites (dendrodendritic) Some local-circuit neurons can enter into synaptic relationships through modified dendrites, telodendrites, that can be either presynaptic or postsynaptic Within the spinal cord, serial axoaxonic synapses are relatively frequent Here, the axon of an interneuron ends on the terminal of a long-distance neuron as that terminal contacts a dendrite in the dorsal horn Many presynaptic axons contain local collections of typical synaptic vesicles with no opposed specialized synaptolemma (termed boutons en passant) Release of transmitter may not occur at such sites The bioelectric properties of neurons and junctions in the CNS generally follow the outlines and details already described for the peripheral autonomic nervous system (seeChapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems) However, in the CNS there is found a much more varied range of intracellular mechanisms (Nicoll et al., 1990; Tzounopoulos et al., 1998) Supportive Cells Neurons are not the only cells in the CNS According to most estimates, neurons are outnumbered, perhaps by an order of magnitude, by the various nonneuronal supportive cellular elements (seeCherniak, 1990) Nonneuronal cells include the macroglia, microglia, the cells of the vascular elements (including the intracerebral vasculature as well as the cerebrospinal fluid-forming cells of the choroid plexus found within the intracerebral ventricular system), and the meninges, which cover the surface of the brain and comprise the cerebrospinal fluid-containing envelope Macroglia are the most abundant supportive cells; some are categorized as astrocytes (nonneuronal cells interposed between the vasculature and the neurons, often surrounding individual compartments of synaptic complexes) Astrocytes play a variety of metabolic support roles including furnishing energy intermediates and supplementary removal of excessive extracellular neurotransmitter secretions (seeMagistretti et al., 1995) A second prominent category of macroglia are the myelinproducing cells, the oligodendroglia Myelin, made up of multiple layers of their compacted membranes, insulates segments of long axons bioelectrically and accelerates action-potential conduction velocity Microglia are relatively uncharacterized supportive cells believed to be of mesodermal origin and related to the macrophage/ monocyte lineage (seeAloisi, 1999; GonzálezScarano and Baltuch, 1999) Some microglia are resident within the brain, while additional cells of this class may be attracted to the brain during periods of inflammation following either microbial infection or other postinjury inflammatory reactions The response of the brain to inflammation differs strikingly from that of other tissues (seeAndersson et al., 1992; Raber et al., 1998; Schnell et al., 1999) and may in part explain its unique reactions to trauma (see below) Blood–Brain Barrier Apart from the exceptional instances in which drugs are introduced directly into the CNS, the concentration of the agent in the blood after oral or parenteral administration will differ substantially from its concentration in the brain Although not thoroughly defined anatomically, the blood–brain barrier is an important boundary between the periphery and the CNS in the form of a permeability barrier to the passive diffusion of substances from the bloodstream into various regions of the CNS (seePark and Cho, 1991; Rubin and Staddon, 1999) Evidence of the barrier is provided by the greatly diminished rate of access of chemicals from plasma to the brain (seeChapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination) This barrier is much less prominent in the hypothalamus and in several small, specialized organs lining the third and fourth ventricles of the brain: the median eminence, area postrema, pineal gland, subfornical organ, and subcommissural organ In addition, there is little evidence of a barrier between the circulation and the peripheral nervous system (e.g., sensory and autonomic nerves and ganglia) While severe limitations are imposed on the diffusion of macromolecules, selective barriers to permeation also exist for small charged molecules such as neurotransmitters, their precursors and metabolites, and some drugs These diffusional barriers are at present best thought of as a combination of the partition of solute across the vasculature (which governs passage by definable properties such as molecular weight, charge, and lipophilicity) and the presence or absence of energy-dependent transport systems Active transport of certain agents may occur in either direction across the barriers The diffusional barriers retard the movement of substances from brain to blood as well as from blood to brain The brain clears metabolites of transmitters into the cerebrospinal fluid by excretion through the acid transport system of the choroid plexus (seeCserr and Bundgaard, 1984; Strange, 1993) Substances that rarely gain access to the brain from the bloodstream often can reach the brain after injection directly into the cerebrospinal fluid Under certain conditions, it may be possible to open the blood–brain barrier, at least transiently, to permit the entry of chemotherapeutic agents (seeEmerich et al., 1998; Granholm et al., 1998; LeMay et al., 1998, for discussion) Cerebral ischemia and inflammation also modify the blood–brain barrier, resulting in increased access to substances that ordinarily would not affect the brain Response to Damage: Repair and Plasticity in the CNS Because the neurons of the CNS are terminally differentiated cells, they not undergo proliferative responses to damage, although recent evidence suggests the possibility of neural stemcell proliferation as a natural means for selected neuronal replacement (seeGage, 2000) As a result, neurons have evolved other adaptive mechanisms to provide for maintenance of function following injury These adaptive mechanisms endow the brain with considerable capacity for structural and functional modification well into adulthood (seeYang et al., 1994; Jones et al., 2000), and they may represent some of the mechanisms employed in the phenomena of memory and learning (seeKandel and O'Dell, 1992) Recent studies have shown that molecular signaling processes employed during brain development also may be involved in the plasticity seen in the adult brain, relying on specific neurotrophic agents (seeBothwell, 1995; Casaccia-Bonnefil et al., 1998; Chao et al., 1998); see below) Integrative Chemical Communication in the Central Nervous System The capacity to integrate information from a variety of external and internal sources epitomizes the cardinal role of the CNS, namely to optimize the needs of the organism within the demands of the individual's environment These integrative concepts transcend individual transmitter systems and emphasize the means by which neuronal activity is normally coordinated Only through a detailed understanding of these integrative functions, and their failure in certain pathophysiological conditions, can effective and specific therapeutic approaches be developed for neurological and psychiatric disorders The identification of molecular and cellular mechanisms of neural integration is productively linked to clinical therapeutics, because untreatable diseases and unexpected nontherapeutic side effects of drugs often reveal ill-defined mechanisms of pathophysiology Such observations can then drive the search for novel mechanisms of cellular regulation The capacity to link molecular processes to behavioral operations, both normal and pathological, provides one of the most exciting aspects of modern neuropharmacological research A central underlying concept of neuropsychopharmacology is that drugs that influence behavior and improve the functional status of patients with neurological or psychiatric diseases act by enhancing or blunting the effectiveness of specific combinations of synaptic transmitter actions Four research strategies provide the neuroscientific substrates of neuropsychological phenomena: