Mechanism Of Action Of Cocaine Psychology Essay

Cocaine dependence treatment faces a number of problems, both connected with the variety of factors involved in the development of cocaine dependence, and with the often concomitant presence of other disorders like depression or multiple uses of psychoactive substances like other stimulants, alcohol, or opioids so that it becomes difficult to discern what effect is to attribute purely to cocaine addiction, as opposed to other substances or other disorders. This paper is intended to review the current knowledge on the neurobiological mechanisms that lead to cocaine dependence and the pharmacological treatments used to sustain abstinence and prevent relapse.

Mechanism of action of cocaine

Cocaine is a stimulant substance derived from the leaves of the coca plant, original of South America. The processing of the coca leaves gives a white powder, which is the form of the drug that is typically used by snorting: the substance is rapidly absorbed by the mucosa of the nose. Another method of use of cocaine is the crack, a further processing of cocaine that comes in blocks similar to small rocks and is either smoked or injected. Crack is a more potent substance than cocaine and, when smoked or injected, it reaches the brain very quickly. The effect of a single dose of cocaine is of intense euphoria and the user feels confident and alert. It can also produce hypersexuality, hypervigilance and psychomotor agitation (Kosten, 2002). Cocaine has a quick but short action: the effects may start after 8 minutes (although this may vary, depending on the way of assumption) and lasts around 20-30 minutes (Davey, 2008). Such an intense, pleasant and short effect usually leaves the user an immediate longing for more.

The mechanism of action of cocaine is to inhibit the re-uptake of dopamine after it has been released in the synaptic space. In normal conditions, after being released, dopamine binds with the dopamine receptors of the post-synaptic neuron, activating them and producing a sense of pleasure. After its action, dopamine gets recycled by the pre-synaptic neuron: the dopamine transporters located on the wall of the pre-synaptic neuron bind the dopamine and transport it back inside the neuron. When cocaine is present, it binds the dopamine transporters and inhibits the normal re-uptake of dopamine from the synaptic space. This increased availability of dopamine in the synaptic space determines the intense sense of pleasure that is the effect of the drug. Cocaine has an effect mainly through the dopamine system, but it also has an effect on norepinephrine and serotonin and indirectly on glutamate, GABA and k-opioid systems (Kosten, 2002). Although all of these systems impacted by cocaine will have a role in the selection of pharmacological treatment of cocaine dependence, the main responsible for the development of cocaine addiction is the dopamine system, as it triggers a potent reward mechanism that sustains craving and, through relapses, a continued use of the drug. The effect of cocaine can be understood if we consider that dopamine responsive neurons are highly concentrated in the mesolimbic system, impacting emotions and learning: the neurons of the mesolimbic system originate in the ventral tegmental area and project frontally into a number of structures, among which the amigdala and the nucleus accumbent. The addictive effect of cocaine is due to neuromodifications in the dopamine reward systems of the brain. A reward system is a brain system that mediates the “rewarding” sense of pleasure that govern behavior in the presence of a specific stimulus, like for example food, drink or a sexual partner (Bozarth, 1994). The presence of the stimulus triggers a specific behavior and the outcome of the behavior activates the reward systems, producing a sense of pleasure, reinforcing thus the desire of repeating the behavior in order to reproduce the pleasure feeling. This mechanism is mediated by neurons that originate in the ventral tegmental area of the brain and project frontally in the nucleus accumbents, using dopamine as main neurotransmitter, although in mammals this systems is integrated with others systems in the brain to produce a more sophisticated response to stimuli (Esch & Stefano, 2008). Normally, the reward systems serve to learn behaviors that lead to a favorable goal and therefore to learn a response to a stimulus that supports survival or reproduction. However, an action as potent as that of cocaine, or of other addictive drugs, can lead to what has been called “motivational toxicity” (Bozarth, 1994), meaning the loss of ability of normal rewards to influence behavior. In other words, the mechanism of addiction is the total control of behavior by the drug, overcoming other normally powerful motivational elements (like food, sex or other socially appealing elements like career) so that all the attention of the addicted person is towards further assumption of the drug. In fact, from occasional use, eventually, although it may take some years, cocaine use becomes uncontrolled and its assumption turns from repeated episodes with increasing doses to extended binge use (O’Malley & Gawin, 1990). Binges can last for 8 to 24 hours and end only when all the cocaine available to the user is finished. They are followed by periods of non-use between half a day and 5 days.

