National Institute on Drug Abuse
Director's Report to the National Advisory Council on Drug Abuse
May, 1998
Research Findings
Intramural Research
Cellular Neurobiology Branch
Cellular Neurophysiology Section
Contributions of Neurons in the Nucleus Accumbens and the Amygdala to Drug Self- Administration
Work in the Cellular Neurophysiology Section has included continued study of the contribution of neurons in the nucleus accumbens and the amygdala to drug self-administration. These studies are conducted by recording from large groups of individual neurons of the rat brain during self-administration of addictive drugs. In association with co-workers at the Wake Forest University School of Medicine, we have found distinct groups of accumbens neurons code for different drug (cocaine, heroin, and alcohol) and non-drug (sweetened water) rewards. Woodward, Janak, and Chang, ACER, 22, pp. 3-22, 1998; Chang, Janak, and Woodward, J.Neurosci., 18, pp. 3098-3115, 1998.
Cellular Neurobiology Branch
Molecular Neuropsychiatry Section
Free Radicals and the Pathobiology of Brain Dopamine Systems
Oxygen is an essential element for normal life. However, reactive oxygen species (ROS) can also participate in deleterious reactions that can affect lipid, protein, and nucleic acid. Normal physiological function thus depends on a balance between these ROS and the scavenging systems that aerobic organisms have developed over millennia. Tilting of that balance towards a pro-oxidant state may result from both endogenous and exogenous causes. In this paper, investigators elaborate on the thesis that the neurodegenerative effects of two drugs, namely methamphetamine (METH) and methylenedioxymethamphetamine (MDMA) are due to ROS overproduction in monoaminergic systems in the brain. The authors also discuss the role of oxygen-based species in 6-hydroxydopamine-induced nigrostriatal dopaminergic degeneration and in Parkinson's disease. Studies are underway to identify specific cellular and molecular mechanisms that are regulated by oxygen species. These studies promise to further clarify the role of oxidative stress in neurodegeneration and in plastic changes that occur during the administration of addictive agents that affect the brain. Free Radicals and the Pathobiology of Brain Dopamine Systems. Cadet, J.L and Brannock, C. Neurochem. Int. 32, pp. 117-131, 1998.
Methampetamine Causes Apopotosis
Methamphetamine (METH) is an amphetamine analog that produces degeneration of the dopaminergic system in mammals. The neurotoxic effects of the drug are thought to be mediated by oxygen-based free radicals. In this study investigators used immortalized neural cells obtained from rat mesencephalon in order to further assess the role of oxidative stress in METH-induced neurotoxicity. Authors tested if the anti-death proto-oncogene, bcl-2, could protect against METH-induced neurotoxicity. METH caused dose-dependent loss of cellular viability in control cells while bcl-2- expressing cells were protected against these deleterious effects. Using flow cytometry, immunofluorescent staining, and DNA electrophoreses, authors show that METH exposure can cause DNA strand breaks, chromatic condensation, nuclear fragmentation, and DNA laddering. All these changes were prevented by Bcl-2 expression. These observations provide further support for the involve-ment of oxidative stress in the toxic effects of amphetamine analogs and document that METH- induced cytotoxicity is secondary to apoptosis. These findings may be of relevance to the cause(s) of Parkinson's disease which involves degeneration of the nigrostriatal dopamin-ergic pathway. Methamphetamine Induces Apoptosis in Immortalized Neural Cells: Protection by the Protoncogene, bcl-2. Cadet, J.L., Ordonez, S.V. and Ordonez, J.V. Synapse, 25, pp. 176-184, 1997.
