RESEARCH OVERVIEW 2005
Alcohol and Drug Abuse Research Program
Division Directors: Nancy K. Mello, Ph.D.; and Jack H. Mendelson, M.D.
Department Directors: Jack Bergman, Ph.D.; S. Barak Caine, Ph.D.; S. Stevens Negus, Ph.D.; John L. Neumeyer, Ph.D.
Opioid agonists with both kappa and mu activity antagonize some of the abuse-related effects of cocaine in preclinical studies. Translation of these findings into clinical studies has been difficult, because relatively few mixed mu/kappa opioid agonists have been approved for human studies. Nalbuphine is a clinically-approved analgesic that has both mu and kappa opioid activity. The ADARC Clinical Research Program examined the safety of nalbuphine in combination with cocaine. When nalbuphine and cocaine were given to cocaine abusers, this combination was safe and without synergistic effects on heart rate, systolic or diastolic blood pressure. Moreover, cocaine did not increase the subjective effects of nalbuphine in comparison to nalbuphine alone. The effects of chronic treatment with nalbuphine on cocaine abuse and dependence remain to be determined.
There is increasing evidence that the hormonal effects of cocaine may contribute to its abuse-related effects. In early follicular phase females, cocaine induced a significant increase in luteinizing hormone (LH) within 8 minutes, and this stimulated a subsequent increase in estradiol and testosterone within 16 min after cocaine administration. Cocaine also significantly increased LH in males, but there were no significant changes in estradiol and T. These data suggest that the cocaine-induced increase in LH release stimulates the subsequent increase in estradiol release rather than estradiol stimulating LH as occurs at the peri-ovulatory phase of the menstrual cycle. The rapid cocaine-induced increases in estradiol and LH in follicular-phase females could contribute to the disruptions of the menstrual cycle during chronic cocaine administration.
The Medicinal Chemistry Laboratory currently focuses on the design, synthesis and evaluation of mixed kappa/mu opioids potentially useful for the treatment of cocaine abuse and dependence. We have observed that both acute and chronic treatment with mixed kappa/mu opioids reduced cocaine self-administration does-dependently and produced fewer side-effects than kappa-selective agonists. In an effort to further extend the duration and to manipulate selective affinity and efficacy at kappa and mu receptors, we are using innovative approaches to synthesis of mixed kappa/mu opioids such as the synthesis of morphinans with aminothiazole bioisosteric substitution of the phenol moiety in opioids, and the synthesis of bivalent morphinans. Other ongoing studies in this laboratory include the development of novel agents interacting at dopaminergic receptors that are targeted as potential therapeutic agents for such neurological disorders as Parkinson's disease, and developing innovative imaging agents (PET, SPECT, fMRI) for evaluating the ideology and progress of Parkinson's disease in human brains. This laboratory collaborates with scientists in pharmacology, psychiatry, nuclear medicine and clinicians working at McLean and other institutions for the development of useful substances and pharmacological tools.
The recent synthesis of systematically active delta opioid agonists permits exploration of the interactions between delta, mu and kappa opioid receptors. Researchers in the Neurobiology Program of ADARC's Behavioral Science Laboratory discovered that delta agonists increased the pain-relieving effects of several mu agonists (but not kappa agonists) in a preclinical assay of thermal nociception. Moreover, administration of a delta receptor antagonist blocked the enhanced alleviation of pain, and this indicates that these effects were delta receptor mediated. These findings suggest that delta and mu opioid combinations also may produce safer and more effective analgesic medications. Moreover, delta and mu combinations may reduce some undesirable effects of mu opioids such as sedation.
The relative advantages of agonist as opposed to antagonist medications for drug abuse treatment is a topic of continuing debate. There is no effective medication available to treat cocaine abuse, and researchers in ADARC’s Behavioral Science Laboratory recently discovered that the long acting agonist, d-amphetamine, selectively reduced cocaine self-administration with minimal effects on food-maintained responding. Chronic d-amphetamine treatment significantly reduced cocaine self-administration in three different behavioral models, and these preclinical findings are concordant with recent clinical trials of amphetamine treatment.
The contribution of gender and gonadal steroid hormones to the reinforcing properties of cocaine and other abused drugs are poorly understood. Researchers in the Neuroscience Program of ADARC’s Behavioral Science Laboratory have found that sex and gonadal hormone replacement after gonadectomy, did not significantly alter the shape or position of the cocaine self-administration dose-effect curve. The behavioral training history, the reinforcement schedule and the unit dose of cocaine appear to be important determinants of the effects of gender and gonadal hormones on cocaine self-administration.
The development of more sensitive and effective preclinical models to evaluate potential drug abuse treatment medications is an ongoing challenge. Scientists in the Neurobiology Program of ADARC’s Behavioral Science Laboratory have developed a drug vs food choice procedure to evaluate candidate pharmacotherapies. Drug choice increased with increasing drug doses and a drug choice dose effect curve could be determined in a single experimental session.
