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National Institute on Drug Abuse

Director's Report to the National Advisory Council on Drug Abuse
September, 1999

Research Findings

Intramural Research

Molecular Neuropsychiatry Section, Cellular Neurobiology Branch

Comparative Toxic Effects of Methamphetamine and Dopamine in Cell Culture Potentiation by Serum Withdrawal

Methamphetamine (METH)-and dopamine (DA)-have been shown to cause neurotoxic damage both in vitro and in vivo. The mechanisms of action are thought to involve the production of pathophysiologic concentration of free radicals. It is, however, not clear to what extent the effects of these two toxins mimic each other. The present study was undertaken to compare and contrast the toxic effects of METH and DA by using an immortalized neural cell line. Both METH and DA caused dose-dependent increased production of reactive oxygen species (ROS) and cell death. Cell death caused by these agents was characterized by cytoplasmic vacuolar formation, shrinkage of cytoplasm and nuclear dissolution. Flow cytometric evaluation also revealed that these toxins cause changes similar to those observed in cells undergoing apoptosis. Furthermore, DNA electrophoresis showed that both METH-and DA-induced DNA ladder formation. When taken together these observations suggest the METH and DA cause these cells in low (1%) serum or in the absence of serum markedly enhanced the apoptotic effects of both drugs. These data provide further support for the idea that both METH and DA can cause ROS mediated apoptosis. Cadet, J.L., Ordonez, S., and Burrell, S., Panel Presentation, 1999. Satellite Meeting of the International Society for Neurochemistry and European Society of Neurochemistry, Cellular and Molecular Mechanisms of Drugs of Abuse: Cocaine, Ibogaine and Substituted Amphetamines, Berlin, Germany, August 7-15. 1999.

Clinical Pharmacology Section/Clinical Pharmacology & Therapeutics Branch

Influence of Enforced Abstinence on Cocaine Use by Research Subjects

Clinical experience suggests that enforced abstinence, per se, without treatment intervention, has little influence on future drug use, nor does research exposure to abusable drugs. We addressed these issues in 14 chronic heavy cocaine users undergoing 90 days of abstinence (with 6 subjects getting an intranasal cocaine challenge at the end of the first and last weeks) on the closed NIDA IRP research ward. Subjects were followed for several weeks prior to admission to evaluate their baseline pattern of drug use by self-report and urine drug screening. There were no explicit treatment activities on the ward. Subjects returned for follow-up visits weekly for the first month after discharge; none were participating in treatment. At each visit they reported their daily drug use since the last visit and provided a sample for urine toxicology. Over the month prior to admission and after discharge, subjects used cocaine on 74+5% and 28+7% of the days, respectively (p=0.003), and spent $41.60+10.10 and $56.40+14.00 per day of use on cocaine (p=0.26). There were no significant changes in subjects' alcohol or marijuana use. Subjects receiving a cocaine challenge did not differ from others in drug use after discharge. These findings suggest that a period of enforced abstinence without treatment during research participation can significantly decrease the frequency of cocaine use in the short-term, while not changing amount of cocaine used per day of use. Study limitations include small sample size (yielding low power to detect differences) and 22% missing data. Gorelick, D.A., Sacks, N., Nelson, R., Bencherif, B., and Frost, J.J. Influence of Enforced Abstinence on Cocaine Use by Research Subjects. Presented at American Society of Addiction Medicine, 30th Annual Medical-Scientific Conference, New York, NY, April, 1999. Journal of Addictive Diseases 18(2), p. 115, 1999.

Chemistry & Drug Metabolism Section/Clinical Pharmacology & Therapeutics Branch

Smoking Enhances Cognitive Performance and Decreases Tobacco Craving

This study investigated the effects of nicotine deprivation and smoking on cognitive abilities and tobacco craving. Twenty smokers with histories of drug abuse completed the Questionnaire on Smoking Urges (QSU) and two cognitive tests before and after smoking two cigarettes during two 90-min sessions. After two cigarettes were smoked at Session 1, subjects were tobacco abstinent for 18 hr until Session 2 the next morning. Response time on a logical reasoning test was unchanged by tobacco deprivation and was faster after smoking on Session 2. Deprivation slowed responding on a letter search test, which was reversed by smoking to predeprivation baseline. Tobacco deprivation increased scores on the QSU; smoking after deprivation reduced craving scores to smoking baseline levels. These results confirmed the utility of the QSU to measure changes in craving induced by tobacco deprivation and smoking. Further, the data suggest that deprivation-induced deficits and smoking-induced enhancements in performance may be specific to certain cognitive domains. Bell, S.L., Taylor, R.C., Singleton, E.G., Henningfield, J.E. and Heishman, S.J. Nicotine and Tobacco Research, 1, pp. 45-52, 1999.

