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National Institute on Drug Abuse

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

September, 2000

Research Findings

Intramural Research

Chemistry & Drug Metabolism Section, Clinical Pharmacology & Therapeutics Research Branch

Reinforcing and Subjective Effects of Morphine in Human Opioid Abusers: Effect of Dose and Alternative Reinforcer

Although most opioid self-administration research has been conducted with laboratory animals, such research with humans is necessary to answer questions unique to human drug-taking behavior. IRP scientists investigated the influence of morphine dose and an alternative nondrug reinforcer on choice between morphine versus money and examined the relationship between drug-reinforced behavior and subjective euphoria. Five male opioid users participated in the 7-week study. During the first 5 weeks, a single dose of morphine (0, 4, 8, 16, or 32 mg/70 kg) was available each week. On Monday, subjects received an i.m. injection of the dose tested that week. On Tuesday, Thursday, and Friday, subjects could work for morphine or money under a second-order, progressive ratio schedule. For each primary ratio completed on the drug lever, subjects earned 1/9 of the available drug dose, and for each ratio completed on the money lever, subjects earned $1. Total amount of drug earned was administered in a single i.m. injection at the end of the session; money earned was credited to the subject's account. As morphine dose increased, responding for drug increased in an orderly manner and responding for money decreased. During the final phase of the study, the lowest and highest doses that maintained drug responding for each subject were repeated, and the value of the alternative reinforcer was increased to $2 per ratio. This manipulation was associated with decreased drug-maintained responding at the lowest, but not the highest, reinforcing dose of morphine. The progressive ratio, concurrent access procedure may be useful in predicting the outcome of drug abuse treatment interventions that use alternate reinforcement strategies. Heishman, S.J., Schuh, K.J., Schuster, C.R., Henningfield, J.E., and Goldberg, S.R. Psychopharmacology, 148, pp. 272-280, 2000.

Clinical Pharmacology Section, Clinical Pharmacology & Therapeutics Research Branch

Pathological Gambling Among Cocaine-Dependent Outpatients

Pathological gambling has a high-comorbidity rate with drug abuse, but comparatively little is known about their relative order of onset or the influence of gambling on the outcome of addiction treatment. These issues were studied in 313 cocaine-dependent (200 also opiate-dependent) outpatients who participated in clinical trials of medication for treatment of cocaine dependence. Subjects were assessed for pathological gambling (DSM-IIIR criteria) using the Diagnostic Interview Schedule. Treatment outcome was assessed in terms of length of stay (LOS) in treatment and proportion of cocaine-positive urine samples given during treatment. Pathological gambling had a lifetime occurrence rate of 8% and a current (past month) occurrence rate of 4%. Onset of pathological gambling preceded the onset of cocaine dependence in 72% of patients (and the onset of opiate dependence in 44%). Patients diagnosed with pathological gambling (either lifetime or current) did not differ significantly from other patients in LOS in treatment or proportion of cocaine-positive urine samples. Compared to other patients, those with lifetime pathological gambling were significantly more likely to have tobacco dependence (84% vs 61%) and antisocial personality disorder (56% vs 20%), to be unemployed (80% vs 49%), to have recently engaged in illegal activity for profit (64% vs 40%), and to have spent time incarcerated (64% vs 36%). These findings show that pathological gambling is substantially more prevalent among cocaine-dependent outpatients than in the general population, and support the incorporation of material on pathological gambling into substance abuse treatment. Hall, G.W., Carriero, N.J., Takushi, R.Y., Montoya, I.D., Preston, K.L., and Gorelick, D.A. American Journal of Psychiatry 157, pp. 1127-1133, 2000.