P-53 is Involved in the Toxic Effects of Methamphetamine
p53-Knockout mice provide a useful model to test the role of p53 in the neurotoxic effects of drugs in vivo. To test the involvement of p53 in methamphetamine (METH)-induced toxicity, wild-type mice, as well as heterozygous and homozygous p53-knockout male mice, were administered four injections of three different doses (2.5, 5.0, and 10.0 mg/kg) of the drug given at 2-h intervals within the space of 1 day. METH caused a marked dose-dependent loss of dopamine transporters in both the striatum and the nucleus accumbens of wild-type mice killed 2 weeks after drug adminis-tration. However, this METH-induced decrease in dopamine transporters was attenuated in both homozygous and heterozygous p53-knockout mice, with homozygous animals showing significantly greater protection. The possibility for -p53 involvement in METH-induced toxicity was also supported by the observation that METH caused marked increases in p53- knockout mice, with homozygous animals showing significantly greater protection. The possibility for p53 involvement in METH-induced toxicity was also supported by the observation that METH caused marked increases in p53-like immunostaining in the homo-zygous p53-knockout mice. Further support for p53 involvement was provided by the fact that METH treatment caused significant decreases in dopamine transporter mRNA and the number of tyrosine hydroxylase-positive cells in the substantia nigra pars compacta and the ventral tegmental area of wild-type but not homozygous p53-knockout mice killed 2 weeks after cessation of METH administration. These results provide concordant evidence for a role of the tumor suppressor, p53, in the long-term deleterious effects of a drug acting on brain dopamine system. p53-Knockout mice are protected against the long-term effects of methamphetamine on dopaminergic terminals and cell bodies. Hirata H., and Cadet J.L. J. of Neurochem, 69, pp. 780-790, 1997.
Kainic-acid Toxicity Occurs through Production of Superoxide Radicals
Peripheral administration of kainic acid (KA) can cause cell death in the hippocampus of rodents. This is thought to involve oxidative stress. In this study invesigators tested the possibility that KA-induced neuronal cell death might be attenuated in CuZn superoxide dismutase transgenic (SOD-Tg) mice. Acute administration of KA causes animal death in a dose-dependent fashion; this was attenuated in SOD-Tg mice. Similarly, KA caused dose-dependent neuronal cell death in the hippocampus of wild-type mice; this cell death was attenuated in the SOD-Tg mice, in a gene-dosage-dependent fashion, with homozygous mice showing complete protection even at the highest dose (45 mg/kg) of KA used in this study. These results provide further support for the involvement of oxygen-based radicals in the toxic effects of KA. Kainate-Induced Hippocampal DNA Damage is Attenuated in Superoxide Dismutase Transgenic Mice. Hirata H., and Cadet J.L. Molecular Brain Research, 48, pp. 145-148, 1997.
Methamphetamine (METH-induced) Serotonergic Nerve Terminals
Methamphetamine (METH) causes deleterious effects in brain monoaminergic systems. Evidence has accumulated to suggest that these effects may be mediated via the overproduction of the superoxide radicals. IRP investigators have recently shown that METH-induced dopamine (DA) depletion is attenuated in copper-zinc superoxide dismutase (CuZnSOD) transgenic (Tg) mice. In this study, autoradiographic studies of [125I]RTI-55 labeled serotonin (5-HT) uptake sites were used to evaluate the effect of a two dosing schedule (5 mg/kg over 10 mg/kg x4) of METH on striatal 5-HT uptake sites in nontransgenic (Non-Tg), heterozygous (Hetero and homozygous (Homo) SOD-Tg mice. The low dose caused no significant changes in striatal 5-HT uptake sites in any of the groups. The high dose caused marked decreases (-74%) in striatal 5-HT uptake sites in Non-Tg mice. In contrast, 5-HT uptake sites showed only a 31% decrease in homozygous SOD-Tg mice whereas heterozygous SOD-Tg mice showed 63% depletion. These results suggest that increased SOD activity can protect against METH- induced neurotoxicity in striatal serotonergic terminals. These data provide further evidence for a role of oxidative stress in the neurotoxic effects of METH. Methamphetamine- Induced Serotonin Neurotoxicity is Mediated by Superoxide Radicals. Hirata H., Ladenheim B., Rothman R.B., Epstein C., and Cadet J.L.
Hydrogen Peroxide Causes Apoptosis to Immortalized Neurons which is Abrogated by Catalase Overexpression
Hydrogen peroxide (h3O2) is a known toxicant which causes its damage via the production of hydroxyl radicals. It has been reported to cause both necrotic and apoptotic cell death. The present study was undertaken to evaluate the mode of h3O2- induced cell death and to assess if overexpression of catalase could protect against its toxicity. h3O2 causes cell death of immortalized CSM 14.1 neural cells in a dose-dependent manner. h3O2-induced death was associated wit hDNA laddering as shown by agarose gel electro- phoresis. Stable overexpression of catalase by transfection of a vector containing human cDNA into these dells markedly attenuated h3O2-induced toxic effects. Transfection of a vector containing a SOD cDNA afforded no protection. These results indicated that h3O2 can lead to the activation of endonuclease enzymes that break DNA into oligosomes. These cells which overexpress catalase or SOD will help to determine the specific role of h3O2 or O2- in the deleterious effects of a number of toxins. Overexpression of Superoxide Dismutase and Catalase in Immortalized Neuronal Cells: Toxic Effects of Hydrogen Peroxide. Mann H., McCoy M.T., Subramaniam J., Van Remmen H., and Cadet J.L. Brain Research, 770, pp. 163-168, 1997.
