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National Institute on Drug Abuse

Director's Report to the National Advisory Council on Drug Abuse

May, 1997

Research Findings

Intramural Research

Adrenalectomy Modifies Nicotine-Induced Dopamine Release and Locomotor Activity in Rats

Removal of adrenal glands can significantly modify sensitivity to both the behavioral and neurochemical effects of nicotine. The locomotor depressant effects of high doses of nicotine show potentiation and the locomotor activating and dopamine-releasing properties elicited by low doses of nicotine attenuate after adrenalectomy. This suggests that these two effects of nicotine may be mediated via similar neural substrates. In view of the modulatory role of corticosteroids, these hormones warrant further investigation as their manipulation may have therapeutic utility in the treatment of certain tobacco addictions. Shoaib, M., Shippenberg, T.S., Adrenalectomy Attenuates Nicotine-Induced Dopamine Release and Locomotor Activity in Rats. Psychopharmacology. 128, pp. 3443-350, 1996.

The Opiate Peptide DADLE Enhances Recovery of Myocardial Function in Preserved Hearts

To assess the clinical practicality of using DADLE, an opiate peptide, as a potential organ preservation agent, we examined if DADLE might prolong the survival of a single organ. Isolated rabbit hearts were monitored for baseline functions in a Langendorff apparatus before being subjected to 18 hrs of hypothermic global ischemic storage. Standard cardioplegia (CP), currently used in cardiac transplantation, restored myocardial function to only 20-30% of the preischemic values. Preperfusion of the heart with DADLE for 15 min before standard CP treatment produced a 60-80% recovery of myocardial function compared to the preischemic values. DADLE may, thus, be an important, useful agent for myocardial preservation and cardiac transplantation. Bolling, S.F., Su, T-P., Childs, K.F., Ning, X-H., Horton, N., Kilgore, K., and Oeltgen, P.R.. The Use of Hibernation Induction Triggers for Cardiac Transplant Preservation. Transplantation, 63, pp. 326-329, 1997.

Methamphetamine Induces Apoptosis in Immortalized Neural Cells: Protection by the Protoncogene, bcl2

Methamphetamine (METH) is an amphetamine analog that produces degeneration of the dopaminergic systems in mammals. The neurotoxic effects of drug are thought to be mediated by oxygen-based free radicals. In the present report, we have used immortalized neural cells obtained from rat mesencephalon in order to further assess the role of oxidative stress in METH-induced neurotoxicity. These findings may be of relevance to the cause(s) of Parkinson's disease which involves degeneration of the nigrostriatal dopaminergic pathway. Cadet, J.L., Ordonez S.V., and Ordonez J.V. Methamphetamine Induces Apoptosis in Immortalized Neural Cells: Protection by the Protoncogene, bcl2. Synapse, 25, 1997.

Phentermine Pretreatment Antagonizes the Cocaine-induced Rise in Mesolimbic Dopamine

Coadministration of phentermine and fenfluramine has been used to treat cocaine dependence. Patients who relapse while receiving this treatment report diminished subjective effects of cocaine. Due to the importance of mesolimbic dopamine (DA) in mediating cocaine reinforcement, it was hypothesized that phentermine might attenuate the effects of cocaine on DA transmission. Researchers examined this proposal directly using in vivo microdialysis methods in the nucleus accumbens of awake rats. Rats were pretreated with saline or phentermine (1 mg/kg, iv) and then challenged with cocaine (3 mg/kg, iv). Phentermine alone caused a modest increase in DA, and phentermine pretreatment substantially reduced the cocaine-induced rise in extracellular DA. Alternately, phentermine did not alter the stimulatory effect of cocaine on 5-HT. Findings from this research suggest that phentermine may antagonize the subjective effects of cocaine in humans via a DA mechanism. Rothman, R.B., Ayestas, M., and Baumann, M.H. Phentermine Pretreatment Antagonizes the Cocaine-induced Rise in Mesolimbic Dopamine. Neuroreport 9: pp. 7-9, 1997.

Decrease in Cocaine-Maintained Responding in Rhesus Monkeys with 1-[2-[bis-(4-fluorophenyl)methoxy]ethyl]-4-[3-hydroxy-3-phenylpropyl] Piperazinyl Decanoate

The selective DA reuptake inhibitor GBR 12909 previously has been shown to decrease cocaine-maintained responding without affecting similar levels of food-maintained responding in monkeys, an effect analogous to that expected of a medication designed to treat human cocaine abuse without adverse effect. In the current study, investigators extended this type of effect by developing a decanoate ester of a hydroxylated analog of GBR 12909 (compound 5). Within several days of the administration of an active dose of 5, cocaine-maintained responding had decreased more than 80% while food-maintained responding was unaffected. This selective effect on cocaine-maintained responding lasted almost thirty days with a single injection, and was followed by a return to control levels of responding. These results suggest that a similar formulation, if proven safe for human use, should be tested as a potential medication for cocaine abuse. Sustained Decrease in Cocaine-Maintained Responding in Rhesus Monkeys with 1-[2-[bis-(4-fluorophenyl)methoxy] ethyl]-4-[3-hydroxy-3-phenylpropyl] Piperazinyl Decanoate, a Long-Acting Ester Derivative of GBR 12909. Glowa, J.R., W.E. Fantegrossi, D.B. Lewis, D.M. Matecka, K.C. Rice, and R.B. Rothman. J. Med. Chem. 39(24), pp. 4689-4691, 1996.