Coping with Marijuana Quitting and Withdrawal

There is growing evidence that individuals who stop marijuana use often experience a withdrawal syndrome. However, there is little systematically collected data on how people cope with quit attempts and withdrawal symptoms. This study addressed this issue using data collected retrospectively by self-report questionnaire from 49 physically healthy experienced marijuana smokers (41 men, mean [SD] age 45.3 [8.4] years) who had made at least one serious quit attempt and had no history of intravenous or other illegal smoked drug use. Subjects averaged 23.3 [6.7] years of marijuana use, were currently smoking 2.0 [1.8] joints/day, and had made 3.4 [3.3] quit attempts. The commonest reasons for quitting were to feel in control of their life--71% and concern over health problems--63%. The commonest withdrawal symptoms were marijuana craving--77%, irritability--54%, anxiety--46%, boredom--44%, and difficulty sleeping--42%. Among those using another substance at the time of quitting marijuana use, 59% increased their tobacco use, 58% increased their alcohol use, and 26% increased their coffee use. The most common methods for coping with quitting were getting rid of marijuana supplies (n = 10), encouragement from family (10), stopping association with marijuana-using friends (9), stopping going to places where marijuana was used (9), and encouragement from friends (8). These findings show that marijuana users who report a quit attempt make multiple attempts. A better understanding of the variety of methods used to cope with marijuana quitting, similar to those used with other drugs, may help improve treatment for marijuana abuse. Gorelick, D.A., Dermand, J.C., Nides, M.A., Simmons, M.S., and Tashkin, D.P., Poster, Royal College of Psychiatrists Annual Meeting, Edinburgh, Scotland, July 5, 2000.

Effect of Mobile Methadone Treatment on Crime in Baltimore Neighborhoods

Although methadone treatment programs (MTPs) are effective in reducing crime among their patients, their impact on neighborhood crime rates has not been studied. Alternate theories have been proposed: the presence of a MTP could increase crime rates by attracting drug-using individuals, or reduce crime rates by treating opiate abusers who are neighborhood residents. The present study is an ecological analysis of the impact of a mobile methadone treatment program (MMTP) on neighborhood crime. We examined arrest statistics from May 1994 to April 1996 in four Baltimore neighborhoods with MMTPs. In April 1995, the MMTPs in two of the neighborhoods were discontinued. Generalized estimating equations (GEE) were used to determine whether arrest rates changed during the second year (April 1995-April 1996) in the two neighborhoods where the MMTP left (MMTP-l) compared to the two neighborhoods where the MMTP remained (MMTP-r) and to the rest of Baltimore (BALT), after adjusting for baseline arrest rates and socioeconomic status. No significant changes in arrest rates occurred in the MMTP-l neighborhoods. The MMTP-r neighborhoods experienced significant (p < 0.05) decreases in arrests: all arrests-- 4.1%, drug-related--5.0%, heroin-related--3.8%, cocaine-related--6.4%. Overall, MMTP-r neighborhoods experienced greater decreases in arrests than the remainder of the city. These findings show that MMTPs may have beneficial effects in their surrounding neighborhood, as well as among their individual patients. Boyd, S., Schroeder, J., and Crape, B. Presentation, College on Problems of Drug Dependence annual meeting, San Juan, P.R., June 17, 2000.

Cellular Neurophysiology Section, Cellular Neurobiology Research Branch

Neuroregenerative Effects of BMP-6 and BMP-7 After Stroke in Rats

IRP Investigators and others have previously demonstrated that bone morphogenetic protein-7 (BMP-7) has neuroprotective and neuroregenerative effects against brain ischemia. We recently also found that pretreatment with BMP-6 prior to inducing ischemia reduces cerebral infarction, and decreases Caspase-3 immunoreactivity and TUNEL (+) cells in cerebral cortex. These data suggest that BMP-6 may also provide neuroprotection. The purpose of the current study was to compare the neuroregenerative effects of BMP-6 and BMP-7 after ischemia /reperfusion injury, a paradigm with much greater clinical relevance. Adult Sprague-Dawley rats were anesthetized with chloral hydrate. The middle cerebral artery (MCA) was transiently occluded by a filament, inserted through the right internal carotid artery. The filament was removed after 60 min ischemia to allow reperfusion. Animals developed body asymmetry, as shown by the elevated body swing test. BMP-6, BMP-7, or vehicle was injected directly into the lateral ventricle one day after MCA occlusion. Animals receiving BMP-6 or BMP-7 showed a dose-dependent decrease in body asymmetry beginning 6 days after ischemia. Taken together, our data indicate that treatment with BMP-6 or BMP-7 may have neuroregenerative properties that normalizes motor impairment after ischemia/reperfusion injury. Lin, S.Z., Hoffer, B.J., Kaplan, P., and Wang, Y. Stroke, 30, pp. 126-133, 1999.

