Psychomotor Stimulants – Cocaine Abuse and the Effects of Chronic Cocaine Exposure

Experimental cocaine use may escalate over time to a pattern of cocaine abuse and dependence

Cocaine users give many different reasons for their initial decision to use the drug. Some of these reasons are to satisfy their curiosity; to facilitate social interactions; to relieve feelings of depression, anxiety, or guilt; to have fun and celebrate; or simply to get “high.” Cocaine users typically describe early experimentation with both legal (e.g., alcohol) and illegal drugs, often beginning by 13 or 14 years of age. Early use of other substances may therefore be an important risk factor for the initiation of cocaine use.

People usually begin taking cocaine via the intranasal route, that is, by snorting it. Most individuals who try cocaine do not progress to a pattern of abuse. Some report a strong anxiety response as their initial reaction to cocaine and are thereby dissuaded from further experimentation. Other factors may likewise mitigate against the development of a long-term abuse pattern, including unavailability of the drug, the cost of maintaining a steady supply, the social and legal consequences of illicit drug use, and the very real fear of losing control over one’s drug-taking behavior. These factors often lead to a termination of cocaine use, though there are some intranasal users who maintain long-term periodic and controlled cocaine consumption.

Surveys performed by the National Institute on Drug Abuse suggest that approximately 10 to 15% of initial intranasal users eventually become cocaine abusers. The details of this transition process certainly vary for different individuals, yet a few factors have been identified that may generally be important. The stimulating, euphoric, and confidence-enhancing effects described earlier provide a powerful reinforcing effect during the early stages of cocaine use. Furthermore, these aspects of cocaine reinforcement may be augmented by social responses from friends and acquaintances who respond positively to the user’s newfound energy and enthusiasm. Over time, cocaine use escalates as the individual discovers that higher doses produce a more powerful euphoric effect.

Even more importantly, the user may switch from intranasal administration to crack smoking, freebasing, or IV injection. For many, this is a significant event in their drug history because of the greater abuse potential of these latter routes of administration. Moreover, some individuals develop a pattern of cocaine binges, which are episodic bouts of repeated use lasting from hours to days with little or no sleep. During these periods, nothing is important to the user except maintaining the “high,” and all available supplies of cocaine are consumed in this pursuit. A 3-day free- basing binge may involve the consumption of as much as 150 g of cocaine, which is an enormous amount. Many individuals who abuse cocaine also suffer from other psychiatric disorders, such as depression, anxiety disorders, or personality disorders. A comorbid psychiatric disorder may precede the individual’s cocaine use and predispose him to begin taking the drug, or the disorder may be induced as a consequence of the chronic cocaine exposure.

Chronic psychostimulant exposure can give rise to tolerance or sensitization

As with many drugs, chronic exposure to psychostimulants can lead to reduced responsiveness, or tolerance. Yet the reverse effect, namely sensitization, is also often seen with psychostimulants. One of the amazing aspects of sensitization is that just a few exposures to cocaine or amphetamine can produce an increased responsiveness that lasts for weeks, months, or even longer.

How can psychostimulants produce both tolerance and sensitization? Various studies have shown that which kind of change you observe depends on the pattern of drug exposure, the response that’s being measuftd, and the time interval that has elapsed since the last dose. For example, continuous cocaine infusion into rats causes tolerance to the drug’s locomotor-stimulating effect, whereas once- daily cocaine injections lead to behavioral sensitization, as shown by enhanced stereotyped behaviors. Sensitization can actually increase in strength after the last drug dose (that is, during the period of withdrawal) due to ongoing neurochemical changes in the brain.

Under some conditions, researchers have observed a short-lasting acute tolerance to psychostimulants along with a longer-term sensitization. This combination of effects was found in an experiment in which extracellular DA levels in the striatum were measured in monkeys repeatedly self- administering cocaine over a period of 6 months (Bradberry, 2000). When animals gave themselves two doses of cocaine within a single session, the DA response to the second dose was usually lower than the response to the first dose (acute tolerance). However, when the response to the first dose within each session was examined over the entire 6-month period, there was a gradual escalation in cocaine’s effectiveness in elevating extracellular DA levels (long-term sensitization).

These findings are important because they may help explain both the development of psychostimulant dependence and the drug-taking patterns of dependent individuals. Some researchers believe that a sensitization-like mechanism underlies the increased drug craving experienced by cocaine or amphetamine users who are in the process of developing a dependence on these substances. Moreover, users report that during a cocaine or amphetamine binge, they need more drug later in the binge to obtain the same “high” as they felt at the beginning. Such reports suggest the development of a short-term tolerance that may wear off if sufficient time elapses between successive binges.

Sensitization can be divided into two phases; induction, which means the process by which sensitization is established, and expression, which refers to the process by which the sensitized response is manifested. Somewhat different neurochemical mechanisms underlie these two phases (Vanderschuren and Kalivas, 2000). Activation of glutamate NMDA receptors and (in the case of amphetamine) dopamine D: receptors is necessary for the induction of sensitization. Expression of sensitization is dependent at least partly on enhanced reactivity of dopaminergic nerve terminals in the nucleus accumbens. That is, a given psychostimulant dose causes a greater increase in accumbens extracellular DA levels in sensitized compared to nonsensitized animals.