The Cellular Resistance Developed to the Toxic Effects of Drugs with Different Chemical Structures and Mechanisms of Action is Known as Multidrug Resistance (MDR)
The toxic effects of methamphetamine (METH) (2.5, 5.0, and 10.0 mg/kg) and methylenedioxymeth-amphetamine (MDMA) (5.0, 10.0 and 20.0 mg/kg) on dopaminergic systems were assessed in the striatum and of the nucleus accumbens in mdrla wild-type and knockout mice. METH caused significant dose-dependent decreases of dopamine (DA) DA transporters (DAT) in the striatum and the nucleus accumbens (NAc) of both wild-type and knockout mice. The lowest dose of METH (2.5 mg/kg) caused only small changes in the wild-type, but marked decreases in mdrla knockout mice. The two higher doses (5 mg/kg) caused similar changes in both strain of mice. In contrast to METH, MDMA caused a greater percentage decrease in DAT in the wild-type mice. For example, the lowest dose (5 mg/kg) caused significant decreases in DAT in the NAc of wild-type but not of mdrla knockout mice. The highest dose (20 mg/kg) cased similar changes in both the strains. These results suggest that EMTh and MDMA interact differently with P-glycoproteins. These observations document, for the first time, a role for these proteins in the entry of METH and MDMA in to the brain via the blood -brain barrier, with P-glycoprotein possibly facilitating the entry of MDMA but interfering with that of METH in the brain. Differential Toxic Effects of Methamphetamine (METH) and Methylene-dioxymethamphetamine (MDMA) in Multidrug-Resistant (Mmdrla) Knockout Mice. Mann H., Ladenheim B., Hirata H., Moran T.H., and Cadet J.L.
3,4-Methylenedioxymethamphetamine (MDMA), A Substitute Amphetamine, is Well Known as a Drug of Abuse In the United States and Europe
The drug 3,4-methylene- dioxymethamphetamine (MDMA) is a serotonergic neurotoxiant that causes hyperthermia and depletion of serotonin (5-HT) and 5-hydroxy-indole-3-acetic acid (5-HIAA) in the central nervous system. Formation of neurotoxic metabolites of MDMA, e.g., 2,4,5-tryhydroxy- methamphetamine and 2,4,5-trihydroxyamphetamine, involves hydroxyl and/or superoxide free radicals. This study was designed to determine whether the hydroxyl free-radical- trapping agent salicylate could provide protection against MDMA neurotoxicity in rats. In the acute studies, sodium salicylate (12.5-400 mg/kg, calculated as free acid) was injected inter-peritoneally (IP) 1 h before subcutaneous (SC) injections of MDMA (20 mg/kg as base). In the chronic studies, sodium salicylate (3.1-100 mg/kg) was injected IP 1 h before repeated SC injections of MDMA (10 mg/kg as base, twice daily, at 0830 and 1730 h for 4 consecutive days). Repeated MDMA administration depleted contents of 5-HT and 5-HIAA in the frontal cortex, hippocampus and striatum. Coadministration of salicylate plus MDMA did not significantly alter MDMA-induced depletion of 5-HT and 5-HIAA in these tissues. Thus, salicylate, a hydroxyl free-radical-trapping agent, does not protect against MDMA-induced hyperthermia and depletion of 5-HT and 5-HIAA. These observations suggest that MDMA- induced neurotoxicity may occur mainly through the production of superoxide or other radicals rather than hydroxyl free radicals. Salicylate actually potentiated MDMA-induced hyperthermia and lethality, findings that might be of clinical relevance. Yeh, S.Y. Effects of Salicylate on 3,4-Methylenedioxymethamphetamine (MDMA)-Induced Neurotoxicity in Rats. Pharm. Biohem. & Behav, 58, pp. 701-708, 1997.