Phentermine/Fenfluramine Decreases Cocaine Self-Administration in Rhesus Monkeys

Dopamine reuptake inhibitors can decrease cocaine self-administration at doses that do not decrease food-maintained responding. To assess whether similar effects could be obtained with medications currently considered for substance abuse, fenfluramine/phentermine combinations were given to rhesus monkeys responding under multiple fixed-ratio 30 schedules of food- and cocaine-delivery. Phentermine decreased cocaine-maintained responding while having less of an effect on food-maintained responding. Although fenfluramine did not selectively affect cocaine-maintained behavior, combining a low dose of fenfluramine with phentermine slightly enhanced the selectively of effect of phentermine on these behaviors. These results provide further data supporting the possible efficacy of phentermine/fenfluramine as a pharmacological treatment for cocaine addiction. Phentermine/Fenfluramine Decreases Cocaine Self-Administration in Rhesus Monkeys. Glowa, J.R., K.C. Rice, D. Matecka, and R.B. Rothman. NeuroReport, In press.

Effect of Dopamine Receptor Antagonists on Cocaine Subjective Effects

Schizophrenic patients on neuroleptic medications abuse cocaine and report cocaine-induced euphoria. This study was undertaken to provide better clinical characterization of these phenomena by administering the POMS and a custom designed questionnaire. A group of heavy cocaine users who were not mentally ill served as the control group. The results clearly suggest that schizophrenic patients report cocaine-induced euphoria and post-use craving despite being treated with therapeutic doses of haloperidol or fluphenazine. The responses of the control group were similar to that of the schizophrenic group except that the latter subjects reported a greater degree of anxiety. These results suggest that blockade of D2 receptors is not sufficient to block cocaine-induced subjective effects in humans. Effect of Dopamine Receptor Antagonists on Cocaine Subjective Effects: A Naturalistic Case Study. Ohuoha, D.C., J.A. Maxwell, L.E. Thomson, J.L. Cadet, and R.B. Rothman. J. Subst. Abuse Treat., In press.

Opioid Peptide Receptor Studies

Mutational analysis of opioid receptors indicates that dissimilar receptor domains contribute to the binding affinity and pharmacological effects of different ligands. The availability of four stereoisomers of (±)-cis-N-[1-(2-hydroxy-2-phenylethyl) 3-methyl-4-piperidyl]-N- phenylpropanamide (RTI-4614-4) allowed us to determine if enantiomeric ligands can distinguish among the four parameters of the ligand-receptor interaction: potency (ED50), efficacy (maximal stimulation), intrinsic efficacy (effect as a function of receptor occupation) and binding affinity, since the use of ligand stereoisomers focuses the analysis on asymmetric structural factors while avoiding confounding changes in physiochemical characteristics. The data, obtained with cloned rat receptors, demonstrate that the four isomers of RTI-4614-4 differ in binding affinity, potency, efficacy and intrinsic efficacy. We speculate that this results from binding to different domains of the opioid receptor. Opioid Peptide Receptor Studies. 6. The 3-methylfentanyl Congeners RTI-4614-4 and its Enantiomers Differ in Efficacy, Potency and Intrinsic Efficacy as Measured by Stimulation of [35S]GTP-g-S Binding by Cloned Mu Opioid Receptors. Xu, H., Y.F. Lu, J.S. Partilla, G.A. Brine, F.I. Carroll, K.C. Rice, J. Lai, F. Porrca, and R.B. Rothman. Analgesia, In press.

Doses of GBR12909 Which Suppress Cocaine Self-Administration in Nonhuman Primates Substantially Occupy Dopamine Transporters

