NIDA - Director's Report - February 2003 Home > Publications > Director's Reports Director's Report to the National Advisory Council on Drug Abuse - February, 2003 Index Report Index Research Findings Report for September, 2002 Basic Research Report for May, Behavioral Research 2002 Treatment Research and Development Report for February, Research on AIDS and Other Medical Consequences of Drug 2002 Abuse - AIDS Research Report for Research on AIDS and Other Medical Consequences of Drug September, 2001 Abuse - Non-AIDS Medical Consequences of Drug Abuse Report for May, Epidemiology and Etiology Research 2001 Prevention Research Report for February, 2001 Services Research Report for Intramural Research September, 2000 Program Activities Report for May, 2000 Extramural Policy and Review Activities Report for February, 2000 Congressional Affairs Report for September, 1999 International Activities Report for May, 1999 Meetings and Conferences Report for February, 1999 Media and Education Activities Report for September, 1998 Planned Meetings Report for May, 1998 Publications Report for February, 1998 Staff Highlights Report for September, 1997 Grantee Honors Report for May, 1997 Report for February, 1997 Report from September, 1996 Report from May, 1996 Report from February, 1996 Report from September, 1995 https://archives.drugabuse.gov/DirReports/DirRep203/Default.html[11/17/16, 10:09:34 PM] NIDA - Director's Report - February 2003 Report from May, 1995 Report from February, 1995 NACDA Legislation Archive Home | Accessibility | Privacy | FOIA (NIH) | Current NIDA Home Page The National Institute on Drug Abuse (NIDA) is part of the National Institutes of Health (NIH) , a component of the U.S. Department of Health and Human Services. Questions? _ See our Contact Information. https://archives.drugabuse.gov/DirReports/DirRep203/Default.html[11/17/16, 10:09:34 PM] NIDA - Director's Report - February 2003 Home > Publications > Director's Reports Director's Report to the National Advisory Council on Drug Abuse - February, 2003 Research Findings - Basic Research Index Working Memory and the Endocannabinoid System Research Findings The endocannabinoid system has recently been proposed to modulate a variety of Basic Research physiological processes, including those that underlie cognition. In the past year, Behavioral Research NIDA researchers conducted studies to further elucidate the function of this system in Treatment Research learning and memory using mice lacking the endocannabinoid receptor (CB1). and Development Findings from these studies showed that mice lacking the CB1 receptor exhibited significant deficits in a reversal task. Moreover, the deficit persisted despite being Research on AIDS repeatedly shown the new task solution. These investigators also report that and Other Medical administration of three different cannabinoid agonists, delta-9-THC, WIN 55,212-2 Consequences of and methanandamide disrupted performance in wild-type mice. Furthermore, these Drug Abuse - AIDS cannabinoid-agonist disruptive effects found in wild-type mice were blocked by the Research cannabinoid antagonist SR 141716A. These findings provide strong evidence that Research on AIDS cannabinoids disrupt working memory through a CB1 receptor mechanism of action and Other Medical and suggest that the endocannabinoid system may have a role in facilitating Consequences of extinction and/or forgetting processes. Varvel, S.A. and Lichtman, A.H. Evaluation of Drug Abuse - Non- CB1 Receptors Knockout Mice in Morris Water Maze. Journal of Pharmacology and AIDS Medical Experimental Therapeutics, 301(3), pp. 915-924, 2002. Consequences of Drug Abuse Structural Adaptations in a Membrane Enzyme that Terminates Endocannabinoid Signaling Epidemiology and Etiology Research Endocannabinoids are naturally occurring compounds that bind to receptors in the Prevention Research brain and in peripheral tissues that are also the target of delta-9- tetrahydrocannabinol (THC), the active ingredient in marijuana. Researchers have Services Research been studying the brain's endocannabinoid system to learn more about its function. Intramural Research So far, endocannabinoids have been shown to modulate pain, cognition, feeding, and locomotor activity. In an article in the November 29, 2002, issue of Science, NIDA Program Activities grantee, Dr. Benjamin Cravatt and his colleagues describe the crystal structure of an enzyme (FAAH) that terminates the activity of endocannabinoids. The structure of Extramural Policy and Review FAAH complexed with an arachidonyl inhibitor reveals how a set of discrete structural Activities alterations allows this enzyme, in contrast to soluble hydrolases of the same family, to integrate into cell membranes and establish direct access to