The Intracellular Calcium Mobilizing Effect of Dantrolene - A Drug Used to Treat Malignant Hyperthermia and Neuroleptic Malignant Syndrome
Dantrolene is a hydantoin derivative with muscle relaxant properties that is used to treat both the malignant hyperthermia triggered by a volatile anesthetic such as halothane and the neuroleptic malignant syndrome (NMS) triggered by neuroleptic therapy. The exact mechanism underlying the action of dantrolene, however, is not well known. Dantrolene has also been shown to block long-term potentiation in hippocampal slices. As intracellular calcium ([Ca2+]i) is implicated in these actions affected by dantrolene, investigators examined the effects of dantrolene in this study using rat frontal cortical cultures. Micromolar concentrations of dantrolene inhibited the NMDA- and KCl-induced increase in [Ca2+]i. Dantrolene partially inhibited the caffeine-induced increase in [Ca2+]i whereas it did not affect the bradykinin-induced increase in [Ca2+]i. Blocking the Ca2+ influx into cells did not affect these actions of dantrolene. These results indicate that dantrolene affects the ryanodine-sensitive intracellular calcium pools while not affecting the IP3 receptor-controlled [Ca2+]i. Results also suggest that dantrolene's mobilizing effect on the [Ca2+]i operates independently of the Ca2+ influx from the medium. Hayashi, T., Kagaya, A., Takebayashi, M. Oyamada, T., Inagaki, M., Tahara, Y., Yokota, N., Horiguchi, J., Su T-P. and Yamawaki, S. J. Neural Transmission, 104, pp. 811-824, 1997.
Beneficial Effect of the Sigma Selective Ligand PRE-084 and Neurosteroids on the Impairment of Learning Induced after the Central Administration of ß25-35-Amyloid Peptide
PRE-084, a sigma ligand discovered at the NIDA IRP, improves learning and memory impairment induced by ß25-35-amyloid peptide known to be related to Alzheimer's disease. As a continuing effort to demonstrate its memory-improving effects investigators examined if PRE-084 might affect the mnemonic deficit induced by the central injection of ß25- 35-amyloid peptide which is known to be related to Alzheimer's disease. PRE-084, like certain neurosteroids, dramatically improved the learning and memory impairment induced by the amyloid peptide. Another sigma receptor agonist (+)pentazocine also prevented the learning impairment induced by ß25-35-amyloid. In addition, neurosteroids such as dehydro-epiandrosterone sulfate (DHEAS) and pregnenolone sulfate (PGNS) which have been shown to react with sigma receptors also improved the memory deficit induced by ß25-35-amyloid. Interestingly, progesterone antagonized the memory-improving effects of PRE-084, (+)pentazocine, DHEAS, and PGNS. These results show a cross-beneficial effects between alkaloidal and steroidal classes of sigma receptor ligands and suggest a possibility of the clinical development of PRE-084 as a therapeutic drug for mnemonic deficit. Maurice, T., Su, T-P. and Privat, A. Neuroscience, 83, pp. 413-428, 1998.
Isolation and Partial Characterization of an Opioid-Like 88 KDa Hibernation-Related Protein
In a continual effort to characterize the protein component responsible for the induction of animal hibernation, we first partially purified protein fractions from both winter-hibernating and summer-active woodchucks and performed the differential SDS-PAGE electrophoresis. A 88 KDa protein was thus identified which is much enriched in the winter plasma when compared to the summer sample. A partially purified protein fraction containing the 88 KDa protein fraction was able to inhibit the contractions of mouse vas deferens - indicative of an opioid action in nature. Proteolytic digestion of the protein yielded several peptides whose amino acid sequences were determined. Searches of Genbank and EMBL databases showed no proteins having significant homology with the peptides from the 88 KDa protein. Pursuing the identification of the 88 KDa protein, a 590 bp fragment of the cDNA of the protein was amplified from hibernating woodchuck liver. Search through the SwissProt database of the nuclei acid sequence of the 590 bp produced a single match with an overall identity of 65.4% with a human á1B-glycoprotein. However, despite the high homology, the molecular weight of the á1B-glycoprotein is only 63 KDa. We are pursuing a full clone of the 88 KDa protein in order to determine its genuine identity and biochemical activity. Horton, N.D., Oeltgen, P.R., Kaftani, D., Bruce, D.S., Turker, M., Khattar, N., Su T.-P. and Bolling, S.F. Comparative Biochem. & Physiol., In Press.