molecular, cellular, multicellular (or systems), and behavioral The intensively exploited molecular level has been the traditional focus for characterizing drugs that alter behavior Molecular discoveries provide biochemical probes for identifying the appropriate neuronal sites and their mediative mechanisms Such mechanisms include: (1) the ion channels, which provide for changes in excitability induced by neurotransmitters; (2) the neurotransmitter receptors (see below); (3) the auxiliary intramembranous and cytoplasmic transductive molecules that couple these receptors to intracellular effectors for short-term changes in excitability and for longer-term regulation e.g., through alterations in gene expression (seeNeyroz et al., 1993; Gudermann et al., 1997); (4) transporters for the conservation of released transmitter molecules by reaccumulation into nerve terminals, and then into synaptic vesicles (Blakely et al., 1994; Amara and Sonders, 1998; Fairman and Amara, 1999) Transport across vesicle membranes utilizes a transport protein distinct from that involved in reuptake into nerve terminals (Liu and Edwards, 1997) Research at the molecular level also provides the pharmacological tools to verify the working hypotheses of other molecular, cellular, and behavioral strategies and allows for a means to pursue their genetic basis Thus, the most basic cellular phenomena of neurons now can be understood in terms of such discrete molecular entities It has been known for some time that the basic excitability of neurons is achieved through modifications of the ion channels that all neurons express in abundance in their plasma membranes However, it is now possible to understand precisely how the three major cations, Na+, K+, and Ca2+, as well as the Cl–anion are regulated in their flow through highly discriminative ion channels (seeFigures 12–2 and 12–3) The voltage-dependent ion channels (Figure 12–2), which are contrasted with the "ligand-gated ion channels" (Figure 12–3), provide for rapid changes in ion permeability These rapid changes underlie the rapid propagation of signals along axons and dendrites, and for the excitation-secretion coupling that releases neurotransmitters from presynaptic sites (Catterall, 1988, 1993) Cloning, expression, and functional assessment of constrained molecular modifications have defined conceptual chemical similarities among the major cation channels (seeFigure 12–2A) The intrinsic membrane-embedded domains of the Na+and Ca2+ channels are envisioned as four tandem repeats of a putative six-transmembrane domain, while the K+ channel family contains greater molecular diversity X-ray crystallography has now confirmed these configurations for the K+ channel (Doyle et al., 1998) One structural form of voltageregulated K+ channels, shown in Figure 12–2C, consists of subunits composed of a single putative six-transmembrane domain The inward rectifier K+ channel structure, in contrast, retains the general configuration corresponding to transmembrane spans and with the interposed "pore region" that penetrates only the exofacial surface membrane These two structural categories of K + channels can form heteroligomers, giving rise to multiple possibilities for regulation by voltage, neurotransmitters, assembly with intracellular auxiliary proteins, or posttranslational modifications (Krapivinsky et al., 1995) The structurally defined channel molecules (see Jan et al., 1997; Doyle et al., 1998) now can be examined to determine how drugs, toxins, and imposed voltages alter the excitability of a neuron, permitting a cell either to become spontaneously active or to die through prolonged opening of such channels (seeAdams and Swanson, 1994) Within the CNS, variants of the K+ channels (the delayed rectifier, the Ca2+-activated K+ channel, and the afterhyperpolarizing K+ channel) regulated by intracellular second messengers repeatedly have been shown to underlie complex forms of synaptic modulation (seeNicoll, et al., 1990; Malenka and Nicoll, 1999) Figure 12–2 The Major Molecular Motifs of Ion Channels That Establish and Regulate Neuronal Excitability in the CNS A The subunits of the Ca2+ and Na+channels share a similar presumptive six-transmembrane structure, repeated four times, in which an intramembranous segment separates transmembrane segments and B The Ca2+ channel also requires several auxiliary small proteins ( 2, , , and ) The 2and subunits are linked by a disulfide bond (not shown) Regulatory subunits also exist for Na+channels C Voltage-sensitive K+ channels (Kv) and the rapidly activating K+ channel (Ka) share a similar presumptive six-transmembrane domain currently indistinguishable in overall configuration to one repeat unit within the Na+and Ca2+ channel structure, while the inwardly rectifying K+ channel protein (Kir) retains the general configuration of just loops and Regulatory subunits can alter Kvchannel functions Channels of these two overall motifs can form heteromultimers Opioids Opioid drugs are used primarily for the treatment of pain (see Chapter 23: Opioid Analgesics) Some of the CNS mechanisms that reduce the perception of pain also produce a state of well-being or euphoria Thus, opioid drugs also are taken outside of medical channels for the purpose of obtaining the effects on mood This potential for abuse has generated much research on separating the mechanism of analgesia from that of euphoria in the hope of eventually developing a potent analgesic that does not activate brain reward systems Although this research has led to advances in understanding the physiology of pain, the standard medications for severe pain remain the derivatives of the opium poppy (opiates) and synthetic drugs that activate the same receptors (opioids) Drugs modeled after the endogenous opioid peptides may one day provide more specific treatment, but none of these currently is available for clinical use Medications that not act at opiate receptors, such as the nonsteroidal antiinflammatory drugs, have an important role in certain types of pain, especially chronic pain; but for acute pain and for severe chronic pain, the opioid drugs are the most effective A recent development in pain control stems from a greater understanding of the mechanism of tolerance to "mu" ( )-opioid receptor–mediated analgesia, which involves N-methyl-D-aspartate (NMDA) receptors (Trujillo and Akil, 1991) By combining morphine with dextromethorphan, an NMDA receptor antagonist, tolerance is impaired and analgesia is enhanced without an increase in the dose of opioid The subjective effects of opioid drugs are useful in the management of acute pain This is particularly true in high-anxiety situations, such as the crushing chest pain of a myocardial infarction, when the relaxing, anxiolytic effects complement the analgesia Normal volunteers with no pain given opioids in the laboratory may report the effects as unpleasant because of the side effects, such as nausea, vomiting, and sedation Patients with pain rarely develop abuse or addiction problems Of course, patients receiving opioids develop tolerance routinely, and if the medication is stopped abruptly, they will show the signs of an opioid withdrawal syndrome, the evidence for physical dependence Opioids should never be withheld from patients with cancer out of fear of producing addiction If chronic opioid medication is indicated, it is preferable to prescribe an orally active, slow-onset opioid with a long duration of action These qualities reduce the likelihood of producing euphoria at onset of withdrawal symptoms as the medication wears off Methadone is an excellent choice for the management of chronic severe pain Controlled-release, oral morphine (MS CONTIN, others) or controlled-release oxycodone (OXYCONTIN) are other possibilities Rapid-onset, short-duration opioids are excellent for acute, short-term use, such as during the postoperative period As tolerance and physical dependence develop, however, the patient may experience the early symptoms of withdrawal between doses, and during withdrawal, the