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National Institute on Drug Abuse

Director's Report to the National Advisory Council on Drug Abuse
September, 1996

Research Findings

Intramural Research

Functional Neuroimaging Techniques Provide a Useful Tool in the Evaluation of Remission Due to Peptide T AIDS Dementia Complex

AIDS Dementia Complex (ADC) is the most common presenting neurologic manifestation of human immunodeficiency virus (HIV)-1 infection. A PET study monitored the progress of ADC in a man who completed a 12-week treatment protocol with intranasal peptide T, an octapeptide that blocks the binding of gp120, the HIV envelop protein, to the cell surface antigen CD4. Data from this patient were compared with those from a control group. From the PET images, 34 of 35 brain regions with abnormally high metabolic rates, located in the temporal and parietal lobes, showed remission after peptide T treatment. These preliminary observations suggest that functional neuroimaging is a useful tool in evaluating the response to treatment in ADC patients. Villemagne, V.L., Phillips, R.F.L., Liu, X., Gilson, S.F., Dannals, R.F., Wong, D.F., Harris, P.F., Ruff, M., Pert, C., Bridge, P. and London, E.D. Peptide T and Glucose Metabolism in AIDS Dementia Complex. J. Nucl. Med. 37: pp. 1177-1180, 1996.

Role of Extracellular Dopamine in the Initiation and Long-term Expression of Behavioral Sensitization to Cocaine

Repeated intermittent administration of cocaine sensitizes animals to the locomotor-activating effects of this agent. The neurobiochemical basis of sensitization was characterized by measuring extracellular dopamine levels in the nucleus accumbens in rats after the cessation of repeated cocaine administration. Basal dopamine levels were elevated initially following the cessation of cocaine pretreatment and declined to reach control levels by Day 22. In contrast, the dopaminergic response to cocaine was blunted initially and increased thereafter. The behavioral response to cocaine was enhanced by cocaine pretreatment and followed a different temporal pattern than did dopaminergic activity following the cessation of repeated cocaine treatment. These data suggest that behavioral sensitization is mediated by different neurobiochemical events at different times following the cessation of cocaine pretreatment. Heidbreder, C.H., Thompson, A.C., and Shippenberg, T.C. Role of Extracellular Dopamine in the Initiation and Long-Term Expression of Behavioral Sensitization to Cocaine. J. Pharmacol. Exp. Ther. 278: pp. 490-502, 1996.

A Method for Imaging Nicotinic Acetylcholinergic Receptors in the Brain Using Radiolabeled Pyridyl-7-Azabicyclo [2.2.1] Heptanes

Although nicotinic acetylcholine receptors are major excitatory neurotransmitter receptors in brain, studies of these receptors, by noninvasive external imaging, have been limited due to a need for an appropriate radiotracer. NIDA investigators have used epibatidine, an extract from frog skin, as the basis for design of radiotracers for noninvasive imaging of nAChRs using positron emission tomography and single assessments of nAChRs as a function of chronic drug administration and withdrawal, and may prove useful in diagnosis of neurodegenerative diseases. London, E.D. Kimes, A.S., Horti, A. Dannals, R.F., and Kassiou, M. A Method for Imaging Nicotinic Acetylcholinergic Receptors in the Brain Using Radiolabeled pyridyl-7- azabicyclo [2.2.1] heptanes. US Patent application Serial No. 08/642,636. Filed, May 3, 1996.

Drug Abuse Might be Better Approached as a Disorder of the Brain. In humans, chronic cocaine abuse is associated with CNS changes, including cerebrovascular events, EEG abnormalities, vasculitis, seizures, and decrements in neurobehavioral performance. The acute administration of cocaine is associated with psychotic episodes and paranoid states while withdrawal from the drug is often associated with depressed mood. The mechanistic basis of these behavioral states is not known. Given the structural and functional changes associated with cocaine use, we propose that the chronic heavy use of cocaine may result in a neuropsychiatric syndrome associated with neuropsychological changes that are not obvious during routine clinical evaluation. This syndrome might have deleterious effects on therapeutic interventions in drug abusers. A neurobehavioral approach, comprised of a thorough neurological and psychiatric examination, neuropsychological testing, and imaging studies, would provide a rational basis for cognitive and/or pharmacological therapies. Cadet, J.L., and Bolla, K.I. Chronic Cocaine Use as a Neuropsychiatric Syndrome: A Model for Debate. Synapse 22: pp. 28-34, 1996.

