Neurophysiologic processes underlie the uncontrolled, compulsive behaviors defining the addicted state. These"hard-wired"changes in the brain are considered critical for the transition from casual to addictive drug use. This review of preclinical and clinical (primarily neuroimaging) studies will describe how the delineation between pleasure, reward, and addiction has evolved as our understanding of the biologic mechanisms underlying these processes has progressed. Although the mesolimbic dopaminergic efflux associated with drug reward was previously considered the biologic equivalent of pleasure, dopaminergic activation occurs in the presence of unexpected and novel stimuli (either pleasurable or aversive) and appears to determine the motivational state of wanting or expectation. The persistent release of dopamine during chronic drug use progressively recruits limbic brain regions and the prefrontal cortex, embedding drug cues into the amygdala (through glutaminergic mechanisms) and involving the amygdala, anterior cingulate, orbitofrontal cortex, and dorsolateral prefrontal cortex in the obsessive craving for drugs. The abstinent, addicted brain is subsequently primed to return to drug use when triggered by a single use of drug, contextual drug cues, craving, or stress, with each process defined by a relatively distinct brain region or neural pathway. The compulsive drive toward drug use is complemented by deficits in impulse control and decision making, which are also mediated by the orbitofrontal cortex and anterior cingulate. Within this framework, future targets for pharmacologic treatment are suggested.

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Neurobiologic Processes in Drug Reward and Addiction

Addiction to drugs, such as heroin, cocaine and alcohol, exacts great human and financial costs on society, but the development of pharmacotherapies for addiction has been largely neglected by the pharmaceutical industry. With advances in our understanding of the underlying biology of addictions now opening the door for the development of novel pharmacotherapies, it could be time for a reassessment of involvement in this increasingly important therapeutic area. Here, we summarize the current approved and implemented pharmacotherapeutic approaches to the treatment of addiction, and then highlight the most promising areas for future drug development from the perspective of our laboratory and our National Institutes of Health (NIH) National Institute on Drug Abuse (NIDA) Research Center.

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Pharmacotherapy of addictions

Aims Cocaine dependence is a common and serious condition, associated with severe medical, psychological and social problems, including the spread of infectious diseases This systematic review assesses critically the efficacy of pharmacotherapy for treating cocaine dependence



Methods The literature search strategy included: electronic searches of Cochrane Library holdings, EMBASE, MEDLINE, PsycLIT, Biological Abstracts and LILACS; scans of reference lists of relevant articles, personal communications, conference abstracts, unpublished trials from the pharmaceutical industry and book chapters on the treatment of cocaine dependence Randomized controlled trials (RCTs) focusing on the use of antidepressants (ADs), carbamazepine (CBZ), dopamine agonists (DAs) and other drugs used in the treatment of cocaine dependence were included The reviewers extracted data independently, and relative risks (RR) with 95% confidence interval (CI) were estimated Qualitative assessments were carried out using a Cochrane validated checklist Where possible, analysis was carried out according to ‘intention-to-treat’ principles



Findings The search strategy generated 45 different trials Most studied drugs were ADs (20 studies), DAs and CBZ Data were very heterogeneous, with dropout rates within the studies between 0 and 84% A non-significant trend favoring CBZ was found in terms of dropouts (RR 088; 95% CI 075–103) and results from one trial suggest that fluoxetine patients are less likely to drop out The main efficacy outcome reported in the studies was the presence of cocaine metabolites in the urine No significant results were found, regardless the type of drug or dose used for all relevant outcomes assessed



Conclusions There is no current evidence supporting the clinical use of CBZ, antidepressants, dopamine agonists, disulfiram, mazindol, phenytoin, nimodipine, lithium and NeuRecover-SA in the treatment of cocaine dependence Larger randomized investigation must be considered, while taking into account that these time-consuming efforts should be reserved for medications showing more relevant and promising evidence Given the high dropout rate among the test population, clinicians may wish to consider adding psychotherapeutic supportive measures aimed at keeping patients in treatment programs

Pharmacological treatment of cocaine dependence: a systematic review.

We have previously reported that rats display a circadian pattern of cocaine self-administration if access to drug is limited to 10-min discrete trials that are separated by at least 20 min. In the present study, the pattern of cocaine intake (1.5 mg/kg per injection) was studied in two large groups of animals that were maintained on different 12-h light/dark cycles (3 a.m. to 3 p.m. versus 10 a.m. to 10 p.m.). Regardless of the time of light onset, a circadian pattern of cocaine self-administration was observed. Maximum cocaine intake occurred during the final 6 h of the dark period and was followed by a relative abstinence period during the light phase. This highly predictable pattern of drug taking behavior provided an opportunity to explore the effect of baclofen, a GABAB agonist, on the initiation of self-administration behavior. In two separate studies, acute treatment with baclofen (1.25–5.0 mg/kg) was shown to suppress cocaine intake for at least 4 h. Baclofen had no significant effect on responding for food reinforcement. Previous results have indicated that baclofen appears to reduce specifically the motivation to respond for cocaine. Together, these data suggest that baclofen should be considered as a possible pharmacotherapeutic agent in cocaine addiction.

Baclofen suppression of cocaine self-administration: demonstration using a discrete trials procedure.

List of patient vignettes Acknowledgements Preface 1 Melancholia: a conceptual history 2 Melancholia defined 3 Defining melancholia by psychopathology 4 Defining melancholia: laboratory tests 5 Examination for melancholia 6 The differential diagnosis of melancholia 7 Suicide in melancholia 8 Electroconvulsive therapy for melancholia 9 Achieving effective ECT 10 The validity of the pharmacotherapy literature in melancholia 11 Basic pharmacotherapy for melancholic patients 12 Pharmacotherapy of melancholia: complicating circumstances

Melancholia: The Diagnosis, Pathophysiology and Treatment of Depressive Illness

Twenty-nine cocaine-dependent male veterans without other drug dependence completed a double-blind controlled, randomly-assigned study examining the efficacy of bromocriptine versus placebo in the management of cocaine abstinence symptomatology. Serum prolactin (PL) and growth hormone (GH) levels were obtained prior to and after the study was completed. Patients were seen daily and completed several self-report questionnaires, including the Symptom Checklist-90-Revised, the Beck Depression Inventory, and a Cocaine Craving Report. The patients were also asked to rate a variety of cocaine withdrawal symptoms. Overall, there did not appear to be any advantage to receiving bromocriptine versus placebo during the first 3 weeks following cocaine use cessation with the possible exception of changes in activity and appetite level. The placebo group showed a statistically significant increase in activity level during the first week in treatment and a significant increase in appetite throughout the study. Patients ...

Rebecca Lowery

Papers

Double-blind comparison of bromocriptine and placebo in cocaine withdrawal.