Methamphetamine Exposure Facilitates Ischemic Injury in the Brain

Previous studies have indicated that both methamphetamine (MA) and ischemia/reperfusion injuries involve reactive oxygen formation and activation of apoptotic mechanisms. It is possible that MA may have synergistic or additive effects with stroke-induced brain damage. The purpose of this study was to investigate if administration of MA in vivo will potentiate ischemic brain injury in an animal model. Adult CD-1 mice were treated with MA (10 mg/kg) or saline (i.p., 4 times, each dose two hours apart). Animals were later anesthetized with chloral hydrate and then placed in a stereotaxic frame. A subset of animals received intracerebral administration of GDNF, a protective neurotrophic factor. The right middle cerebral artery (MCA) and bilateral carotids were transiently occluded for 45 minutes. Regional cerebral blood flow was measured by Laser Doppler. Animals were sacrificed for tri-phenyl-tetrazolium chloride (TTC) staining and p53 mRNA Northern blot assay after 24 hours of reperfusion, p53 is a proapoptotic factor. Cortical and striatal glial cell line-derived neurotrophic factor (GDNF) levels were assayed by ELISA. Investigators found that pretreatment with MA increased ischemia-induced cerebral infarction. Ischemia or MA alone enhanced p53 mRNA expression. Moreover, MA potentiated the expression of p53 mRNA in the ischemic mice. MA pretreatment decreased GDNF levels in ischemic striatum. Intracerebral administration of GDNF before ischemia reduced MA -facilitated infarction. These data indicate that MA exacerbates ischemic insults in brain, perhaps through the inhibition of endogenous GDNF-mediated neuroprotective pathways. The data also shows that the mechanism of action of MA may involve an augmentation of apopotosis (programmed cell death) in the critical area surrounding the core of the ischemic lesion. Chiang, Y.H., Lin, S.Z., Su, T.P., Hayashi, T., Tsao, L.I., Borlongan, C.V., and Wang, Y. Society for Neuroscience Annual Meeting Abstracts, Vol 25 (2), page 1851, 1999.

The Neurobiology of Memory Impairment by Marijuana

The psychologically active ingredients of marijuana are known as "cannabinoids", and they are typified by the well-known chemical D9-tetrahydocannabinol (THC). Many studies have shown that marijuana can impair learning, memory, and general cognitive function in both humans and experimental animals. There is also very strong evidence that an area of the brain known as the hippocampus is involved in learning new information and in the recall of that information. This study examined the effects of a synthetic cannabinoid drug on communication among nerve cells (neurons) in the hippocampus, and examined the precise physiological mechanisms through which these effects occurred. It was found that the synthetic cannabinoid drug known as WIN 55,212-2 could diminish the release of the inhibitory neurotransmitter GABA from a specific group of neurons in the hippocampus. These effects were found to be dependent on the dose of WIN 55,212-2, and were reversed by a blocker or antagonist (known as SR-141716A) of a specific cannabinoid receptor known as CB1. In order to determine the precise cellular mechanism by which this inhibition of GABA release occurred investigators next examined the role that various ion channels play by blocking them with specific chemicals during application of WIN 55,212-2. They found that when calcium channels were blocked with cadmium chloride the ability of WIN 55,212-2 to inhibit GABA release was eliminated. In addition, they also eliminated the possibility that potassium channels or sodium channels were involved in the effects of this cannabinoid drug. These data provided strong evidence that the effects of WIN 55,212-2, and marijuana, are likely due to the reduction of GABA release through the inhibition of calcium channels by CB1 receptors located on the axon terminals of these neurons. Because GABA release is known to play an important role in synchronizing the activity of large groups of neurons in the hippocampus (which is necessary for normal cognitive function to occur), it is likely that at least part of the ability of marijuana to impair memory and cognitive activity is due to this inhibition of GABA release. Hoffman, A.F. and Lupica, C.R. The Journal of Neuroscience, 20, pp. 2470-2479, 2000.