Binge cocaine use has been linked to a specific abstinence syndrome

Until the early 1980s, cocaine was not believed to produce a syndrome of dependence and withdrawal, and hence the drug was not considered addictive by classical criteria. For example, cocaine dependence was not listed as a substance abuse disorder in the 1980 version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III). This situation began to change, however, when Frank Gawin and Herbert Kleber (then at Yale University School of Medicine) described a pattern of withdrawal symptoms (abstinence syndrome) hypothesized to occur following a cocaine binge (Gawin and Kleber, 1986,1988). Based on a combination of clinical observations and patient interviews, the investigators concluded that the cocaine abstinence syndrome occurred in three phases that they called crash, withdrawal, and extinction.

During the crash, the user feels exhausted and suffers from a depressed mood. Later, during the withdrawal phase, some of the important symptoms include anhedonia (inability to experience normal pleasures), anergia (a lack of energy), anxiety, and a growing craving for cocaine that increases the risk of relapse. Symptoms subside during the extinction phase, although relapse to cocaine use may still occur. Around the same time as Gawin and Kleber’s report, Dackis and Gold (1985) proposed that the negative mood state and craving associated with cocaine withdrawal stem from temporarily decreased synaptic levels of DA. This hypothesis needs to be tested using appropriate brain imaging techniques during the various phases of a cocaine binge and withdrawal.

Other investigators have studied the pattern of withdrawal in long-term cocaine users following hospitalization (Wed- dington et al., 1990; Satel et al., 1991). Although the subjects exhibited various symptoms at the time of admission, they experienced a gradual decline in these symptoms over time instead of passing through distinct phases of withdrawal. Because these individuals were not known to be binge users, it is possible that Gawin and Kleber’s multiphasic model of cocaine withdrawal does not apply to nonbingers.

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Repeated or high-dose cocaine use can have serious health consequences

Cocaine use, especially at high doses, can have many adverse physiological and behavioral consequences. With respect to the brain, for example, a single dose of cocaine may trigger a stroke or seizure. Effects of chronic use on the brain are discussed later. Complications associated with the heart range from chest pains to cardiac arrhythmias (irregular heart rate), cardiac myopathy (damaged heart muscle), and even myocardial infarction (heart attack). Other organs or systems that can be damaged by cocaine include the lungs, the gastrointestinal system, and the kidneys. Frequent snorting of cocaine can lead to perforation of the nasal septum (the tissue that separates the two sides of the nose). Finally, ingestion of cocaine by a pregnant woman has variable effects on the unborn child. Many offspring seem to escape without obvious harm; others may show attention deficits or other behavioral or cognitive abnormalities; and in a small number of cases, the fetus is killed prior to birth.

Behaviorally, high-dose cocaine use can lead to panic attacks or the development of a temporary paranoid psychosis with delusions and hallucinations. One particularly frightening type of hallucination is called “cocaine bugs,” which refers to the sensation of tiny creatures crawling over the user’s skin. More than 100 years ago, some of Freud’s colleagues were already seeing patients with these kinds of psychotic reactions. Cocaine psychosis occurs more frequently with repeated use, which is consistent with a growing sensitization to the drug.

Pharmacological, behavioral, and psychosocial methods are used to treat cocaine abuse and dependence

Pharmacotherapies High rates of cocaine abuse in our society have spurred a great deal of interest in developing effective therapies for cocaine users. At present, the most widely used agent is probably desipramine, which is a tricyclic antidepressant that mainly inhibits NE uptake. This compound seems to be most helpful as an adjunct therapy in treating patients diagnosed with cocaine abuse (rather than the more severe cocaine dependence) who additionally suffer from depression. Interestingly, the 5-HT reuptake inhibitor fluoxetine (trade name Prozac) seems to be less effective than desipramine in cocaine users.

The National Institute on Drug Abuse is currently directing an active program to identify and test pharmacological agents that might reduce cocaine’s euphoric effects and/or the craving that ensues during cocaine withdrawal. Because of the well-known role of DA in cocaine reinforcement in animal models and its presumed involvement in human cocaine addiction, much attention has been directed to various dopaminergic drugs, including receptor agonists, antagonists, and uptake inhibitors, that might compete with cocaine for access to the DA transporter (Platt et al., 2002).

At this time, the most promising compounds appear to be DA receptor partial agonists, particularly those that bind to Dj or D3 receptors. Partial agonists would compete with DA for access to the receptors, thereby possibly blunting the euphoric effects of cocaine-induced dopaminergic stimulation. They would have much less abuse potential than cocaine, however, because of their lower efficacy at the receptors. BP 897, the D3 receptor partial agonist previously mentioned for its ability to reduce cocaine-seeking behavior in rats, is currently in phase 2 clinical trials. We hope that BP 897 or other D3 selective agents will prove to be more effica-cious against cocaine abuse than compounds currently in use.