Clinical Pharmacology Branch
Chemistry and Drug Metabolism Section
Cocaine Binds Directly to Human Hair: In Vitro Characterization
Previous studies at the IRP have shown that human hair can sequester cocaine. However, detailed binding studies examining the complex nature of binding of cocaine to human hair have never been carried out. The effect of differences between hair types on the extent of drug incorporation into hair is an important issue, because hair is currently being collected and analyzed to identify drug use by individuals in the workplace. A major concern is that hair test results may not be consistent or impartial for individuals with different hair types. Therefore, an understanding of the nature of drug binding to hair is needed in interpreting hair testing results. In this study investigators carried out the in vitro characterization of binding of radiolabeled cocaine to human hair. Results indicate that human hair can bind cocaine directly in a saturable manner with a stereoselectivity favoring the levoisomer of cocaine. Greater radioligand binding occurred in male Africoid hair than in female Africoid hair and in all Caucasoid hair types. Melanin was considered the most likely binding site for cocaine in hair. Differences in radioligand binding between hair types appeared to be due to differences in the density of binding sites formed by melanin in hair. Joseph, R.E., Tsai, W.J., Tsao, L-I, Su T-P and Cone E.J. J. Pharmacol. Exp. Ther., 282, pp. 1228-1241, 1997.
Neuroimaging Research Branch
Atrophy in the Gray Matter of the Prefrontal Cortex of Substance Abusers may Contribute to the Neuropathology of Functional Impairments Associated with Substance Abuse Disorder
Volumes of the prefrontal lobe in subjects with histories of polysubstance abuse (n=25) were measured and compared with those in normal volunteers (n=14), using high-resolution volumetric magnetic resonance imaging (MRI). The total volumes of the prefrontal lobes were significantly smaller in the substance abuse group than in controls. When the prefrontal lobe was segmented for gray and white matter, the deficit in the substance abusers was seen as significantly smaller volumes of gray but not of white matter. These results indicate that hypoplasia and/or atrophy in the prefrontal cortex accompany substance abuse and suggest that structural deficits in the prefrontal cortex may play an essential role in the neuropathological basis of functional impairments in substance abuse disorder, as demonstrated by functional brain imaging and cognitive studies. Liu, X., Matochik, J.A., Cadet, J.L., and London, E.D. Smaller Volume of Prefrontal Lobe in Polysubstance Abusers: A Magnetic Resonance Imaging Study. Neuropsychopharmacology, 18, pp. 243-252, 1998.
A Simple Radiosynthesis of a High Specific Activity Radiofluorinated Ligand for Labeling Nicotinic Acetylcholine Receptors in the Brain is Suitable for in vivo PET Imaging Studies
Only recently have epibatidine-related radioligands for the nicotinic acetylcholine receptor (nAChR) been synthesized that have high specific activity, high affinity for the receptor, and relatively low non-specific binding. IRP scientists have used a new chemical series of 3-pyridyl ethers synthesized by Abbott Laboratories and having subnanomolar affinity for the nAChR to develop a new fluorinated radioligand. The radiosynthesis of 2-[18-F]A-85380 has yielded a radiotracer with a high specific activity (1050 mCi/mol). It is noteworthy that the parent compound, A-85380, has a substantially wider margin of safety than epibatidine-type compounds in animal studies. Therefore, a high specific activity combined with the potential for a wider margin of safety suggest that of 2-[18-F]A-85380 that may be an excellent positron emission tomography (PET) imaging radiotracer for nAChRs. Horti, A.G., Koren, A.O., Ravert, H.T., Musachio, J.L., Mathews, W.B., London, E.D. and Dannals, R.F. Synthesis of a Radiotracer for Studying Nicotinic Acetylcholine Receptors: 2-[18F]fluoro-3-(2(S)-azetidinyl- methoxy)pyridine (2-[18F]A-85380). J. Label Compds. Radiopharm. XLI, pp. 309-318, 1998.