threshold for pain decreases Thus, for chronic administration, the long-acting opioids are recommended The major risk for abuse or addiction occurs in patients complaining of pain with no clear physical explanation or with evidence of a chronic disorder that is not life-threatening Examples are chronic headaches, backaches, abdominal pain, or peripheral neuropathy Even in these cases, an opioid might be considered as a brief emergency treatment, but long-term treatment with opioids should be used only after other alternatives have been exhausted In those relatively rare patients who develop abuse, the transition from legitimate use to abuse often begins with patients returning to their physician earlier than scheduled to get a new prescription or visiting emergency rooms of different hospitals complaining of acute pain and asking for an opioid injection Heroin is the most important opioid drug that is abused There is no legal supply of heroin for clinical use in the United States Some claim that heroin has unique analgesic properties for the treatment of severe pain, but double-blind trials have found it to be no more effective than hydromorphone However, heroin is widely available on the illicit market, and its price dropped sharply in the 1990s while its purity increased tenfold For many years, heroin purchased on the streets in the United States was highly diluted Each 100-mg bag of powder had only about mg of heroin (range to mg), and the rest was inert or sometimes toxic adulterants such as quinine In the mid-1990s, street heroin reached 45% to 75% purity in many large cities, with some samples testing as high as 90% This means that the level of physical dependence among heroin addicts is relatively high and that users who interrupt regular dosing will develop more severe withdrawal symptoms Whereas heroin previously required intravenous injection, the more potent supplies can be smoked or administered nasally (snorted), thus making the initiation of heroin use accessible to people who would not insert a needle into their veins There is no accurate way to count the number of heroin addicts, but based on extrapolation from overdose deaths, number of applicants for treatment, and number of heroin addicts arrested, the estimates range from 800,000 to million In national surveys, approximately three adults report having tried heroin for every one who became addicted to the drug Tolerance, Dependence, and Withdrawal Injection of a heroin solution produces a variety of sensations described as warmth, taste, or high and intense pleasure ("rush") often compared to sexual orgasm There are some differences among the opioids in their acute effects, with morphine producing more of a histamine-releasing effect and meperidine producing more excitation or confusion Even experienced opioid addicts, however, cannot distinguish between heroin and hydromorphone in double-blind tests Thus, the popularity of heroin may be due to its availability on the illicit market and its rapid onset After intravenous injection, the effects begin in less than a minute Heroin has high lipid solubility, crosses the bloodbrain barrier quickly, and is deacetylated to the active metabolites, 6-monoacetyl morphine and morphine After the intense euphoria, which lasts from 45 seconds to several minutes, there is a period of sedation and tranquillity ("on the nod") lasting up to an hour The effects of heroin wear off in to hours, depending on the dose Experienced users may inject two to four times per day Thus, the heroin addict is constantly oscillating between being "high" and feeling the sickness of early withdrawal (Figure 24–4) This produces many problems in the homeostatic systems regulated, at least in part, by endogenous opioids For example, the hypothalamic-pituitary-gonadal axis and the hypothalamic-pituitary-adrenal axis are abnormal in heroin addicts Women on heroin have irregular menses, and men have a variety of sexual performance problems Mood also is affected Heroin addicts are relatively docile and compliant after taking heroin, but during withdrawal, they become irritable and aggressive Figure 24–4 Differences in Responses to Heroin and Methadone A person who injects heroin several times per day oscillates between being sick and being high In contrast, the typical methadone patient remains in the "normal" range (indicated in gray) with little fluctuation after dosing once per day The curves represent the subject's mental and physical state and not plasma levels of the drug Based on patient reports, tolerance develops early to the euphoria-producing effects of opioids There also is tolerance to the respiratory depressant, analgesic, sedative, and emetic properties Heroin users tend to increase their daily dose, depending on their financial resources and the availability of the drug If a supply is available, the dose can be progressively increased 100-fold Even in highly tolerant individuals, the possibility of overdose remains if tolerance is exceeded Overdose is likely to occur when potency of the street sample is unexpectedly high or when the heroin is mixed with a far more potent opioid, such as fentanyl, synthesized in clandestine laboratories Addiction to heroin or other short-acting opioids produces behavioral disruptions and usually becomes incompatible with a productive life There is a significant risk for opioid abuse and dependence among physicians and other health-care workers who have access to potent opioids, thus enabling unsupervised experimentation Physicians often begin by assuming that they can manage their own dose, and they may rationalize their behavior based on the beneficial effects of the drug Over time, however, the typical unsupervised opioid user loses control, and behavioral changes are observed by family and coworkers Apart from the behavioral changes and the risk of overdose, especially with very potent opioids, chronic use of opioids is relatively nontoxic Opioids frequently are used in combinations with other drugs A common combination is heroin and cocaine ("speedball") Users report an improved euphoria because of the combination, and there is evidence of an interaction, because the partial opioid agonist buprenorphine reduces cocaine selfadministration in animals (Mello et al., 1989) Cocaine reduces the signs of opioid withdrawal (Kosten, 1990), and heroin may reduce the irritability seen in chronic cocaine users The mortality rate for street heroin users is very high Early death comes from involvement in crime to support the habit; from uncertainty about the dose, the purity, and even the identity of what is purchased on the street; and from serious infections associated with unsterile drugs and sharing of injection paraphernalia Heroin users commonly acquire bacterial infections producing skin abscesses, endocarditis, pulmonary infections, especially tuberculosis, and viral infections producing hepatitis and acquired immunodeficiency syndrome (AIDS) As with other addictions, the first stage of treatment addresses physical dependence and consists of detoxification The opioid withdrawal syndrome (Table 24–7) is very unpleasant but not lifethreatening It begins within to 12 hours after the last dose of a short-acting opioid and as long as 72 to 84 hours after a very long-acting opioid medication Heroin addicts go through early stages of this syndrome frequently when heroin is scarce or expensive Some therapeutic communities, as a matter of policy, elect not to treat withdrawal so that the addict can experience the suffering while being given group support The duration and intensity of the syndrome are related to the clearance of the individual drug Heroin withdrawal is brief (5 to 10 days) and intense Methadone withdrawal is slower in onset and lasts longer Protracted withdrawal also is likely to be longer with methadone (See more detailed discussions of protracted withdrawal under "Long-Term Management," below.) Pharmacological Interventions Opioid withdrawal signs and symptoms can be treated by three