The Neurotoxic Effects of Stimulants Involves the Production of Free Radicals

Methamphetamine (METH) has long-lasting neurotoxic effects on the nigrastriatal dopamine (DA) system of rodents. METH-induced neurotoxicity is thought to involve release of DA in presynaptic DA terminals, which is associated with increased formation of oxygen-based free radicals. We have recently shown that METH-induced striatal DA depletion is attenuated in transgenic (Tg) mice that express the human CuZn-superoxide dismutase (SOD) enzyme. DIR investigators used receptor autoradiographic studies of DA uptake sites to evaluate the effects of several doses of METH on striatal DA terminals of Non-Tg as well as of heterozygous and homozygous SOD-Tg mice. In Non-Tg mice, METH decreased striatal DA uptake sites in a dose-dependent fashion. The loss of DA terminals caused by METH was attenuated in a gene dosage-dependent fashion, with the homozygous mice showing the greatest protection. Female mice were somewhat more resistant than male mice against these deleterious effects of METH. These results provide further evidence for a role of superoxide radicals in the long-term effects of METH. They also suggest the notion of a gender-specific handling of oxidative stress. Hiroshi, H., Ladenheim, B., Carlson, E., Epstein, C., and Cadet, J.L. Autoradiographic Evidence for Methamphetamine-Induced Striatal Dopaminergic Loss in Mouse Brain: Attenuation in CuZn-Superoxide Dismutase Transgenic Mice. Brain Research 714: pp. 95-103, 1996.

GBR12909 Decanoate Derivative Produced a Long-Acting Decrease in Cocaine- Maintained Responding in Rhesus Monkeys

The selective DA reuptake inhibitor GBR 12909 has been shown to decrease cocaine-maintained behavior without affecting similar levels of food-maintained behavior in monkeys, an effect analogous to that expected of a medication designed to treat human cocaine abuse. In the current study, we extended this effect by developing a decanoate ester of a hydroxylated analog of GBR 12909 (5, DBL 583). Within several days of administration, active doses of 5 had decreased cocaine-maintained responding more than 80%, without affecting control (food-maintained) responding. The effect lasted almost thirty days after a single injection, and was followed by a return of responding to control levels. These results suggest that a similar formulation, if proven safe for human use, should be tested as a potential medication for cocaine abuse. Glowa, J. R., Fantegrossi, W.E., Lewis, D.B., Matecka, D.M., Rice, K.C., and Rothman, R.B.

Serotonin-4 Receptor Antagonists Reverse Cocaine-Induced Cardiac Arrhythmia

The effect of 5-HT antagonists GR113808A and GR125487D were examined in cocaine induced cardiac arrhythmia in the rat. Pre-and post i.v treatment with the 5-HT4 receptor antagonists GR113808A and GR125487D reversed cocaine induced arrhythmia without altering cardiovascular function. The results of this study indicate that 5-HT4 antagonist can reverse cocaine-induced arrhythmias. The clinical implication of this study is clear: 5-HT4 antagonists may be useful in the treatment of acute cocaine induced cardiotoxicity, and may also be useful in reversing cocaine's CNS effects. Further study is needed to understand the exact mechanism of this phenomena. Ohuoha, D.C., Schindler, C.W., and Rothman, R.B.

Effect of Dopamine Receptor Antagonists on Cocaine Subjective Effects: A Naturalistic Case Study

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. Ohuoha, D.C., Maxwell, J.A., Thomson, L.E., Cadet, J.L., and Rothman, R.B.