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From a clinical point of view, episodes of binge use of cocaine can produce a state of mental confusion, known as stimulant delirium, when the person feels confused, disoriented and experiences a strong sense of anxiety. Overdose can also produce seizures, and even strokes as a consequence of the vasoconstriction property of cocaine. Also psychosis can been induced by high doses of cocaine, although it is more frequent with amphetamines which have an effect similar to cocaine, but more prolonged in time. Cocaine psychosis is more frequently observed in users with a pre-existent predisposition to psychosis (Kosten, 2002).

After a cocaine binge, meaning when the drug is no more available and temporarily its use is suspended, the individual goes through an abstinence pattern that includes an initial crash phase, followed by a withdrawal phase and, if no relapse into a binge episode takes place, there may be the extinction phase (Gawin & Kleber 1986, quoted in O’Malley and Gawin, 1990). During the initial crash phase, which can last between 9 hours and 4 days, the major experience is of disphoria and agitation, yielding soon to fatigue, lack of cocaine craving, and an intense desire to sleep. The disphoria is the consequence of the depletion of dopamine reserves occurred during the binge episode, as well as the hypersomnolence, which can last some days, is evidently the need for the body to recover from the intense activity occurred during the binge. It is interesting to note that in this crash phase the craving for cocaine is not present. This is comparable to the state of the post-alcohol intoxication, when the individual recovers from previous abuse of the substance and no interest for the substance is experienced (O’Malley and Gawin, 1990). The second phase of cocaine abstinence, the withdrawal, is characterized by a state of depression and anhedonia, meaning the inability to experience pleasure, which can last between 1 and 10 weeks, or even longer in the case of concomitant psychiatric disorders (O’Malley & Gawin, 1990). This lack of pleasure reactivates the craving for cocaine: cocaine is searched and desired in an attempt to experience again the euphoria that used to be produced by the drug during the binge episode. This is the period of major risk of relapse into use of the substance, when a user tries to exit the dependence. The craving for cocaine, that was absent during the crash phase, gradually increases and is often triggered by cues, like the sight of objects associated with the former use of cocaine, or with emotional states previously soothed by its effects. If relapse in cocaine use does not occur, these cues can become over time less and less strong and eventually the craving may become extinct (O’Malley & Gawin, 1990).

From a neurobiological point of view, if the sense of euphoria determined by a single use of cocaine is the consequence of increased levels of dopamine in the synaptic space, the transition from abuse of cocaine to addiction, meaning to the uncontrolled, compulsive use of the substance, is considered the consequence of modifications in gene expression in the neurons of the nucleus accumbent, including some involved in the regulation of glutamate and natural opioid-like substances (Nestler, 2005). One of the molecules that mediate the impact of cocaine on gene expression is the genetic transcription factor ΔFosB. With every use of cocaine, additional build-up of ΔFosB is created and, due to its long lifespan (6-8 weeks), frequent use of the drug can lead to very high intra-cellular concentrations of the transcription factors (Nestler, 2005). Although the exact molecular effects of ΔFosB are still under research, studies on mice with increased levels of this transcription factor have highlighted a behavior similar to the behavior of cocaine addicted. The prolonged permanence of the build-up of ΔFosB is considered one of the mediators of the mid-term effects of cocaine: the development of dependence and the high rate of relapse in the first 8-10 of abstinence, which coincides with the second phase of abstinence called the withdrawal phase. A longer-term effect of the chronic use of cocaine is cue-dependent reactivation of craving that persists too long to be explained by the prolonged presence of the ΔFosB: in about two months from initiating abstinence, the build-up of ΔFosB should be eliminated and gene expression should be back to normal levels. Instead, in the phase called extinction phase, it is observable a cue-induced craving that seems to stem from a “learned” reaction to those cues developed during the long intense exposure to cocaine. A stream of research is indeed investigating the impact of long-lasting abuse of cocaine, mediated by ΔFosB, on the modification of neuron structures and in particular in the development of new dendrites stemming from the cell body of dopaminergic neurons (Nestler, 2005). A hypothesis is that even after long time of abstinence, these new dendrites may collect, or increase, input from structures like the amigdala and the hippocampus, giving these structures that regulate memory and learning an increased influence over the nucleus accumbent. This may reactivate the drug craving in the presence of cues that remind the abstinent ex-user of situations or emotions connected with cocaine.