the bilayer from its Congressional Affairs active site. The intimate relationship between the active site of FAAH and cell membranes revealed by the enzyme's structure raises the possibility that fatty acid International Activities amides need not be transported through aqueous cellular compartments in order to proceed from site of action to site of degradation. As a consequence, proper Meetings and Conferences endocannabinoid tone may rely on both the expression levels of FAAH and its localization relative to CB receptor systems in vivo. This knowledge should facilitate Media and Education Activities the design of novel targeted compounds that could be used to alter the activity of endocannabinoids, with the potential for use in treating pain, a variety of related Planned Meetings nervous system disorders, and possibly marijuana addiction. Bracey, M.H., Hanson, M.A., Masuda, K.R., Stevens, R.C., and Cravatt, B.F. Structural Adaptations in a Publications Membrane Enzyme that Terminates Endocannabinoid Signaling. Science, 298, pp. 1793-1796, 2002. Staff Highlights Bupropion and Nicotine-Like Discriminative Stimulus Grantee Honors Bupropion, an antidepressant approved in 1997 for smoking cessation, shares discriminative stimulus effects with cocaine and methamphetamine. The discriminative stimulus effects of these drugs, in turn, overlap with those of nicotine. Studies conducted by NIDA-supported researchers investigated the overlap in discriminative stimulus effects of bupropion and nicotine in a rodent model. These https://archives.drugabuse.gov/DirReports/DirRep203/DirectorReport1.html[11/17/16, 10:09:39 PM] NIDA - Director's Report - February 2003 investigators found that bupropion substituted for nicotine. That is, the effects of bupropion were similar to nicotine using this procedure. However, bupropion effects were not blocked by a nicotine antagonist, mecamylamine, suggesting that bupropion may be producing its nicotine-like discriminative stimulus effects through neurobiological mechanisms different from nicotine itself. Given bupropion's shared pharmacology with dopamine transporter inhibitors and nicotine's effects on dopamine, these effects may be produced in part through bupropion's actions on dopaminergic neurotransmission. Wiley, J.E., LaVechia, K.L., Martin, B.R. and Damaj, M.I. Nicotine-like Discriminative Stimulus Effects of Bupropion in Rats. Experimental and Clinical Pharmacology, 10(2), pp. 129-135, 2002. Opiate-Induced Analgesia and Role of Steroids In a recent paper, Dr. Theodore Cicero and his associates at Washington University School of Medicine, St. Louis, determined the role of either the organizational or activational sex steroids in mediating gender differences observed in morphine- induced antinociception in the rat. To examine the organizational aspects, male pups were castrated early in life at postnatal days 1 and 2; females were masculinized by large doses of testosterone early in life on postnatal days 1 and 2. Older adult male and female rats were also castrated over a period of 2 months to examine the role of the acute activational effects of the opiates in the already sexually differentiated adult rat brain. The results showed that the gender differences in opiate analgesia were still evident in castrated older adult male and female rats. On the other hand, in male rats castrated early in life at postnatal days 1 and 2, the sensitivity to morphine analgesic effects was similar to females and, in fact, was almost identical to that observed in untreated females. Conversely, in female rats, masculinized by large doses of testosterone early in prenatal life, the morphine dose-response curve shifted to the left, yielding a dose-response curve similar to the dose-effect function seen in normal males. These results suggest that the sex differences that have been observed in morphine induced analgesia are due to the organizational effects of sex steroids in the early development of the rat brain, rather than to their acute activational effects occurring later in adulthood. These findings could be important in determining further gender differences and drug abuse liability. Cicero, T.J., Nock, B., O'Connor, L., and Meyer, E.R. Role of Steroids in Sex Differences in Morphine-induced Analgesia: Activational and Organizational Effects. Journal of Pharmacology and Experimental Therapeutics, 300, pp. 695-701, 2002. Neuronal Nicotinic Receptor Ligands There is interest in developing new nicotinic ligands in addition to those currently available, in part because of the diversity of nicotinic receptors in the brain. Nicotine receptors comprise various combinations of alpha and beta peptides, suggesting that ligands selective for these subtypes might have differing pharmacology. Additionally,