Cocaine Cross-Sensitization to Dopamine Uptake Inhibitors: Unique Effects of GBR12909

Repeated administration of cocaine will cross-sensitize the locomotor response to a variety of psychomotor stimulants. The ability of cocaine to cross-sensitize the locomotor effects of other psychomotor stimulants provides information relevant to the pharmacological mechanisms underlying the sensitization process. The purpose of the current experiment was to investigate the ability of cocaine to cross-sensitize the locomotor effects of several dopamine uptake blockers with unique pharmacological profiles. Cocaine (40 mg/kg, IP) or saline was administered prior to a locomotor session on day one. On day 2, a full dose-effect curve was established for the locomotor effects of cocaine, RTI-55, mazindol, and GBR12909. Previous exposure to cocaine significantly affected locomotor activity and stereotopy-like behavior produced by cocaine, mazindol, RTI-55, and GBR12909. However, GBR12909 was unique in that the maximal stimulant effect and slope of the dose-effect curve was significantly depressed and the stereotopy-like behavior was unchanged. Thus, despite the similarity of these compounds in their ability to inhibit dopamine uptake, cocaine-induced sensitization did not generalize to GBR12909. This study further demonstrates the unique pharmacology of GBR12909 and supports the further study of this compound as a potential treatment medication for cocaine abuse. Elmer, G.I., Brockington, A., Gorelick, D.A., Carroll, F.I., Rice, K.C., Matecka, D., Goldberg, S.R., and Rothman, R.B.

Evidence for Alterations in Presynaptic Serotonergic Function During Withdrawal from Chronic Cocaine in Rats

The effects of repeated cocaine administration on serotonin (5-hydroxytryptamine, 5-HT) function were investigated by comparing the corticosterone response to 5-HT receptor agonists in cocaine-treated and vehicle-treated rats. Male rats were fitted with indwelling jugular catheters and received cocaine (15 mg/kg i.p., b.i.d.) or saline for 7 days. Rats were challenged with either saline, the 5-HT releaser fenfluramine (1.2 mg/kg i.v.). the 5-HT1a receptor agonist 8-OH-DPAT (50 mg/kg i.v.). or the 5-HT1c receptor agonist DOI (100 mg/kg i.v.) 42 h and 8 days after the final chronic treatment. Repeated blood samples were withdrawn immediately before and at 15, 30 and 60 min after acute challenge injections. All 5-HT receptor agonists increased plasma corticosterone, but the fenfluramine-induced increase in corticosterone was significantly attenuated in cocaine-treated rats withdrawn for 42 h. This blunted response to fenfluramine exhibited only partial recovery when examined at 8 days post-chronic treatment. Corticosterone responses to 8-OH-DPAT and DOI were not affected by cocaine exposure. Our data suggest that chronic cocaine produces deficits in presynaptic 5-HT function and alterations in 5-HT neurotransmission which may underlie the dysphoria experienced by abstinent cocaine users. Neuroendocrine challenge tests should be performed in human addicts to evaluate potential 5-HT dysfunction associated with cocaine abuse. Baumann, M.H., Becketts, K.M., and Rothman, R.B.

Effects of Intravenous Cocaine on Plasma Cortisol and Prolactin in Human Cocaine Abusers

The aim of the present work was to examine the cortisol and prolactin responses to acute cocaine administration in human cocaine users. Each subject served as its own control during intravenous saline placebo and cocaine (40 mg) infusion sessions. Cocaine significantly elevated plasma cortisol but did not affect prolactin. The rise in cortisol coincided with an increase in heart rate and blood pressure after cocaine. In agreement with studies in animals our data suggest that cocaine activates the hypothalamic-pituitary-adrenal axis in humans. However, based on the well-known importance of dopamine as a prolactin-inhibiting factor the failure of cocaine to suppress prolactin in the present study raises questions concerning the role of dopamine in the mechanism of acute cocaine action in humans. Baumann, M.H., Gendron, T.M., Becketts, K.M., Henningfield, J.E., Gorelick, D.A., and Rothman, R.B.