Cigarette smoking and cocaine abuse are addictive disorders associated with a high rate of morbidity and mortality. Researchers in ADARC’s Clinical Research Program discovered that high dose nicotine cigarette smoking and intravenous cocaine administration both significantly increased luteinizing hormone (LH), a hormone that regulates sexual function. Both drugs immediately increased ratings of "high" and feelings of pleasure, and these subjective and hormonal effects were correlated with rapid increases in plasma levels of nicotine and cocaine. Placebo-cocaine and low dose nicotine cigarettes did not produce significant hormonal or subjective changes. These findings illustrate the similar behavioral and neurobiological effects of cocaine and nicotine and may suggest new approaches to treatment.
Cocaine abusers are vulnerable to infections, including HIV, but the mechanisms by which cocaine compromises the immune system are unclear. Researchers in ADARC’s Clinical Research Program used an innovative model to study cocaine’s effects on the pro-inflammatory cytokine, interleukin 6 (IL-6). The IL-6 response to an inflammatory challenge was significantly reduced in men and women who received a dose of intravenous cocaine in comparison to placebo. These data suggest that cocaine’s suppression of IL-6 may be one factor that increases rates of infection in cocaine abusers. Moreover, cocaine’s stimulation of the hypothalamic-pituitary-adrenal axis may contribute to IL-6 suppression as a consequence of corticosteroid release.
In the search for novel medications to treat cocaine abuse, researchers in ADARC’s Medicinal Chemistry Laboratory have synthesized a novel series of dimeric morphinans with activity at both mu and kappa receptors. Importantly, the receptor affinity of these ligands was sensitive to the character and length of the spacers that connected the pharmacophores. These novel dimeric ligands may provide a basis for improved medications to reduce cocaine abuse. Another series of novel aminothiazole derived morphinans, benzomorphans and morphine, were synthesized. Although their affinities were somewhat lower than their phenolic prototypes, one compound (ATPM), possesses high affinity and selectivity at kappa receptors. This novel compound may be valuable for development of long-acting analgesics as well as for drug abuse treatment medications.
The recent synthesis of systematically active delta opioid agonists permits exploration of the interactions between delta, mu and kappa opioid receptors. Researchers in the Neurobiology Program of ADARC’s Behavioral Science Laborator discovered that delta agonists increased the pain-relieving effects of several mu agonists (but not kappa agonists) in a preclinical assay of thermal nociception. Moreover, administration of a delta receptor antagonist blocked the enhanced alleviation of pain, and this indicates that these effects were delta receptor mediated. These findings suggest that delta and mu opioid combinations also may produce safer and more effective analgesic medications. Moreover, delta and mu combinations may reduce some undesirable effects of mu opioids such as sedation.
Biological Psychiatry Laboratory
Directors: Harrison G. Pope, Jr., M.D. and James I. Hudson, M.D., Sc.D.
Associate Director, Psychopharmacology Research: William P. Carter, M.D.
Associate Director, Substance Abuse Research: Amanda J. Gruber, M.D. and John H. Halpern, M.D.
Associate Director, Child and Adolescent Research: Justine K. Lalonde, M.D.
The Biological Psychiatry Laboratory is one of the departments within the Alcohol and Drug Abuse Research Center. The lab's researcher are continuing a range of studies in the area of substance abuse, including neuroimaging studies, which have shown abnormalities in the brains of heavy marijuana users while they were performing various types of tasks. These abnormalities persist for at least seven days, and in some cases even for 28 days, after individuals have stopped smoking marijuana. The laboratory has also studied young users of MDMA ("ecstasy") using paper-and-pencil neuropsychological tests, and have demonstrated deficits in mental processing speed that appear to persist for weeks or months after the last use of ecstasy. By contrast, in another study, looking at Native Americans who regularly use the hallucinogenic cactus, peyote, as a religious sacrament, the researchers were unable to find neuropsychological deficits related to peyote use. Finally, the researchers have published additional studies of users of anabolic steroids, showing that these individuals often do not trust their physicians, and often do not disclose their anabolic steroid use to any health professional.
In addition, researchers in the Biological Psychiatry Laboratory have completed a large family study assessing whether binge eating disorder runs in families. Binge eating disorder is frequently associated with obesity, and is increasingly recognized as an important public health problem. The data from this study, based on personal interviews of 300 overweight individuals and 888 of their immediate relatives, strongly suggest that binge eating disorder has a genetic component, and further that these genetic factors may contribute to obesity independently of other genetic factors for obesity. The investigators will continue in a long-term follow-up study of individuals with binge eating disorder to evaluate the stability of this condition.