different approaches The first and most commonly used depends on cross-tolerance and consists of transfer to a prescription opioid medication and then gradual dose reduction The same principles of detoxification apply as for other types of physical dependence It is convenient to change the patient from a short-acting opioid such as heroin to a long-acting one such as methadone The initial dose of methadone is typically 20 to 30 mg This is a test dose to determine the level needed to reduce observed withdrawal symptoms The first day's total dose then can be calculated depending on the response and then reduced by 20% per day during the course of detoxification A second approach to detoxification involves the use of clonidine, a medication approved only for the treatment of hypertension (see Chapter 33: Antihypertensive Agents and the Drug Therapy of Hypertension) Clonidine is an 2-adrenergic agonist that decreases adrenergic neurotransmission from the locus ceruleus Many of the autonomic symptoms of opioid withdrawal—such as nausea, vomiting, cramps, sweating, tachycardia, and hypertension—result from the loss of opioid suppression of the locus ceruleus system during the abstinence syndrome Clonidine, acting via distinct receptors but by cellular mechanisms that mimic opioid effects, can alleviate many of the symptoms of opioid withdrawal However, clonidine does not alleviate generalized aches and opioid craving characteristic of opioid withdrawal A similar drug, lofexidine (not yet available in the United States), is associated with less of the hypotension that limits the usefulness of clonidine in this setting A third method of treating opioid withdrawal involves activation of the endogenous opioid system without medication The techniques proposed include acupuncture and several methods of CNS activation utilizing transcutaneous electrical stimulation While theoretically attractive, this has not yet been found to be practical Rapid antagonist-precipitated opioid detoxification under general anesthesia has received considerable publicity, because it promises detoxification in several hours while the patient is unconscious and thus not experiencing withdrawal discomfort A mixture of medications has been used, and morbidity and mortality as reported in the lay press are unacceptable, with no demonstrated advantage in long-term outcome Long-Term Management If patients are simply discharged from the hospital after withdrawal from opioids, there is a high probability of a quick return to compulsive opioid use Addiction is a chronic disorder that requires long-term treatment There are numerous factors that influence relapse One factor is that the withdrawal syndrome does not end in to days There are subtle signs and symptoms often called the protracted withdrawal syndrome (Table 24–7) that persist for up to months Physiological measures tend to oscillate as though a new set point were being established (Martin and Jasinski, 1969); during this phase, outpatient drug-free treatment has a low probability of success, even when the patient has received intensive prior treatment while protected from relapse in a residential program The most successful treatment for heroin addiction consists of stabilization on methadone Patients who repeatedly relapse during drug-free treatment can be transferred directly to methadone without requiring detoxification The dose of methadone must be sufficient to prevent withdrawal symptoms for at least 24 hours Levomethadyl acetate hydrochloride (ORLAAM) is another maintenance option that will block withdrawal for 72 hours Agonist Maintenance Patients receiving methadone or levomethadyl acetate will not experience the ups and downs they experienced while on heroin (Figure 24–4) Drug craving diminishes and may disappear Neuroendocrine rhythms eventually are restored (Kreek, 1992) Because of cross-tolerance (from methadone to heroin), patients who inject street heroin report a reduced effect from usual heroin doses This cross-tolerance effect is dose-related, so that higher methadone maintenance doses result in less illicit opioid use as determined by random urine testing Patients become tolerant to the sedating effects of methadone and become able to attend school or function in a job Opioids also have a persistent, mild, stimulating effect noticeable after tolerance to the sedating effect, such that reaction time is quicker and vigilance is increased on a stable dose of methadone Antagonist Treatment Another pharmacological option is opioid antagonist treatment Naltrexone (see Chapter 23: Opioid Analgesics) is an antagonist with a high affinity for the -opioid receptor; it will competitively block the effects of heroin or other -opioid-receptor agonists Naltrexone has almost no agonist effects of its own and will not satisfy craving or relieve protracted withdrawal symptoms For these reasons, naltrexone treatment does not appeal to the average heroin addict, but it can be utilized after detoxification for patients with high motivation to remain opioid-free Physicians, nurses, and pharmacists with opioid addiction problems have frequent access to opioid drugs and make excellent candidates for this treatment approach New Treatment Options Two important advances in the treatment of opioid addiction are currently in clinical trials Buprenorphine, a partial agonist at opioid receptors (see Chapter 23: Opioid Analgesics) produces minimal withdrawal symptoms, has a low potential for overdose, a long duration of action, and the ability to block heroin effects In order to make treatment of opioid addiction more accessible, buprenorphine is proposed for use in physicians' offices rather than methadone programs A depot formulation of naltrexone which provides 30 days of medication after a single injection is also in clinical trials This formulation would eliminate the necessity of daily pill-taking and prevent relapse when the recently detoxified patient leaves a protected environment Cocaine and Other Psychostimulants Cocaine More than 23 million Americans are estimated to have used cocaine at some time, but the number of current users declined from an estimated 8.6 million occasional users and 5.8 million regular users to 3.6 million who still identified themselves as sometimes using cocaine in 1995 The number of frequent users (at least weekly) has remained steady since 1991 at about 640,000 persons Not all users become addicts, and the variables that influence this risk are discussed at the beginning of this chapter A key factor is the widespread availability of relatively inexpensive cocaine in the alkaloidal (free base, "crack") form suitable for smoking and the hydrochloride powder form suitable for nasal or intravenous use Drug abuse in men occurs about twice as frequently as in women However, smoked cocaine use is particularly common in young women of childbearing age, who may use cocaine in this manner as commonly as men The reinforcing effects of cocaine and cocaine analogs correlate best with their effectiveness in blocking the transporter that recovers dopamine from the synapse This leads to increased dopaminergic stimulation at critical brain sites (Ritz et al., 1987) However, cocaine also blocks both norepinephrine (NE) and serotonin (5-HT) reuptake, and chronic use of cocaine produces changes in these neurotransmitter systems as measured by reductions in the neurotransmitter metabolites MHPG (3-methoxy-4-hydroxyphenethyleneglycol) and 5-HIAA (5- hydroxyindoleacetic acid) The general pharmacology and legitimate use of cocaine are discussed in Chapter 15: Local Anesthetics Cocaine produces a dose-dependent increase in heart rate and blood pressure accompanied by increased arousal, improved performance on tasks of vigilance and alertness, and a sense of self-confidence and well-being Higher doses produce euphoria, which has a brief duration and often is followed by a desire for more drug Involuntary motor activity, stereotyped behavior, and paranoia may occur after repeated doses Irritability and increased