GBR12909 (GBR) is a high affinity, selective and long-acting inhibitor of DA uptake which has been proposed as a potential treatment agent. GBR produces a persistent and noncompetitive blockade of DA transporters and substantially reduces cocaine-induced increases in extracellular DA. Slow iv infusion of GBR to Rhesus monkeys selectively reduced (1 mg/kg) and eliminated (3 mg/kg) cocaine self-administration. This study tested the hypothesis that doses of GBR which reduce cocaine self-administration in nonhuman primates produce significant occupation of DA transporters. DA transporters were quantitated in two baboons using [11C]WIN35,428 and PET. The baboons underwent four PET scans (performed on two separate study days, 3-4 weeks apart). Blood pressure, temperature, heart rate and oxygen saturation were monitored throughout each study. On the first scan of the first study day the baboon received saline (3 ml/kg) 90 min before the injection of the radiotracer. GBR (1 mg/kg i.v.) was infused 90 min before the second [11C]WIN 35,428 study. The second study (3-4 weeks from the first study day) was conducted identically to the first study, except that the dose of GBR was 3 mg/kg. Doses of 1 (n=1) and 3 mg/kg (n=2) produced % reductions of binding potential of 18 and 53%, respectively. GBR was well tolerated in all baboons. One baboon showed transient bradycardia (that lasted less than 5 min) immediately after the injection of 1 mg of GBR. No changes in blood pressure or oxygen saturation were observed in any of the baboons. These results demonstrate that doses of GBR which suppress cocaine self-administration in nonhuman primates also produce high occupancy of the DA transporter. Viewed collectively with other work, these data strongly suggest that occupancy for the DA transporter by GBR explains its ability to attenuate cocaine-induced increases in extracellular DA and to suppress cocaine self-administration. Moreover, these data suggest that clinical trials (planned) of orally administered GBR should use doses which produce at least 50% occupancy of the DA transporter. Doses of GBR12909 Which Suppress Cocaine Self-Administration in Nonhuman Primates Substantially Occupy Dopamine Transporters. Villemagne, V., Wong, D.F., Yokoi, F., Rice, K.C., Matecka, D. and Rothman, R.B.

An Open-Label Study of a Functional Opioid Kappa Antagonist in the Treatment of Opioid Dependence

Several lines of evidence, including the well-established observation that kappa opiate agonists produce dysphoria and psychotomimetic effects in humans, suggest that dysfunction of the endogenous kappa opioid system may contribute to opioid and cocaine addiction. The objective of this open-label study was to determine the effectiveness of a functional kappa antagonist as a treatment for opioid dependence. Fifteen treatment-seeking heroin dependent (DSM-IV) men (41±7 yrs old; 19±8 years heroin use) who were eligible for methadone maintenance but did not want it enrolled in the study. After inpatient detoxification at the VA and a naloxone-challenge test to verify that they were not physically dependent on opioids, subjects received naltrexone (50 mg po per day) to block mu opioid receptors. On the fourth day patients received liquid buprenorphine (4 mg sl), a partial mu agonist and a kappa antagonist, in addition to naltrexone. All patients received medication at the clinic six days per week and a full program of psychosocial treatment. Outcome variables included pupillary diameter, urine toxicology, self-reported drug use, the SCL-90, ASI and the Beck Depression Inventory. Five patients (33%) completed the three-month study. Four were abstinent from opioids and cocaine for the entire study, and one was abstinent from opioids and cocaine for the last nine weeks. Six subjects dropped out due to either minor side effects or disliking the sensation of sublingual buprenorphine. Initial analysis of the data shows no changes in pupillary diameter. The positive response to treatment exceeds that ordinarily expected from naltrexone alone (90% drop-out). These promising results suggest that controlled studies of this medication combination should be conducted. An Open-Label Study of a Functional Opioid Kappa Antagonist in the Treatment of Opioid Dependence. Rothman, R.B., Gorelick, D.A., Eichmiller, P.R., Hill, B.H., Norbeck, J., and Liberto, J.G.

Anatomical Distribution of a Novel Kappa2 Opioid Receptor in Guinea Pig Brain

Visualized with [125I]IOXY. Previous studies demonstrated unique opioid receptor distributions in guinea pig brain sections at the level of the caudate putamen. Mu, delta, and kappa1 receptors were depleted by the irreversible ligands BIT, FIT, and UPHIT, and opioid receptors were labeled with the opioid antagonist [125I]IOXY and subjected to autoradiographic analysis. The objective of this study was to characterize further these unique binding sites (designated kappa2). Kappa2 binding was quantitated by autoradiography in specific regions of four different levels of guinea pig brain (olfactory bulb, caudate putamen, hippocampus, and substantia nigra) for a total of 37 determinations across all levels. The kappa2 distribution was then compared with the binding sites labeled by [125I]DAMGO (mu), [125I]deltorphin II (delta), and [125I]IOXY under kappa1 conditions to identical regions in adjacent guinea pig brain sections. The results are: (1) kappa2 binding greatly exceeded mu and delta binding in all regions; (2) kappa2 binding exceeded kappa1 binding in all regions except the deep cortex at the level of the hippocampus; (3) the kappa2 distribution was different than that of mu, delta or kappa1 receptors. These results provide further evidence for the existence of a novel opioid binding site in guinea pig brain. Anatomical Distribution of a Novel Kappa2 Opioid Receptor in Guinea Pig Brain Visualized with [125I]IOXY. Partilla, J.S., Ni, Q., Rice, K.C., Matecka, D., and Rothman, R.B.

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