Other factors have been studied for their involvement in the mid and long term effects of cocaine abuse, like the extracellular signal-regulated kinase (ERK), the brain-derived neurotrophic factor (BDNF), the glutamate transmission, having all an effect of synaptic plasticity, meant as long term potentiation or depression, which makes the affected neurons more responsive to cue associated with cocaine or to stress (Thomas, Kalivas & Shaham, 2008), being stress another factor that has been observed to increase the risk of relapse.

Therapy

There is currently no pharmacological treatment specifically indicated for cocaine dependence. All the attempts to support the abstinence from cocaine in chronic users have used medications indicated for different pathologies, following as a rationale based on the clinical symptom observed during abstinence and the underlying chemical and neurobiological modifications. In reviewing the pharmacotherapies that have been tried to support abstinence, it is therefore important to first define the goal of the selected therapy. If the ultimate goal is the reach of the extinction phase, with the elimination of cocaine craving and use, intermediate goals are the reductions of symptoms of the withdrawal such as depression, and reduction of the craving, as this may lead to a relapse.

As we have seen, typical symptoms in the crash and withdrawal phase of abstinence are depressive symptoms, dysphoria and anhedonia. This has led to a frequent use of antidepressants in these early phases of abstinence. The clinical effect of antidepressants is mediated by the potentiation of the serotoninergic transmission through four categories of mechanisms of action: selective inhibition of the reuptake of norepinephrine (like desipramine), of 5-HT (like fluoxetine), non-selective enhancement of norepinephrine and 5-HT (like amitriptyline), while the fourth category includes those antidepressants whose mechanism is not completed understood (like bupropione)(Lenox & Frazer, 2002). A widely studied antidepressant is desipramine, a tricyclic (following the classification of antidepressant according to their molecular structure) that selectively inhibits the reuptake of norepinephrine. Despite its extensive use in the therapy of cocaine dependence, evidence of its effectiveness (as well as of other antidepressants of the same class) is not well demonstrated (Kosten, 2002). Other antidepressants tested in the treatment of cocaine dependence include fluoxetine (a selective serotonin reuptake inhibitor, or SSRI), which while giving some indication of effectiveness in decreasing the effects of cocaine measured as subjective feeling, has not shown any difference compared to placebo in reducing positives in urine detection of cocaine and its use is no more considered relevant in cocaine dependence treatment (Kosten, 2002). This shows that an objective measurement of abstinence such as the presence of cocaine in the urine related to the relevant goal of maintaining abstinence has been considered more relevant in the evaluation of the use of fluoxetine than a subjective factor related to an intermediate goal, such as the perception of decrease in the effects of cocaine. This ambiguity in the evaluation of the effectiveness of antidepressants in cocaine dependence, but also in the treatment of depression itself, may be one of the factors that explain the wide range of effectiveness data in clinical trials.