Preclinical Pharmacology Section/Behavioral Neuroscience Branch

Noradrenergic Modulation of the Discriminative-Stimulus Effects of Methamphetamine

Although most behavioral effects of methamphetamine are mediated by the dopaminergic neurotransmitter system, neurochemical findings suggest that there is also strong involvement of noradrenergic neurotransmission. To analyze the involvement of norepinephrine in the subjective effects of methamphetamine, IRP scientists tested different noradrenergic compounds in Sprague-Dawley rats trained to discriminate methamphetamine from saline. Antidepressants such as desipramine and nisoxetine, and selective norepinephrine uptake inhibitors, that increase brain norepinephrine levels, potentiated the discriminative-stimulus effects of methamphetamine, whereas antagonists of alpha-2 (yohimbine) and partially also alpha-1 (prazosin) adrenergic receptors, attenuated methamphetamine's discriminative-stimulus effects. These findings suggest that the noradrenergic system plays a modulatory role in mediation of the subjective effects of methamphetamine. These effects appear to involve norepinephrine uptake sites and alpha-2 receptors, with limited involvement of alpha-1 receptors. Noradrenergic compounds might produce their effects either directly or, more likely, indirectly through the modulation of dopaminergic transmission. Munzar, P. and Goldberg, S.R. Psychopharmacology, 143, pp. 293-301, 1999.

Potent Local Anesthetic-like Effects of Cocaine on Cardiovascular Function

Cocaine use continues to be associated with a large number of hospital emergency room admissions, many of which are related to cardiovascular complications. To determine the potential role of cocaine's local anesthetic properties in these effects, the cardio-respiratory effects of cocaine were compared to various local anesthetic (sodium channel blocking) Class I antiarrhythmics. Anesthetized rabbits were treated with various doses of cocaine, quinidine, procainamide, lidocaine or flecainide. Cocaine produced larger increases in QRS duration, an effect typically related to sodium channel blockade, than were observed for the 4 sodium channel blockers. All 5 drugs produced comparable increases in respiratory rate. The large effect of cocaine on QRS duration suggests that cocaine may act at sodium channels in a manner different from the other drugs. This unique effect of cocaine may contribute to the sudden death associated with cocaine use in some individuals. Erzouki, H. K., Goldberg, S. R. and Schindler, C. W. European Journal of Pharmacology, 377, pp. 195-206, 1999.

Neuroimaging Research Branch

Accurate Determination of the Binding Constants for the High Affinity Nicotinic Agonist Epibatidine Requires Precise Experimental Conditions

Several compounds, such as epibatidine, A-85380, and their analogs, have been identified recently as high affinity nicotinic cholinergic receptor ligands whose affinities lie in the low picomolar range. Accurate measurement of such high affinities is fraught with certain technical difficulties, which may account for the inconsistency of previously reported affinities of epibatidine, ranging from 4 to 60 pM. Using newly developed conditions specifically for ligands with subnanomolar affinities, it was demonstrated that ()-[3H]epibatidine (1--500 pM) binds to a single population of sites in rat brain with KD of 8 2 pM. This affinity was confirmed in both kinetic experiments and competition assays with ()-[3H]epibatidine and (-)-[3H]cytisine using the same conditions. Variations from these conditions decreased the observed affinities. Gndisch, D., London, E.D., Terry, P., Hill, G.R. and Mukhin. A.G. NeuroReport, 10, pp. 1631-1636, 1999.

Dopaminergic Abnormalities in the Midbrain of Children Diagnosed With ADHD

Attention-Deficit/Hyperactivity Disorder (ADHD) is a highly prevalent childhood psychiatric disorder characterized by impaired attention, excessive motor activity, and impulsivity. Despite extensive investigation of the neuropathophysiology of ADHD by many methodologies, its neurobiochemical substrate is still unknown. Converging evidence, however, suggests a primary role of the dopaminergic system. This study examined the integrity of presynaptic dopaminergic function in ADHD children using positron emission tomography and the tracer [F-18]fluoroDOPA (18F-DOPA). Accumulation of 18F-DOPA in synaptic terminals, a measure of DOPA decarboxylase activity, was quantified in regions rich in dopaminergic innervation, including caudate nucleus, putamen, frontal cortex, and midbrain (i.e., substantia nigra and ventral tegmentum). Accumulation of 18F-DOPA in the right midbrain, was higher by 48% in 10 ADHD children than in 10 normal children, and values of 18F-DOPA in this region were correlated with symptom severity. No other dopamine-rich regions significantly differed between groups. These findings suggest a dopaminergic dysfunction at the level of the dopaminergic nuclei in ADHD children. Abnormality in DOPA decarboxylase activity may be primary or secondary to deficits in other functional units of the dopamine pathway. Efforts toward defining the origin of this abnormality should help delineate mechanisms of midbrain control of attention and motor behavior important for the understanding of the causes and treatment of ADHD. Given the role of dopaminergic abnormalities in substance abuse, this finding could potentially explain the increased incidence of substance abuse in individuals with histories of ADHD. Ernst, E., Zametkin, A.J., Matochik, J.A., Pascualvaca, D., Jons, P.H. and Cohen, R.M. Am J Psychiatry, 156, pp. 1209-1215, 1999.

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