risk of violence are found among heavy chronic users The half-life of cocaine in plasma is about 50 minutes, but inhalant (crack) users typically desire more cocaine after 10 to 30 minutes Intranasal and intravenous uses also result in a "high" of shorter duration than would be predicted by plasma cocaine levels, suggesting that a declining plasma concentration is associated with termination of the high and resumption of cocaine seeking This theory is supported by positron emission tomography imaging studies using C11-labeled cocaine, which show that the time course of subjective euphoria parallels the uptake and displacement of the drug in the corpus striatum (Volkow et al., 1999) Addiction is the most common complication of cocaine use Some users, especially intranasal users, can continue intermittent use for years Others become compulsive users despite elaborate methods to maintain control Stimulants tend to be used much more irregularly than opioids, nicotine, and alcohol Binge use is very common, and a binge may last hours to days, terminating only when supplies of the drug are exhausted The major route for cocaine metabolism involves hydrolysis of each of its two ester groups Benzoylecgonine, produced upon loss of the methyl group, represents the major urinary metabolite and can be found in the urine for to days after a binge As a result, benzoylecgonine tests are useful for detecting cocaine use; heavy users have been found to have detectable amounts of the metabolite in urine for up to 10 days following a binge Cocaine frequently is used in combination with other drugs The cocaine-heroin combination is discussed above, with opioids Alcohol is another drug that cocaine users take to reduce the irritability experienced during heavy cocaine use Some develop alcohol addiction in addition to their cocaine problem An important metabolic interaction occurs when cocaine and alcohol are taken concurrently Some cocaine is transesterified to cocaethylene, which is equipotent to cocaine in blocking dopamine reuptake (Hearn et al., 1991) Toxicity Other risks of cocaine use, beyond the potential for addiction, involve cardiac arrhythmias, myocardial ischemia, myocarditis, aortic dissection, cerebral vasoconstriction, and seizures Death from trauma also is associated with cocaine use (Marzuk et al., 1995) Pregnant cocaine users may experience premature labor and abruptio placentae (Chasnoff et al., 1989) Attributing the developmental abnormalities reported in infants born to cocaine-using women simply to cocaine use is confounded by the infant's prematurity, multiple drug exposure, and overall poor pre- and postnatal care Cocaine has been reported to produce a prolonged and intense orgasm if taken prior to intercourse, and its use is associated with compulsive and promiscuous sexual activity Long-term cocaine use, however, usually results in reduced sexual drive; complaints of sexual problems are common among cocaine users presenting for treatment Psychiatric disorders—including anxiety, depression, and psychosis—are common in cocaine users who request treatment While some of these psychiatric disorders undoubtedly existed prior to the stimulant use, many develop during the course of the drug abuse (McLellan et al., 1979) Tolerance, Dependence, and Withdrawal Sensitization is a consistent finding in animal studies of cocaine and other stimulants Sensitization is produced by intermittent use and typically is measured by behavioral hyperactivity In human cocaine users, sensitization for the euphoric effect typically is not seen On the contrary, most experienced users report requiring more cocaine over time to obtain euphoria, i.e., tolerance In the laboratory, tachyphylaxis (rapid tolerance) has been observed with reduced effects when the same dose is given repeatedly in one session Sensitization may involve conditioning (Figure 24–2) Cocaine users often report a strong response on seeing cocaine before it is administered, consisting of physiological arousal and increased drug craving (O'Brien et al., 1992) Sensitization in human beings has been linked to paranoid, psychotic manifestations of cocaine use based on the observation that cocaine-induced hallucinations are typically seen after long-term exposure (mean 35 months) in vulnerable users (Satel et al., 1991) Repeated administration may be required to sensitize the patient to experience paranoia Since cocaine typically is used intermittently, even heavy users go through frequent periods of withdrawal or "crash." The symptoms of withdrawal seen in users admitted to the hospital are listed in Table 24–8 Careful studies of cocaine users during withdrawal show gradual diminution of these symptoms over to weeks (Weddington et al., 1990) Residual depression may be seen after cocaine withdrawal and should be treated with antidepressant agents if it persists (see Chapter 19: Drugs and the Treatment of Psychiatric Disorders: Depression and Anxiety Disorders) Pharmacological Interventions Since cocaine withdrawal generally is mild, treatment of withdrawal symptoms usually is not required The major problem in treatment is not detoxification but helping the patient to resist the urge to restart compulsive cocaine use Rehabilitation programs involving individual and group psychotherapy based on the principles of Alcoholics Anonymous and behavioral treatments based on reinforcing, cocaine-free urine tests result in significant improvement in the majority of cocaine users (Alterman et al., 1994; Higgins et al., 1994) Nonetheless, there is great interest in finding a medication that can aid in the rehabilitation of cocaine addicts Numerous medications have been tried in clinical trials with cocaine addicts (O'Brien, 1997) While several drugs have been reported in individual studies to produce significant reductions in cocaine use, none has been found to be associated with consistent improvement in controlled clinical trials The dopamine and serotonin systems have been the focus of many unsuccessful studies using both agonist and antagonist approaches The concept that works well for opioid addiction, that of a longacting agonist to satisfy drug craving and stabilize the patient so that normal function is possible, is difficult to transfer to the pharmacology of stimulants Recent attention has been directed toward two novel approaches: a compound that competes with cocaine at the dopamine transporter and a vaccine that produces cocaine-binding antibodies However, these should be regarded as innovative ideas that have yet to be shown to be clinically useful For now, the treatment of choice for cocaine addiction remains behavioral, with medication indicated for specific coexisting disorders such as depression Other CNS Stimulants Amphetamine and Related Agents Subjective effects similar to those of cocaine are produced by amphetamine, dextroamphetamine, methamphetamine, phenmetrazine, methylphenidate and diethylpropion Amphetamines increase synaptic dopamine primarily by stimulating presynaptic release rather than by blockade of reuptake, as is the case with cocaine Intravenous or smoked methamphetamine produces an abuse/dependence syndrome similar to that of cocaine, although clinical deterioration may progress more rapidly Methamphetamine can be produced in small, clandestine laboratories starting with ephedrine, a widely available nonprescription stimulant It became a major problem in the western United States during the late 1990s Oral stimulants, such as those prescribed in weight-reduction programs, have short-term efficacy because of tolerance development Only a small proportion of patients introduced to these appetite suppressants subsequently exhibit dose escalation or drugseeking from various physicians Such patients may meet diagnostic criteria for abuse or addiction Fenfluramine (no longer marketed in the United States) and phenylpropanolamine reduce appetite with no evidence of significant abuse potential Mazindol also reduces appetite, with less stimulant properties than amphetamine