The Neurobiology of Marijuana Effects on Brain Drug Reward Circuits

The nucleus accumbens is a brain structure that plays an important role in the addictive effects of a number of commonly abused drugs, such as cocaine, amphetamine, ethanol and heroin (opioids). Studies using animal models of drug reward have demonstrated that subjects will self administer many of these drugs directly into the nucleus accumbens. Such data indicate that part of the "rewarding" actions of abused drugs is encoded by the direct actions of these drugs on nerve cells (neurons) within this brain region. Since neurons within the nucleus accumbens communicate with a number of different brain areas, including those involved in processes ranging from movement to memory, a disruption of the ongoing communication (termed synaptic transmission) among these neurons has the ability to profoundly alter behavior. By studying the effects of drugs of abuse on synaptic transmission, IRP investigators hope to be able to better understand how these drugs may play a role in disrupting normal brain function. The widespread use and abuse of marijuana has led a number of investigators to attempt to characterize the actions of this drug's active components (termed cannabinoids) in the brain. These studies have shown that cannabinoids interact with specific targets (receptors) on nerve cells, and that these receptors are found in a number of different brain areas, including the nucleus accumbens. In this study, researchers examined the effects of a synthetic cannabinoid drug called WIN 55,212-2 on synaptic transmission in the nucleus accumbens. It was found that WIN 55,212-2 produced a decrease in the release of an inhibitory neurotransmitter (GABA), but had little effect on the release of an excitatory neurotransmitter (glutamate). These effects were found to be dose-dependent and could be prevented by a synthetic blocker (antagonist) of brain cannabinoid receptors known as SR141716A. Interestingly, it was also found that a synthetic opioid (DAMGO) had the opposite effect of the cannabinoid, since it inhibited glutamate release but did not affect GABA release. These data provide strong evidence that cannabinoids do have direct effects on synaptic transmission in the nucleus accumbens, and that these actions may contribute to the abuse potential of marijuana. The differences between the actions of opioids and cannabinoids in the nucleus accumbens, although not completely understood at this time, may highlight important differences among various classes of abused drugs. Hoffman, A.F. and Lupica, C.R. Society for Neuroscience Annual Meeting Abstracts, New Orleans, LA, November 4-9, 2000.

Molecular Neuropsychiatry Section, Cellular Neurobiology Research Branch

Differential Effects of Cocaine and Cocaine and Alcohol on Neurocognitive Performance

Chronic use of cocaine is associated with persistent decrements in cognitive function that are most pronounced in heavy users. Specific neurobehavioral deficits in areas such as executive function and impulsivity would make it difficult for the cocaine abuser to discontinue using drugs. Because alcohol is often used in conjunction with cocaine, the CNS effects of alcohol when taken with cocaine deserve further investigation. The dose-related effects of cocaine with or without alcohol use on the CNS were investigated by measuring performance on neurobehavioral tests. The authors evaluated the dose-related effects of cocaine and alcohol use on performance in a variety of neuropsychological tests after 1 to 3 days of abstinence and again after 4 weeks of abstinence. Fifty-six chronic cocaine abusers who had used cocaine during the past 24 to 48 hours volunteered to perform a battery of neuropsychological tests on two separate occasions during a period of enforced abstinence. In addition to using cocaine, most of the volunteers consumed alcohol. Approximately half of the participants consumed more than 10 alcohol-containing drinks per week. After controlling for the effects of age, sex, and intelligence on performance, the authors found dose-related associations between neurobehavioral performance and cocaine dose and alcohol dose. When the influences of cocaine and alcohol on neurobehavioral performance were taken separately, cocaine and alcohol each selectively affected performance on different neurobehavioral tests after 1 to 3 days of abstinence, with these effects persisting after 4 weeks of abstinence. The concomitant use of cocaine and alcohol may have additive negative effects on the brain as compared to the use of only one of these two substances. Bolla, K.I., Funderburk, F.R. and Cadet, J.L. Neurology 54, pp. 2285-2292, 2000.