Development of Novel, Potent and Selective Dopamine Reuptake dors through Alteration of the Piperazine Ring of GBR 12935 and GBR 12909.

The design, synthesis and biological evaluation of compounds related to the dopamine (DA) uptake inhibitors GBR 12395 (1) and GBR 12909 (2), directed towards the development and identification of new ligands interacting with high potency and selectivity at the dopamine transporter (DAT) is reported. The substitution of the piperazine ring in the GBR structure with other diamine moieties resulted in the retention of the high affinity of new ligands for the DAT. Some of the modified GBR analogs (e.g. 8, 10, (-)-49 or (-)-50) displayed substantially higher selectivity (4732-to 694-fold) for the DA versus the serotonin (5-HT) reuptake site than the parent compounds. The bis(p-fluoro) substitution in the diphenylmethoxyethyl fragment slightly increased the affinity of the ligands at the DA reuptake site but reduced their selectivity at this site (e.g. 9 and 8, 11 and 10 or 17 and 16, respectively). Congeners, such as the series of mono-and symmetrically disubstituted piperazine and trans-2,5-dimethylpiperazine, which lack the diphenylmethoxyethyl substituent ("left" fragment of GBR molecule), lost the affinity for the DAT, yet exhibited very high potency for binding to the sigma receptors (e.g. 28). The chiral pyrrolidine derivatives of GBR 12935, (-)-49 and (+)-49, exhibited an enantioselectivity ratio of 181 and 146 for the inhibition of DA reuptake and binding to the DAT, respectively. Matecka, D., Rothman, R.B., Radesca, L., de Costa, B.R., Dersch, C.M., Partilla, J.S., Pert, A., Glowa, J.R., Wojnicki, F.H.E., and Rice, K.C.

A Continuum Model of Central Dopamine-Serotonin Interactions: Studies with Amphetamine

Dopamine (DA) neuronal activity is modulated by serotonin (5-HT) in a complex manner. In the present work, investigators examined the relationship between DA and 5-HT function by testing a series of amphetamine analogs in neurochemical and behavioral assays. In vivo microdialysis was performed in the nucleus accumbens of awake rats. Phentermine, chlorphentermine, fenfluramine, or a mixture of phentermine plus fenfluramine (PHEN/FEN), was administered locally through the probe and by ip injection. Phentermine preferentially elevated extracellular DA whereas fenfluramine elevated 5-HT. Chlorphentermine and PHEN/FEN produced concurrent increases in DA and 5-HT. These agents were tested for their ability to release preloaded [3H]DA and [3H]5-HT from rat brain synaptosomes; the relative potencies and DA/5-HT selectivity ratios determined in vitro were similar to in vivo findings. Phentermine produced robust locomotor activation in mice, but fenfluramine and chlorphentermine did not. Interestingly, coadministration of fenfluramine antagonized the stimulant effects of phentermine. Our data support historical literature that suggests DA and 5-HT neuronal systems can be viewed as opposing forces along a continuum, with the net behavioral state being defined by the sum total of these forces. Shifting the balance in favor of DA is expressed as behavioral activation whereas shifting the balance in favor of 5-HT results in behavioral inhibition. Baumann, M.H., Ayestas, M.A., Dersch, C.M., and Rothman, R.B.