Khat is a plant material widely chewed in East Africa and Yemen for its stimulant properties; these are due to alkaloidal cathinone, a compound similar to amphetamine (Kalix, 1990) Methcathinone, a congener with similar effects, has been synthesized in clandestine laboratories throughout the midwestern United States, but widespread use in North America has not been reported Caffeine Caffeine, a mild stimulant, is the most widely used psychoactive drug in the world It is present in soft drinks, coffee, tea, cocoa, chocolate, and numerous prescription and over-the-counter drugs It increases norepinephrine secretion and enhances neural activity in numerous brain areas Caffeine is absorbed from the digestive tract; it is rapidly distributed throughout all tissues and easily crosses the placental barrier (see Chapter 28: Drugs Used in the Treatment of Asthma) Many of caffeine's effects are believed to occur by means of competitive antagonism at adenosine receptors Adenosine is a neuromodulator that influences a number of functions in the CNS (see Chapters 12: Neurotransmission and the Central Nervous System and 28: Drugs Used in the Treatment of Asthma) The mild sedating effects that occur when adenosine activates particular adenosine receptor subtypes can be antagonized by caffeine Tolerance occurs rapidly to the stimulating effects of caffeine Thus, a mild withdrawal syndrome has been produced in controlled studies by abrupt cessation of as little as one to two cups of coffee per day Caffeine withdrawal consists of feelings of fatigue and sedation With higher doses, headaches and nausea have been reported during withdrawal; vomiting is rare (Silverman et al., 1992) Although a withdrawal syndrome can be demonstrated, few caffeine users report loss of control of caffeine intake or significant difficulty in reducing or stopping caffeine if desired (Dews et al., 1999) Thus caffeine is not listed in the category of addicting stimulants (American Psychiatric Association, 1994) Cannabinoids (Marijuana) The cannabis plant has been cultivated for centuries both for the production of hemp fiber and for its presumed medicinal and psychoactive properties The smoke from burning cannabis contains many chemicals, including 61 different cannabinoids that have been identified One of these, -9tetrahydrocannabinol ( -9-THC), produces most of the characteristic pharmacological effects of smoked marijuana Surveys have shown that marijuana is the most commonly used nonlegal drug in the United States Usage peaked during the late 1970s, when about 60% of high school seniors reported having used marijuana and nearly 11% reported daily use This declined steadily among high school seniors to about 40% reporting some use during their lifetime and 2% reporting daily use in the mid-1990s, followed by a gradual increase to more than 5% reporting daily use in 1999 It must be noted that surveys among high school seniors tend to underestimate drug use because school dropouts are not surveyed A cannabinoid receptor has been identified in the brain (Devane et al., 1988) and cloned (Matsuda et al., 1990) An arachidonic acid derivative has been proposed as an endogenous ligand and named anandamide (Devane et al., 1992) While the physiological function of these receptors or their putative endogenous ligand has not been fully elucidated, they are widely dispersed, with high densities in the cerebral cortex, hippocampus, striatum, and cerebellum (Herkenham, 1993) Specific cannabinoid receptor antagonists have been developed, and these should facilitate understanding the role of this neurotransmitter system, not only in marijuana abuse but also in normal CNS functions The pharmacological effects of -9-THC vary with the dose, route of administration, experience of the user, vulnerability to psychoactive effects, and setting of use Intoxication with marijuana produces changes in mood, perception, and motivation, but the effect sought after by most users is the "high" and "mellowing out." This effect is described as different from the stimulant high and the opiate high The effects vary with dose, but the typical marijuana smoker experiences a high that lasts about two hours During this time, there is impairment of cognitive functions, perception, reaction time, learning, and memory Impairment of coordination and tracking behavior has been reported to persist for several hours beyond the perception of the high These impairments have obvious implications for the operation of a motor vehicle and performance in the workplace or at school Marijuana also produces complex behavioral changes, such as giddiness and increased hunger Although some users have reported increased pleasure from sex and increased insight during a marijuana high, these claims have not been substantiated Unpleasant reactions such as panic or hallucinations and even acute psychosis may occur; several surveys indicate that 50% to 60% of marijuana users have reported at least one anxiety experience These reactions commonly are seen with higher doses and with oral rather than smoked marijuana, because smoking permits the regulation of dose according to the effects While there is no convincing evidence that marijuana can produce a lasting schizophrenia-like syndrome, there are numerous clinical reports that marijuana use can precipitate a recurrence in people with a history of schizophrenia One of the most controversial of the effects that have been claimed for marijuana is the production of an "amotivational syndrome." This syndrome is not an official diagnosis, but it has been used to describe young people who drop out of social activities and show little interest in school, work, or other goal-directed activity When heavy marijuana use accompanies these symptoms, the drug often is cited as the cause, even though there are no data that demonstrate a causal relationship between marijuana smoking and these behavioral characteristics There is no evidence that marijuana use damages brain cells or produces any permanent functional changes, although there are animal data indicating impairment of maze learning that persists for weeks after the last dose These findings are consistent with clinical reports of gradual improvement in mental state after cessation of chronic high-dose marijuana use Several medicinal benefits of marijuana have been described These include antinausea effects that have been applied to the relief of side effects of anticancer chemotherapy, muscle-relaxing effects, anticonvulsant effects, and reduction of intraocular pressure for the treatment of glaucoma These medical benefits come at the cost of the psychoactive effects that often impair normal activities Thus, there is no clear advantage of marijuana over conventional treatments for any of these indications (Institute of Medicine, 1999) With the cloning of cannabinoid receptors and the discovery of an endogenous ligand, it is hoped that medications can be developed that will produce specific therapeutic effects without the undesirable properties of marijuana Tolerance, Dependence, and Withdrawal Tolerance to most of the effects of marijuana can develop rapidly after only a few doses, but it also disappears rapidly Tolerance to large doses has been found to persist in experimental animals for long periods after cessation of drug use Withdrawal symptoms and signs are not typically seen in clinical populations In fact, relatively few patients ever seek treatment for marijuana addiction A withdrawal syndrome in human subjects has been described following close observation of marijuana users given regular oral doses of the agent on a research ward (Table 24–9) This syndrome, however, is seen clinically only in persons who use marijuana on a daily basis and then suddenly stop Compulsive or regular marijuana users not appear to be motivated by fear of withdrawal symptoms, although this has not been systematically studied Pharmacological Interventions Marijuana abuse and addiction have no specific treatments Heavy users may suffer from accompanying