Brain Imaging Section, Neuroimaging Research Branch

6-[F-18]Fluoro-A-85380, a Novel PET Tracer for nAChRs

A novel positron emission tomography (PET) radiotracer, 6-[F-18]fluoro-3-(2(S)-azetidinyl-methoxy)pyridine (6-[F-18]fluoro-A-85380, 6-[F-18]FA) was synthesized by a no-carrier-added fluorination. In vitroo assays of 6-[F-18]FA binding to nicotinic acetylcholine receptors (nAChRs) in rat brain showed that it bound with very high affinity (Kd 28 pM). In PET studies, 6-[F-18]FA specifically labeled central nAChRs in the brain of the Rhesus monkey and demonstrated highest levels of accumulation of radioactivity in brain regions enriched with the alpha4 beta2 subtype of nAChR. 6-[F-18]FA exhibited a target-to-non-target ratio (estimated as radioactivity in the thalamus to that in the cerebellum) of binding in primate brain similar to that previously determined for a labeled analog of epibatidine, [F-18]FPH. In contrast to [F-18]FPH, the novel tracer is expected to exhibit substantially less toxicity. Thus, the novel radioligand, 6-[F-18]FA, appears to be a suitable candidate for imaging nAChRs in human brain. Horti, A.G., Chefer, S.I., Mukhin, A.G., Koren, A.O., Gundisch, D., Links, J.M., Kurian, V., Dannals, R.F., and London, E.D. Life Sciences, 67, pp. 463-469, 2000.

Tobacco Smoking in Adolescents

This review summarizes what is currently known about tobacco use in children and adolescents. Throughout the tobacco epidemic, long-term nicotine dependence has resulted primarily from the initiation of tobacco use during adolescence, and many adolescents try to quit and fail. Strategies to prevent the onset and treat adolescent tobacco dependence have had limited success. In addition, adolescents do not benefit from the same level of societal support for cessation attempts as adults, and they may be less motivated to quit despite the negative health consequences. Overall, the impact of adolescent smoking cessation clinics has been disappointing due to low participation, high attrition, and low quit rates. This review considers the therapeutic reduction of smoking rates (exposure reduction) as an intermediate therapeutic goal for adolescent individuals who are dependent or dependence-prone, but for whom initial treatment interventions do not yield complete cessation. Moolchan, E.T., Ernst, M., and Henningfield, J.E. Journal of American Academy of Child and Adolescent Psychiatry, 39, pp. 682-693, 2000.

Plasma Catecholamines in Lesch-Nyhan Disease

Noradrenergic dysfunction and abnormality in monoamine oxidase (MAO) enzyme activity have been reported previously in Lesch-Nyhan (LN) disease. This study examines peripheral indices of adrenergic, noradrenergic and MAO function in children and young adults with LN disease (n=11), and healthy subjects (n=9). The LN subjects had significantly higher epinephrine (EPI) levels by 245% (p<0.00) and lower 3-methoxy-4-hydroxyphenylglycol (DHPG) levels by 42% (p<0.00) compared to the control group. No group differences were noted in NE plasma levels. Cognitive function (IQ tested by Stanford Binet Intelligence Scale) was associated with levels of plasma EPI in the LN group (r=0.77, p=0.009), but not in the control group. The abnormally high EPI plasma concentrations may indicate another biochemical dysfunction secondary to the absence of the hypoxanthine guanine phosphoribosyl transferase enzyme in LN patients. Such a biochemical deficit is likely to originate from the adrenal medulla, which is the primary site of EPI synthesis. The adrenal medulla may be directly affected by the absence of hypoxanthine guanine phosphoribosyl transferase enzyme, or may receive inappropriately high descending activation input from the brain. The abnormally low DHPG levels, in the context of normal NE levels, indicates low MAO activity, either as a primary deficit, or as secondary adaptive changes to spare NE levels that would otherwise be too low for adequate noradrenergic function. Ernst, M., Zametkin, A.J., Pascualvac, D., Matochik, J.A., Eisenhofer, G., Murphy, D.L., and Cohen, R.M. Neuropsychopharmacology, 22, pp. 320-326, 2000.