Preclinical Pharmacology Branch
Behavioral Pharmacology Section
Chronic Exposure to Caffeine Changes the Behavioral Effects of Psychostimulant Drugs
Epidemiological surveys in humans demonstrate that caffeine, the main psychoactive ingredient of coffee, is a positive correlate in drug abuse. To characterize the behavioral nature of caffeine interactions with other psychostimulants, we examined the effects of chronic exposure to caffeine in the drinking water on the behavioral response to nicotine, amphetamine, and cocaine in rats responding under a fixed interval (FI) schedule of food reinforcement. Chronic exposure to caffeine produced complete and insurmountable tolerance to the response-rate increasing (stimulant) effects of acute caffeine in caffeine-drinking rats but it sensitized rats to the stimulant effects of amphetamine and cocaine on schedule-controlled, food maintained- behavior. In contrast to amphetamine and cocaine, the behavioral effects of nicotine remained unaffected by chronic caffeine exposure. The results of this experiment (1) suggest that different pharmacological mechanisms precipitate the behavioral response to different psychomotor stimulant drugs, and, more generally, (2) warns against the simplistic notion of nicotine as an abused substance through its stimulatory actions on dopaminergic reinforcement process. Jaszyna, M., Gasior, M., Shoaib, M., Yasar, S. and Goldberg S.R. Behavioral Effects of Nicotine, Amphetamine and Cocaine under a Fixed-Interval Schedule of Food Reinforcement in Rats Chronically Exposed to Caffeine. Psychopharmacology, In Press.
Motivational Properties of Stimuli Associated with Cocaine
Compounding stimuli previously associated with two different appetitive reinforcers produces additive summation (an increase in responding to the compound over the elements). However, compounding stimuli associated with appetitive and aversive reinforcers produces no increases in responding. Therefore, by compounding a drug-associated stimulus with an appetitive reinforcer we can determine whether the drug reinforcer controls responding through appetitive or aversive motivational states. NIDA researchers recently showed that compounding stimuli associated with cocaine and food reinforcement produces additive summation comparable, to that seen when food and water associated stimuli are compounded. These results suggest that discriminative stimuli associated with cocaine reinforcement are appetitive in nature and that stimuli associated with non-drug appetitive reinforcers may increase the motivation to self-administer cocaine. Panlilio, L.V., Weiss, S.J., and Schindler, C.W. Motivational Effects of Compounding Discriminative Stimuli Associated with Food and Cocaine. Psychopharmacology, 136, pp. 70-74, 1998.
Butyrylcholinesterase as a Cocaine Abuse Treatment
A primary enzyme for the metabolism of cocaine is butyrylcholinesterase (BChE). To determine whether the systemic administration of BChE could increase metabolism of cocaine sufficiently to alter a behavioral effect, rats were tested in a locomotor activity chamber following 17 mg/kg cocaine IP. In rats pretreated IV with 5000 IU horse-serum derived BChE, the locomotor activating effect was significantly attenuated. The BChE pretreatment produced a peak increase of approximately 400 fold in plasma BChE levels. When added to rat plasma, this amount of BChE reduced the cocaine half-life from over 5 hours to less than 5 min. BChE altered the cocaine metabolic pattern such that the relatively non-toxic metabolite ecgonine methyl ester was produced, rather then benzoylecgonine. These results suggest that systemic administration of BChE can increase metabolism of cocaine sufficiently to alter a behavioral effect of cocaine, and thus should be investigated as a potential treatment for cocaine abuse. Carmona, G.N., Schindler, C.W., Shoaib, M., Jufer, R., Cone, E.J., Goldberg, S.R., Greig, N.H., Yu, Q.-S. and Gorelick, D.A. Attenuation of Cocaine-Induced Locomotor Activity by Butyrylcholinesterase. Exp. Clin. Psychopharmacology, In Press.