depression and thus may respond to antidepressant medication, but this should be decided on an individual basis considering the severity of the affective symptoms after the marijuana effects have dissipated The residual drug effects may continue for several weeks Psychedelic Agents Perceptual distortions that include hallucinations, illusions, and disorders of thinking such as paranoia can be produced by toxic doses of many drugs These phenomena also may be seen during toxic withdrawal from sedatives such as alcohol There are, however, certain drugs that have as their primary effect the production of perception, thought, or mood disturbances at low doses with minimal effects on memory and orientation These are commonly called hallucinogenic drugs, but their use does not always result in frank hallucinations In the late 1990s, the use of "club drugs" at all-night dance parties became popular Such drugs include methylenedioxymethamphetamine ("Ecstasy," MDMA), lysergic acid diethylamide (LSD), phencyclidine (PCP), and ketamine They often are used in association with illegal sedatives such as flunitrazepam (ROHYPNOL) or gamma hydroxybutyrate (GHB) The latter drug has the reputation of being particularly effective in preventing memory storage, so it has been implicated in "date rapes." The use of psychedelics received much public attention in the 1960s and 1970s, but their use waned in the 1980s In 1989, the use of hallucinogenic drugs again began to increase in the United States By 1993, a total of 11.8% of college students were reporting some use of these drugs during their lifetime The increase was most striking in younger cohorts, beginning in the eighth grade While psychedelic effects can be produced by a variety of different drugs, major psychedelic compounds come from two main categories The indoleamine hallucinogens include LSD, DMT (N,N-dimethyltryptamine), and psilocybin The phenethylamines include mescaline, dimethoxymethylamphetamine (DOM), methylenedioxyamphetamine (MDA), and MDMA Both groups have a relatively high affinity for serotonin 5-HT2 receptors (see Chapter 11: 5Hydroxytryptamine (Serotonin): Receptor Agonists and Antagonists), but they differ in their affinity for other subtypes of 5-HT receptors There is a good correlation between the relative affinity of these compounds for 5-HT2 receptors and their potency as hallucinogens in human beings (Rivier and Pilet, 1971; Titeler et al., 1988) The 5-HT2 receptor is further implicated in the mechanism of hallucinations by the observation that antagonists of that receptor, such as ritanserin, are effective in blocking the behavioral and electrophysiological effects of hallucinogenic drugs in animal models However, LSD has been shown to interact with many receptor subtypes at nanomolar concentrations, and at present it is not possible to attribute the psychedelic effects to any single 5-HT receptor subtype (Peroutka, 1994) LSD LSD is the most potent hallucinogenic drug and produces significant psychedelic effects with a total dose of as little as 25 to 50 g This drug is more than 3000 times more potent than mescaline LSD is sold on the illicit market in a variety of forms A popular contemporary system involves postage stamp–sized papers impregnated with varying doses of LSD (50 to 300 g or more) A majority of street samples sold as LSD actually contain LSD In contrast, the samples of mushrooms and other botanicals sold as sources of psilocybin and other psychedelics have a low probability of containing the advertised hallucinogen The effects of hallucinogenic drugs are variable, even in the same individual on different occasions LSD is rapidly absorbed after oral administration, with effects beginning at 40 to 60 minutes, peaking at to hours, and gradually returning to baseline over to hours At doses of 100 g, LSD produces perceptual distortions and sometimes hallucinations; mood changes including elation, paranoia, or depression; intense arousal; and sometimes a feeling of panic Signs of LSD ingestion include pupillary dilation, increased blood pressure and pulse, flushing, salivation, lacrimation, and hyperreflexia Visual effects are prominent Colors seem more intense and shapes may appear altered The subject may focus attention on unusual items such as the pattern of hairs on the back of the hand Claims about the potential of psychedelic drugs for enhancing psychotherapy and for treating addictions and other mental disorders have not been supported by controlled treatment outcome studies Consequently, there is no current indication for these drugs as medications A "bad trip" usually consists of severe anxiety, although at times it is marked by intense depression and suicidal thoughts Visual disturbances usually are prominent The bad trip from LSD may be difficult to distinguish from reactions to anticholinergic drugs and phencyclidine There are no documented toxic fatalities from LSD use, but fatal accidents and suicides have occurred during or shortly after intoxication Prolonged psychotic reactions lasting two days or more may occur after the ingestion of a hallucinogen Schizophrenic episodes may be precipitated in susceptible individuals, and there is some evidence that chronic use of these drugs is associated with the development of persistent psychotic disorders (McLellan et al., 1979) Tolerance, Physical Dependence, and Withdrawal Frequent, repeated use of psychedelic drugs is unusual, and thus tolerance is not commonly seen Tolerance does develop to the behavioral effects of LSD after three to four daily doses, but no withdrawal syndrome has been observed Cross-tolerance among LSD, mescaline, and psilocybin has been demonstrated in animal models Pharmacological Intervention Because of the unpredictability of psychedelic drug effects, any use carries some risk Dependence and addiction not occur, but users may require medical attention because of "bad trips." Severe agitation may require medication, and diazepam (20 mg orally) has been found to be effective "Talking down" by reassurance also has been shown to be effective and is the management of first choice Neuroleptic medications (dopamine receptor antagonists; see Chapter 20: Drugs and the Treatment of Psychiatric Disorders: Psychosis and Mania) may intensify the experience A particularly troubling aftereffect of the use of LSD and similar drugs is the occurrence of episodic visual disturbances in a small proportion of former users These originally were called "flashbacks" and resembled the experiences of prior LSD trips There now is an official diagnostic category called the hallucinogen persisting perception disorder (HPPD) (American Psychiatric Association, 1994) The symptoms include false fleeting perceptions in the peripheral fields, flashes of color, geometric pseudohallucinations, and positive afterimages (Abraham and Aldridge, 1993) The visual disorder appears stable in half of the cases and represents an apparently permanent alteration of the visual system Precipitants include stress, fatigue, entry into a dark environment, marijuana, neuroleptics, and anxiety states MDMA ("Ecstasy") and MDA MDMA and MDA are phenylethylamines that have stimulant as well as psychedelic effects MDMA became popular during the 1980s on college campuses because of testimonials that it enhances insight and self-knowledge It was recommended by some psychotherapists as an aid to the process of therapy, although no controlled data exist to support this contention Acute effects are dose-dependent and include tachycardia, dry mouth, jaw clenching, and muscle aches At higher doses, the effects include visual hallucinations, agitation, hyperthermia, and panic attacks MDA and MDMA produce degeneration of serotonergic nerve cells and axons in rats While nerve degeneration has not been demonstrated in human beings, the cerebrospinal fluid of chronic MDMA users has been found to contain low levels of serotonin metabolites (Ricaurte et al., 2000) Thus there is possible neurotoxicity with no evidence that the claimed benefits