Pictorial Instrument for Child and Adolescent Psychiatry

The pictorial instrument for child and adolescent psychiatry (PICA-III-R) is presented as part of a comprehensive review of the tools used to diagnose psychiatric disorders in children and adolescents. The development of the PICA-III-R, its content, its initial psychometric properties, and directions for its use are described. The PICA-III-R assesses all DSM-III-R Axis-I psychiatric disorders in children aged 6 to 16 years, categorically (diagnosis present or absent) and dimensionally (range of severity). It comprises 137 pictures organized in modules that cover five diagnostic categories, including disorders of anxiety, mood, psychosis, disruptive behavior, and substance abuse. Its initial psychometric properties are promising with good internal consistency, significant discriminative power for diagnoses, and sensitivity to changes. Despite a large interest expressed by child psychiatrists, further testing has not been possible for practical reasons unrelated to the scientific importance of this work. Although it needs to be modified to follow DSM-IV criteria, the PICA-III-R can be of significant help to child psychiatrists, for clinical as well as research diagnostic purposes. Additionally, it can be used for the assessment of non-English speaking, or hearing/speech impaired children. Ernst, M., Cookus, B.A., and Moravec, B.C. Journal of American Academy of Child and Adolescent Psychiatry, 39, pp. 94-99, 2000.

Preclinical Pharmacology Section, Behavioral Neuroscience Research Laboratory

Butyrylcholinesterase Accelerates Cocaine Metabolism: In vitroo and in vivo Effects in Non-human Primates and Humans

Butyrylcholinesterase (BChE) is know to metabolize cocaine in humans. In the present study, IRP investigators determined whether the administration of horse serum-derived BChE would accelerate the metabolism of cocaine. The addition of BChE to squirrel monkey plasma reduced the In vitroo half-life of cocaine by over 80%. The administration of BChE to anesthetized squirrel monkeys reduced the in vivo peak concentration of cocaine observed. Finally, the addition of BChE to human plasma resulted in a dose-dependent decrease in the In vitroo cocaine half-life. Together these results indicate that exogenously administered BChE can accelerate cocaine metabolism in such a way as to potentially lessen the behavioral and toxic effects of cocaine. Therefore, BChE may be useful as a treatment for cocaine addiction and toxicity. Carmona, G.N., Jufer, R.A., Goldberg, S.R., Gorelick, D.A., Greig, N.H., Yu, Q.-S., Cone, E.J. and Schindler, C.W. Drug Metabolism and Disposition, 28, pp. 367-371, 2000.

Psychobiology Section, Medications Discovery Research Branch

Novel Dopamine Uptake Inhibitors as Potential Therapeutics for Cocaine Abuse

Several analogs of benztropine (BZT) have been characterized as like cocaine in that they occupy the sites in the brain where cocaine produces its potent behavioral effects. However, these compounds do not have all of the behavioral effects of cocaine. If these compounds do not produce effects like cocaine, yet occupy the sites in the brain where cocaine acts, they may serve as antagonists to cocaine and could be useful leads for the discovery of drugs to treat cocaine abuse. One critical effect of cocaine that is considered important for its liability for abuse is its reinforcing effects - that is, whether a laboratory subject will make a simple response that results in the intravenous infusion of the drug. The present study examined the reinforcing effects of BZT and some of its analogs to determine if they have reinforcing effects. If these compounds have reinforcing effects they are likely to have abuse liability of their own and therefore would not be good candidates for cocaine-abuse therapeutics. Four monkeys were trained to self-administer intravenous injections of cocaine. Once they reliably self-administered cocaine the effects of placebo and various doses of cocaine, BZT and its analogs were assessed. Self-administration was maintained under the FR schedule by cocaine, and to a lesser extent by two analogs of BZT. BZT did not maintain self-administration. This study confirms and extends previous results demonstrating that BZT analogs do not have behavioral effects similar to those of cocaine. Because these compounds compete for the sites in the brain at which cocaine acts, the findings support the suggestion that this group of compounds may provide useful leads for development of pharmacotherapeutic agents for the treatment of drug abuse. Woolverton W.L., Rowlett, J.K., Wilcox, K.M., Paul, I.A., Kline, R.H., Newman, A.H., and Katz, J.L. 3' and 4'-Chloro-substituted Analogs of Benztropine: Intravenous Self-Administration and In vitroo Radioligand Binding Studies in Rhesus Monkeys. Psychopharmacology, 147, pp. 426-435, 2000.

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