In a much different approach, researchers have recently shown that animals can be immunized against cocaine. The resulting antibodies may simply bind cocaine molecules (Carrera et al., 2001), or alternatively, they may have catalytic activity that actually breaks down cocaine in the bloodstream (Deng et al„ 2002). Both methods cause less cocaine to get into the brain, and both have been shown to reduce (or even completely block) cocaine’s psychoactive effects in animals. Initial clinical trials showed that humans can also be immunized against cocaine, but the anticocaine antibodies gradually disappeared over time (Kosten et al., 2002). Much more research must be done before we will know whether vaccination is a viable therapeutic option against cocaine abuse and addiction.

Behavioral and psychosocial therapies It should be apparent that researchers have not yet discovered any compound that is broadly effective in treating cocaine abusers.

Although this situation could change with the development of newer medications, it is necessary to consider the potential role of behavioral and social therapies in dealing with this problem. While pharmacotherapy may aid in patient stabilization (e.g., by reducing craving or other abstinence symptoms), equally important are counseling and support structures that enable the patient to learn new coping responses, avoid triggers for relapse, and function effectively in a drug- free lifestyle.

There are a variety of different treatment programs for cocaine-dependent individuals. Many are conducted on an outpatient basis, although the most severe cases usually receive the greatest benefit from hospitalization and either short- or long-term inpatient treatment. Psychosocial treatment programs involve individual, group, or family counseling designed to educate the user, promote behavioral change, and alleviate some of the problems caused by the cocaine abuse. Cognitive behavior therapies are aimed at restructuring cognitive (thought) processes and training the user either to avoid high-risk situations that might cause relapse or to employ appropriate coping mechanisms to manage such situations when they occur. This approach is sometimes called relapse prevention therapy. Also available are 12-step programs such as Narcotics Anonymous or Cocaine Anonymous. The general approach of all 12-step programs is based on that of Alcoholics Anonymous.

One of the most interesting approaches to treating cocaine users was developed by Stephen Higgins and his coworkers at the University of Vermont (Higgins et al., 1994). This is a 24-week, outpatient, multicomponent behavioral treatment program based on the premise that drug taking is an operant response that persists mainly due to the reinforcing properties of the drug. Hence altering reinforcement contingencies to reduce drug-associated reinforcement and to increase the availability of nondrug reinforcers should help promote abstinence and the adoption of a drug-free lifestyle. As part of this program, each negative urine test by the client is reinforced with a voucher. These vouchers cannot be redeemed for money per se, to avoid patients accumulating funds for drug purchases; however, they can be exchanged for items approved by the individual’s counselor, particularly things that promote a healthy lifestyle such as YMCA passes and educational materials. Another aspect of this program involves a Community Reinforcement Approach (CRA) (Hunt and Azrin, 1973), which is designed to enhance the patient’s social (including family) relationships, recreational activities, and job opportunities.

Post Summary

Early use of other substances seems to be an important risk factor for the initiation of cocaine use. Some users quickly stop taking cocaine for various reasons, some maintain controlled use for long periods of time, and still others progress to a pattern of uncontrolled use (i.e., abuse). Such a progression may come about through dose escalation and/or switching from intranasal use to smoking or IV injection, routes of administration with greater abuse potential. Cocaine abuse may be manifested by daily or near-daily use or by a pattern of bingeing. Many individuals who abuse cocaine also suffer from other psychiatric disorders. Chronic exposure to cocaine or other psychostimulants can lead to tolerance and/or sensitization. Changes in drug responsiveness depend on the pattern of drug exposure, the outcome measure, and the time since the last dose. Some pat- terns of psychostimulant exposure cause a short-term toler- ance but a longer-term sensitization. Different neural mecha- nisms underlie the induction and expression of sensitization. For many years, cocaine was thought not to produce any kind of dependence.

This view changed when investigators began to observe various psychological symptoms occurring during cocaine withdrawal. In particular, cocaine binges are reportedly followed by a complex abstinence syndrome of craving, anhedonia, and anergia that places the user at high risk for relapse. These symptoms have been hypothesized to result from a tempo- rary reduction in synaptic DA availability. The adverse effects of repeated or high- dose cocaine use include stroke or seizure, cardiovascular problems including heart attack, damage to other organ systems, and possible abnormalities in the development of offspring exposed to cocaine prenatally. High-dose cocaine use can also lead to panic attacks or the onset of a paranoid psychotic reaction.

Finally, much effort in the area of treating cocaine abuse has been focused on the development of medications that might reduce craving and promote abstinence among users. Possible medications include DA receptor partial agonists such as the D3- selective compound BP 897, as well as anti- cocaine vaccines. Pharmacotherapy alone, however, will probably not be completely successful in dealing with our society’s cocaine abuse problem. Effective behavioral and counseling programs must therefore also be implemented. Current approaches include psychosocial treatment programs, cognitive behavior therapies aimed at relapse prevention, 12-step programs like Narcotics Anonymous and Cocaine Anony- mous, and behavioral programs based on a combination of vouchers and CRA. Over time, these and other novel methods, along with new pharmacotherapies, may help reverse the devastating effects of cocaine on our society.

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