Pharmacologic Effects and Mechanisms of Abuse and Dependence

Cocaine is a stimulant as well as a local anesthetic with potent vasoconstrictor properties. It induces a complex pattern of subjective effects that have been described as intense euphoria and alertness, increased confidence and strength, heightened sexual feelings, and indifference to concerns and cares. Yet these sensations rapidly change to their antithesis, so that despondency, dejection, and despair prevail. Euphoria is restored by the next dose of the drug, and it is this rapid alternation between ecstasy and dejection that purportedly leads to the “binge” pattern of cocaine use, in which the drug is used repeatedly at short intervals until either the supply or the user is exhausted. Cocaine, like many drugs, produces both pleasure and dysphoria, so the simplistic notion of “reward” does not accurately describe its effects. Instead, cocaine has reinforcing effects, which may be defined as any effect, positive, negative, or both, that maintains the behavior that leads to the continued administration of the drug. The reinforcing properties of cocaine appear to be related to the rapid onset and brief duration of its stimulant effects.

Cocaine can be used orally, intranasally (by insufflation), by inhalation, by intravenous injection, or by the smoking or inhalation of coca paste, cocaine freebase, or “crack” cocaine (freebase prepared with sodium bicarbonate). The onset of salient subjective effects is determined in part by the route of administration and frequency of use. Mood enhancement occurs very rapidly after smoking crack cocaine and after intravenous use, but less rapidly after intranasal administration. Cocaine rapidly increases the heart rate and blood pressure in a dose-related manner. These subjective and physiologic effects are not sustained, however, and cocaine abusers report using the drug repeatedly and frequently during a binge.

Cocaine has a relatively short plasma half-life (approximately 60 minutes) and is metabolized primarily by plasma esterases; its metabolites are excreted in urine. It is often used sequentially or simultaneously with other abused drugs. Combinations of cocaine and alcohol produce a metabolite, cocaethylene, that has cardiovascular effects similar to those of cocaine alone. Cocaethylene may also lengthen cocaine-induced euphoria and reduce the unpleasant symptoms of withdrawal.

The accelerating frequency of cocaine abuse has economic and social consequences that are well documented. The seemingly evanescent pleasures of using the drug are accompanied by the risk of death from cardiac arrhythmia, respiratory depression, and convulsions. Disorders of cerebral blood flow and perfusion defects due to the potent vasoconstrictive effects of the drug on cerebral arteries are also associated with chronic cocaine abuse.

The medical sequelae of cocaine use, including addiction, now challenge health professionals in nearly every major specialty. There is a growing consensus that much can be done in the primary care setting to facilitate public health efforts to reduce the prevalence of cocaine use and to treat those with cocaine-related disorders. Thus, there is a strong need for an authoritative work on the topic. Unfortunately, clinicians may be disappointed if they expect Cocaine to be useful as either a clinical handbook or a bibliographic resource.

This book will provide clinicians and lay audiences with some generally interesting historical and scientific information about cocaine. Gold also gives a strong argument for increasing the involvement of health care professionals in reducing cocaine use and the medical care of the cocaine user.

The neurobiologic mechanisms underlying the effects of cocaine are not well understood. There is considerable evidence, however, that the initiation and continuation of cocaine use are associated with the effects of the drug on the dopaminergic and neuroadrenergic modulation of central nervous system function. Studies in animals suggest that the mesocorticolimbic dopaminergic pathways are important mediators of cocaine’s reinforcing properties. Species may differ, however, with respect to the distribution and interaction of neurons with dopamine receptors and subtypes. Dopaminergic systems are probably not homogeneous. Recent studies of drug self-administration in rodents indicate that dopamine D3 receptors contribute to its reinforcing properties. To date, five dopamine-receptor subtypes have been identified, and their role in inducing and perpetuating cocaine abuse and dependence in humans remains to be determined.

A “dopamine depletion” hypothesis has been advanced to explain the occurrence of symptoms such as depression and anergia after the cessation of cocaine use. Alterations in dopaminergic function after protracted cocaine use may also result in hyperprolactinemia, an indication of impaired dopaminergic regulation of prolactin secretion. Dysregulation of the dopamine system may contribute to immunologic as well as neuroendocrine disorders in cocaine-dependent men and women. The drug also affects serotonergic functions in the central nervous system, and cocaine-induced changes in serotonergic activity may underlie disorders of sleep and wakefulness that occur during chronic cocaine use and during withdrawal.

One of the best chapters is “The Neurobiology of Cocaine.” It is not generally understood that self-administration of cocaine can become chronic, in part because of previous exposure to the drug. This lack of understanding undoubtedly contributes to the belief that cocaine use is a problem of self-control and a lack of awareness of the dangers of its use, as opposed to a behavioral syndrome no less biologically determined than depression or panic. This mini-review convincingly demonstrates that the cellular mechanisms underlying the pathophysiology of cocaine addiction are at least as well understood as the pathophysiologic consequences of cocaine use, such as myocardial infarction.

Cocaine also makes a compelling case that the fundamental strategies for treating cocaine dependence encompass the following triad: diagnosis, accompanied by objective testing of blood samples or other specimens; implementation of structured therapy tailored to the individual patient; and follow-up. The discussion of potential benefits with respect to health care and costs is timely in view of the national debate over services for treating drug addiction.

Jack E. Henningfield, Ph.D.
National Institute on Drug Abuse
Baltimore, MD 21224

Cocaine also affects neuroendocrine systems that modulate responsivity to stress and sexual behavior. The drug induces a rapid increase in corticotropin secretion in humans and rhesus monkeys. Cocaine-induced stimulation of corticotropin secretion in rodents was inhibited by the administration of antiserum to corticotropin-releasing hormone. This increased secretion of corticotropin may be associated in humans with the reinforcing properties of cocaine and its rapid enhancement of perceived pleasure and diminution of concern about environmental stressors. Cocaine also stimulates the secretion of luteinizing hormone in rhesus monkeys and humans. This effect may be related to the perception of enhanced sexual interest and responsivity after the drug is used. Altered neuroendocrine function during protracted cocaine abuse may result in serious disorders, including altered stress and immune responses, as well as impairment of reproductive function in both sexes.

Important advances have been made in understanding the neuropharmacologic concomitants of cocaine use by humans, subhuman primates, and rodents, but the specific neurochemical and neurophysiologic bases of cocaine reinforcement remain to be determined. Although neuroadrenergic, dopaminergic, and serotonergic functions of the central nervous system are directly affected by cocaine, it is likely that interactions between these neurochemical systems are of considerable importance in understanding the reinforcing properties of cocaine.

Source Information
From Harvard Medical School, Boston, and McLean Hospital, Belmont, Mass.

Address reprint requests to Dr. Mendelson at McLean Hospital, 115 Mill St., Belmont, MA 02178.


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Jack H. Mendelson, M.D., and Nancy K. Mello, Ph.D.

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