Other ways in which it has been tried to address the withdrawal symptoms of cocaine is the administration of substances that mime the effect of the cocaine, but with less potency or a gradual effect that does not produce the high, and a way of administration that may have a reduced risk of abuse. In the therapy of opiate addiction, a typical example of this kind of therapy rationale is methadone, which is administered orally and therefore determines a gradual on-set of the effect (Carlson, 2010). This replacement of the effects of cocaine should reduce the disphoria and intense craving, as they are a consequence of the reduced presence of dopamine in the synaptic space. One type of dopamine agonist substances that could have been interesting in the treatment of cocaine dependence are agents used in the Parkinson’s disease, like bromocriptine, amantadine and L-deprenyl, as this disease determines a degeneration of the dopaminergic neurons of the nigrostriatal system, so that effective therapy requires a potentiation of the dopaminergic action. Other substances include treatments for Attention Deficit Hyperactivity Disorder like methylphenidate, or even appetite suppressants like manzitol. The DA-agonist effect can be expressed as dopamine receptors binding producing their activation like with bromocriptine, or it can be the inhibition of the reuptake of dopamine (which is the same mechanism of action of cocaine) like with mazindol, or an induction of dopamine release, like with methylphenidate, or inhibition of the catabolism of dopamine, as in the case of IMAO like L-deprenyl. All these products have been tried in supporting cocaine abstinence. However, although the rationale seemed attractive, the clinical studies have not shown clear evidence in reducing relapse and thus sustaining abstinence (Kosten, 2002).

Another desired effect of pharmacological treatment is the reduction of the effect of administration of cocaine thus reducing the interest in new assumption of cocaine and reducing relapses. Dopamine antagonists should contrast the on-set of euphoria and make cocaine less effective, in the same way that methadone’s prolonged effect in occupying the opiate receptors is reducing the effects of heroin in the treatment of opiate dependence (Carlson, 2010). In the case of cocaine addition, this effect has been searched in the use of dopamine antagonists such as haloperidol and flupenthixol, antipsychotic agents available as injections to be administered every 3-4 weeks. However, also in this cases, despite the rationale of use has been attractive, the trials conducted to evaluate their clinical effectiveness have proved discouraging (Kosten, 2002). Another way to block or reduce the effect of cocaine is to prevent it from reaching its target. This means that if cocaine is sequestered by antibodies directly in the bloodstream, it will not pass the ematoencephalic barrier and eventually gets metabolized. The possibility to develop a vaccine against cocaine is also particularly attractive, as it would inactivate the drug while not being a psychoactive substance (Martell, Orson, Poling, Mitchell, Rossen, Gardner & Kosten, 2009). The studies on animals show promising results and in humans the research for some products has reached phase I and II, demonstrating safety and showing some effectiveness in maintaining abstinence, although further research is needed to provide products that can be widely utilized (Orson, Kinsey, Singh, Wu & Kosten, 2009). Also, it has been observed that increased doses of cocaine can override the effect of the immunization so that the motivation of the patient is a factor that can be relevant for the success of the vaccine prophylaxis of relapse (Orson, Kinsey, Singh, Wu & Kosten, 2009) and a psychosocial treatment needs to complement this approach.

Other substances with diverse mechanisms of action tried in cocaine dependence include disulfiram, an agent in use for alcohol dependence which seems to have some effect on decreasing craving and positives in urine screens. All other substances have failed to show sound evidence of effectiveness (Kosten, 2002).

Conclusions

No pharmacological treatment exists that has demonstrated effectiveness specifically in the treatment of cocaine dependence. To date, the selection of the pharmacological therapy has been determined by the known neurobiological modification induced by chronic use of cocaine that was intended to be addressed, or by a specific withdrawal symptom like depression or craving. However, the demonstrated effectiveness is currently relatively low for almost all of the tried substances. If on one side the efforts and progress in developing a vaccine specific for cocaine seem to open new perspectives in the treatment of such a complex issue, on the other side further efforts should be placed in reinforcing the existing favorable data on the possible effectiveness of pharmacological treatment in combination with psychological treatments such as cognitive behavioral therapy, contingency management and other forms of psychosocial interventions.