Characterization of a Novel Cocaine Binding Site Identified with [125I]RTI-55 in Membranes Prepared from Human, Monkey and Guinea Pig Caudate

[125I]RTI-55 is a cocaine analog with high affinity for dopamine (DA) and serotonin (5-HT) transporters. Quantitative ligand binding studies revealed a novel high affinity [125I]RTI-55 binding site assayed under 5-HT transporter (SERT) conditions which has low affinity for almost all classic biogenic amine transporter ligands, including high affinity 5-HT transporter inhibitors such as paroxetine, but which retains high affinity for cocaine analogs. This site, termed SERTsite2 for its detection under 5-HT transporter conditions (not for an association with the SERT) occurs in monkey caudate, human caudate and guinea pig caudate membranes, but not in rat caudate membranes. SERTsite2 is distinguished from the DA transporter (DAT) and SERT by several criteria, including a distinct ligand-selectivity profile, the inability to detect SERTsite2 in cells stably expressing the cloned human DAT, insensitivity to irreversible ligands which inhibit [125I]RTI-55 binding to the DAT and SERT, and an anatomical distribution distinct from the SERT. Perhaps the most striking finding about SERTsite2 is that a wide range of representative antidepressant agents have very low affinity for SERTsite2. The affinity of cocaine for this site is not very different from the concentration cocaine achieves in the brain at pharmacological doses. Viewed collectively with the observation that ligands with high affinity for SERTsite2 are mostly cocaine analogs, these data lead us to speculate that actions of cocaine which differ from those of classic biogenic amine uptake inhibitors may be mediated in part via SERTsite2. Rothman, R.B., Silverthorn, M.L., Glowa, J.R., Matecka, D., Rice, K.C., Carroll, F.I., Partilla, J.S., Uhl, G.R., Vandenbergh, D.J., and Dersch, C.M.

Changes in Cocaine Metabolism Alter the Acute Behavioral Effects of Cocaine

Scientists in the Pharmacotherapy Section, Treatment Branch, in collaboration with colleagues in the Behavioral Pharmacology & Genetics Section, Preclinical Pharmacology Laboratory, and the National Institute on Aging Gerontology Research Center, recently completed a study showing that changes in cocaine metabolism could significantly alter the acute behavioral effects of cocaine. Rats were injected IV with a cocaine dose that substantially increased their motor activity over a 2-hour period. Separate groups of rats were pretreated with either butyrylcholinesterase (BChE), a major cocaine-metabolizing enzyme, or cymserine, a specific inhibitor of BChE. Rats pretreated with BChE had significantly less of an increase in motor activity than those pretreated with saline, while those pretreated with cymserine had more of an increase. These findings suggest that speeding up cocaine metabolism can reduce acute behavioral effects of cocaine, and could have potential therapeutic benefits. Gorelick, D.A., and Schindler, C.W.

Distinctive Pharmacological Mechanisms of Cocaine Tolerance and Sensitization

Sari Izenwasser of the DIR's Psychobiology Section has found evidence that tolerance and sensitization to cocaine are mediated by distinctive pharmacological mechanisms. When cocaine is injected on a daily basis, sensitization occurs, whereas continuously infused cocaine leads to tolerance in laboratory animals. Rats treated with cocaine pumps showed large increases in locomotor activity, compared to saline controls, after the pumps were implanted and partial tolerance to this effect developed over the course of five days. Activity levels dropped to saline levels shortly after the pumps were removed. Rats receiving a challenge injection of cocaine showed significant elevations in locomotor activity which were greater in rats that were not exposed to cocaine. The cocaine dose-effect curve was shifted to the right compared to saline controls in these subjects. When the rats were injected again on the next day their activity levels were increased even further showing sensitization. Despite this sensitization the cocaine-exposed rats were still tolerant compared to the saline controls. These findings indicate that tolerance and sensitization can exist simultaneously, implying a mediation by distinctive neuronal mechanisms.

Central Role of mu Receptor in Morphine Effects

At the International Narcotics Research Committee (INRC) Dr. George Uhl of the NIDA-IRP presented data on "knockout" transgenic mice deficient in the morphine-preferring mu opiate receptor. These mice, developed and tested in his laboratory by Drs. Sora and Miner, display increased sensitivity to painful stimuli without morphine. They also show no morphine analgesia. These results provide, for the first time, dramatic demonstration of the central role that the mu receptor, whose cDNA and gene was cloned by Dr. Uhl's laboratory (as well as others) in 1993 plays in morphine effects and even on day-to-day nociception.

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