Novel Rapid Cardiovascular and Behavioral Actions of Cocaine
In collaboration with scientists at Georgetown University IRP scientists have recently reported a novel pharmacological effect of cocaine. This novel effect is rapid in onset and brief in duration and precede cocaine's prolonged dopamine-dependent pharmacological effects. This rapid effect appears to be independent of its inhibitory effects either on monoamine transporters or sodium channels. The rapid effect consisted of marked increases in blood pressure and heart rate and an intense, abrupt behavioral arousal. In humans, intravenous cocaine has been shown to produce a rapid and brief "rush" followed by a prolonged "high." There are pharmacological and time-course similarities between the "rush" reported in humans and the present novel rapid effect in animals. Further studies are underway to characterize the neuropharmacological mechanisms that precipitate these rapid onset, brief duration, cardiovascular and behavioral effects of cocaine. Tella, S.R. and Goldberg, S.R. Monoamine Transporter and Sodium Channel Mechanisms in the Rapid Pressor Response to Cocaine. Pharmacol Biochem Behav, 59, pp. 305-312, 1998.
Genotype and Previous Nicotine Exposure Are Determinants of the Reinforcing Effects of Nicotine in Rats
In the course of studying various pharmacological and genetic influences on i.v. nicotine self-administration in monkeys and rats, we have recently developed an acquisition paradigm in rats free from previous food shaping and food deprivation, which allows us to assess the initiation phase of nicotine-seeking behavior. Sprague-Dawley rats acquired nicotine self-administration over a 10-to-14 day test period, while a Long-Evans strain showed less reliable acquisition and Fisher and Lewis rats failed to show acquisition. To examine consequences of adaptation to motivational effects of nicotine, we examined the effects of chronic nicotine treatment prior to acquisition tests, using a regimen found to facilitate conditioning of nicotine-induced place preferences. Results strongly suggest that nicotine's effects as a reinforcer in rodents can be altered by previous nicotine exposure and that genotypic differences may govern sensitivity to the reinforcing properties of nicotine. Shoaib, M., Schindler, C.W. and Goldberg, S.R. Nicotine Self-administration in Rats: Strain and Nicotine Pre-exposure Effects on Acquisition. Psychopharmacology, 129, pp. 35-43, 1997; Shoaib, M., Thorndike, E., Schindler, C.W. and Goldberg, S.R. Discriminative Stimulus Effects of Nicotine and Chronic Tolerance. Pharmacology, Biochemistry and Behavior, 56, pp. 167-173, 1997.
Behavioral Effects of Selegiline Alone and in Combination with Amphetamine and Cocaine
Selegiline, an irreversible ß-type monoamine oxidase inhibitor, in clinical use for treatment of Parkinson's disease, is metabolized to l-methamphetamine and l-amphetamine which release dopamine from presynaptic nerve terminals. A series of studies have been conducted in rats, squirrel monkeys and rhesus monkeys that involve assessment of the behavioral actions of ß-PEA and the stereoisomers of amphetamine, methamphetamine and selegiline alone, and of selegiline as a pretreatment prior to assessing the behavioral actions of ß-PEA, amphetamine and methamphetamine. In i.v. self-administration studies conducted in rhesus monkeys, l-methylamphetamine, the major metabolite of l-deprenyl, was as effective and only slightly less potent a reinforcer as methamphetamine (d-methylamphetamine) and was as effective a reinforcer as l-cocaine. In contrast, selegiline failed to maintain self-admin- istration behavior above saline levels, even at high doses. Acute i.m. treatment with selegiline up to a 1.0 mg/kg dose, which was as high as we could go without signs of nonspecific toxicity such as reduction of food intake, had no effect on either l-methamphetamine or l-cocaine self- administration. There was, however, a dramatic potentiation of ß-PEA self-administration, indicating strong MAO-B inhibiting activity. In drug-discrimination studies with both rats and squirrel monkeys, selegiline had dose-dependent amphetamine- and methamphetamine-like discriminative stimulus properties but only at doses tenfold or more above the clinically relevant dose range. Results indicate that selegiline (1) has amphetamine-like discriminative stimulus effects attributable to its metabolites at very high doses, (2) does not function as a reinforcer under conditions normally used to assess abuse liability in animals and, (3) does not appear promising as a medication for treatment of stimulant abuse, although further studies under more chronic dosing conditions are underway. Goldberg, S.R. and Yasar, S. Methamphetamine Administration and Associated Neurotoxicity: Effects of Selegiline (l-Deprenyl). In: Teelken, A.W. and Korf, J. (eds.) Neurochemistry: Cellular, Molecular, and Clinical Aspects, Plenum Pub. Corp., pp. 327-330, 1997.
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