of MDMA actually occur Phencyclidine (PCP) PCP deserves special mention because of its widespread availability and because its pharmacological effects are different from those of the psychedelics such as LSD PCP originally was developed as an anesthetic in the 1950s and later was abandoned because of a high frequency of postoperative delirium with hallucinations It was classed as a dissociative anesthetic because, in the anesthetized state, the patient remains conscious with staring gaze, flat facies, and rigid muscles PCP became a drug of abuse in the 1970s, first in an oral form and then in a smoked version enabling a better regulation of the dose The effects of PCP have been observed in normal volunteers under controlled conditions As little as 50 g/kg produces emotional withdrawal, concrete thinking, and bizarre responses to projective testing Catatonic posturing also is produced and resembles that of schizophrenia Abusers taking higher doses may appear to be reacting to hallucinations and exhibit hostile or assaultive behavior Anesthetic effects increase with dosage; stupor or coma may occur with muscular rigidity, rhabdomyolysis, and hyperthermia Intoxicated patients in the emergency room may progress from aggressive behavior to coma, with elevated blood pressure and enlarged, nonreactive pupils PCP binds with high affinity to sites located in the cortex and limbic structures, resulting in blocking of NMDA-type glutamate receptors (see Chapter 12: Neurotransmission and the Central Nervous System) LSD and other psychedelics not bind NMDA receptors There is evidence that NMDA receptors are involved in ischemic neuronal death caused by high levels of excitatory amino acids; as a result, there is interest in PCP analogs that block NMDA receptors but have fewer psychoactive effects Tolerance, Dependence, and Withdrawal PCP is reinforcing in monkeys, as evidenced by self-administration patterns that produce continuous intoxication (Balster et al., 1973) Human beings tend to use PCP intermittently, but some surveys report daily use in 7% of users queried There is evidence for tolerance to the behavioral effects of PCP in animals, but this has not been studied systematically in human beings Signs of a PCP withdrawal syndrome were observed in monkeys after interruption of daily access to the drug These include somnolence, tremor, seizures, diarrhea, piloerection, bruxism, and vocalizations Pharmacological Intervention Overdose must be treated by life support, since there is no antagonist of PCP effects and no proven way to enhance excretion, although acidification of the urine has been proposed PCP coma may last to 10 days The agitated or psychotic state produced by PCP can be treated with diazepam Prolonged psychotic behavior requires neuroleptic medication such as haloperidol Because of the anticholinergic activity of PCP, neuroleptics with significant anticholinergic effects, such as chlorpromazine, should be avoided Inhalants Abused inhalants consist of many different categories of chemicals that are volatile at room temperature and produce abrupt changes in mental state when inhaled Examples include toluene (from airplane glue), kerosene, gasoline, carbon tetrachloride, amyl nitrite, and nitrous oxide (see Chapter 68: Nonmetallic Environmental Toxicants: Air Pollutants, Solvents and Vapors, and Pesticides for a discussion of the toxicology of such agents) There are characteristic patterns of response for each substance Solvents such as toluene typically are used by children The material usually is placed in a plastic bag and the vapors inhaled After several minutes of inhalation, dizziness and intoxication occur Aerosol sprays containing fluorocarbon propellants are another source of solvent intoxication Prolonged exposure or daily use may result in damage to several organ systems Clinical problems include cardiac arrhythmias, bone marrow depression, cerebral degeneration, and damage to liver, kidney, and peripheral nerves Death occasionally has been attributed to inhalant abuse, probably via the mechanism of cardiac arrhythmias, especially accompanying exercise or upper airway obstruction Amyl nitrite produces dilation of smooth muscle and has been used in the past for the treatment of angina It is a yellow, volatile, flammable liquid with a fruity odor In recent years, amyl nitrite and butyl nitrite have been used to relax smooth muscle and enhance orgasm, particularly by male homosexuals It is obtained in the form of room deodorizers and can produce a feeling of "rush," flushing, and dizziness Adverse effects include palpitations, postural hypotension, and headache progressing to loss of consciousness Anesthetic gases such as nitrous oxide or halothane are sometimes used as intoxicants by medical personnel Nitrous oxide also is abused by food service employees, because it is supplied for use as a propellant in disposable aluminum minitanks for whipped-cream canisters Nitrous oxide produces euphoria and analgesia and then loss of consciousness Compulsive use and chronic toxicity rarely are reported, but there are obvious risks of overdose associated with the abuse of this anesthetic Chronic use has been reported to cause peripheral neuropathy Treatment of Drug Abuse and Addiction The management of drug abuse and addiction must be individualized according to the drugs involved and to the associated psychosocial problems of the individual patient Pharmacological interventions have been described for each category when medications are available An understanding of the pharmacology of the drug or combination of drugs ingested by the patient is essential to rational and effective treatment This may be a matter of urgency for the treatment of overdose or for the detoxification of a patient who is experiencing withdrawal symptoms It must be recognized, however, that the treatment of the underlying addictive disorder requires months or years of rehabilitation The behavior patterns encoded during thousands of prior drug ingestions not disappear with detoxification from the drug, even after a typical 28-day inpatient rehabilitation program Long periods of outpatient treatment are necessary There probably will be periods of relapse and remission While complete abstinence is the preferred goal, in reality most patients are at risk to slip back to drug-seeking behavior and require a period of retreatment Maintenance medication can be effective in some circumstances, such as methadone for opioid dependence The process can best be compared to the treatment of other chronic disorders such as diabetes, asthma, or hypertension Long-term medication may be necessary, and cures are not likely When viewed in the context of chronic disease, the available treatments for addiction are quite successful (McLellan et al., 1992; O'Brien, 1994) Long-term treatment is accompanied by improvements in physical status as well as in mental, social, and occupational function Unfortunately, there is general pessimism in the medical community about the benefits of treatment, so that most of the therapeutic effort is directed at the complications of addiction, such as pulmonary, cardiac, and hepatic disorders Prevention of these complications can be accomplished by addressing the underlying addictive disorder For further discussion of alcoholism and drug dependency see Chapters 372 to 375 in Harrison's Principles of Internal Medicine, 16th ed., McGraw-Hill, New York, 2005 ... portion The preganglionic neurons of the autonomic nervous system (seeChapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems) are found in the intermediolateral columns of the. .. its special considerations Induction The "induction" of general anesthesia occurs when a conscious or otherwise responsive being is rendered unconscious by the effects on the nervous system of inhaled... frequent Here, the axon of an interneuron ends on the terminal of a long-distance neuron as that terminal contacts a dendrite in the dorsal horn Many presynaptic axons contain local collections of typical