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National Institute on Drug Abuse

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

February 1997


Research Findings


Intramural Research


Activation of Memory Circuits During Cue-Elicited Cocaine Craving
Evidence accumulated over more than 45 years has indicated that environmental stimuli can induce craving for drugs of abuse in individuals who have addictive disorders. However, the brain mechanisms that subserve such craving have not been elucidated. Here, a positron emission tomographic study shows increased glucose metabolism in cortical and limbic regions implicated in several forms of memory when human volunteers who abuse cocaine were exposed to drug-related stimuli. Correlations of metabolic increases in the dorsolateral prefrontal cortex, medial temporal lobe (amygdala) and cerebellum with self-reports of craving suggest that a distributed neural network, which integrates emotional and cognitive aspects of memory, links environmental cues with cocaine craving. Identifying patterns of brain activation correlated with cocaine craving can direct future investigations in the mechanism of and therapeutic interventions for craving associated with drug addiction. Grant, S., London, E.D., Newlin, D.B., Villemagne, V.L., Liu, X., Contoreggi, C., Phillips, R.L., Kimes, A.S., Margolin, A. Proc. Natl. Acad. Sci., 93: pp. 12040-12045, 1996.

Subjective and Cardiovascular Effects of Nicotine in Human Volunteers
The subjective and cardiovascular effects of intravenous nicotine were assessed in smokers and nonsmokers. Both smokers and nonsmokers manifested significant increases in systolic and diastolic blood pressure and heart rate 1 min after administration of single doses of nicotine (0.75 or 1.5 mg). The most prominent difference between groups was the increase in heart rate was greater and more sustained in nonsmokers than in smokers. Nonsmokers and smokers also differed in subjective self-reports. In response to items on visual analogue scales indicative of positive effects (e.g., "good effects," "like drug," "use again," and "feel energetic"), smokers, but not nonsmokers, reported high scores after nicotine injection. In addition, responses on the MBG and LSD subscales of the Addiction Research Center Inventory indicated that smokers experienced positive subjective effects after the test doses, whereas nonsmokers experienced disorientation. The fact that intravenous nicotine was not associated with positive subjective effects in nonsmokers indicates that repeated exposure is required to establish positive reinforcing effects of nicotine. Soria, R., Stapleton, J.S., Gilson, S.F., Sampson-Cone, A., Henningfield, J.E., and London, E.D. Psychopharmacology 128: pp. 221-226, 1996.

PPBP[4-Phenyl-l-l(4-phenylbutyl) piperidine] Decreased Brain Injury Following Transient Focal Ischemia in Rats.
Sigma-receptor ligands have been hypothesized to be therapeutically beneficial in the setting of focal cerebral ischemia. Previous studies in the cat were extended to the rat to test if intravenous administration of the potent sigma receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) initiated half-way through a 2 h period of transient focal ischemia and continuing for 23 h would decrease postischemic brain infarction volume occurring over 22 h of reperfusion in unanesthetized animals. The infarction volume of cerebral cortex (saline, 39Å6%; PPBP, 21Å7% of the ipsilateral hemisphere) and striatum (saline, 68Å6%; PPBP, 33Å8% of the ipsilateral striatum) was smaller in rats treated with PPBP than in rats treated with saline. Thus, PPBP effectively decreases brain injury from transient focal ischemia, when administered after the onset of ischemia and during reperfusion, and suggests sigma-receptors may influence the progression of injury in ischemic border regions. Takahashi, H., Kirsch, J.R., Hashimoto, K., London, E.D., Koehler, R.C., Traystman, R.J. Stroke 27: pp. 2120-2123, 1996.

Methamphetamine-Induced Neurotoxicity
These papers show that METH can cause increase in AP-1 binding activity. This activation is secondary to the production of superoxide radicals because transgenic mice that overexpress superoxide dismutase show much less of a response. These results are consistent with previous findings that showed that AP-1 activation is dependent on cellular redox status. These papers also identify a role for AP-1 in the neurodegeneration of the dopaminergic system of mice. Methamphetamine-Induced Neurotoxicity is Associated with Increased Striatal AP-1 DNA-binding Activity in Mice. Sheng, P., Ladenheim B., Moran T.H., and Cadet J.L. Molecular Brain Res. 42: pp., 171-174, 1996; AP-1 DNA Binding Activation by Methamphetamine Involves Oxidative Sress. Sheng P., Wang X-B., Ladenheim B., Epstein C., and Cadet J.L. Synapse 24: pp. 213-217, 1996.

Neuroadaptive Changes Following Chronic Cocaine Administration
This paper shows that chronic cocaine self-administration causes increases in the number of dopamine uptake sites in the striatum, nucleus accumbens, and the ventral tegmental areas. The use of the cocaine analog GBR-12909 reduced self-administration. Moreover, GBR-12909 caused a reversal of the biochemical changes caused by cocaine. These results indicate that GBR-12909 might be an important drug in the treatment arsenal being built against cocaine addiction. Differential Reinforcing Effects of Cocaine and GBR-12909: Biochemical Evidence for Divergent Neuroadaptive Changes in the Mesolimbic Dopaminergic System. Tella S.R., Ladenheim B., Andrews A.M., Goldberg S.R., and Cadet J.L. Journal of Neuroscience, 16: pp. 7416-7427, 1996.

Neurotoxicity of 2'Nh3-MPTP
These studies show that superoxide radicals are involved in the neurotoxicity of 2'Nh3-MPTP. These results extend the role of free radicals to the neurodegeneration of serotonergic and noradrenergic systems in rodent brains. Transgenic mice with high levels of superoxide dismutase activity are protected from the neurotoxic effects of 2'-Nh3-MPTP on serotonergic and noradrenergic nerve terminals. Andrews A.M., Ladenheim B., Epstein C.J., Cadet J.L., and Murphy D.L. Molecular Pharmacology 50: pp. 1511-1519, 1996.

PD-128, 907--A Selective D3 Dopamine Receptor Agonist with an Atypical Antipsychotic Profile
The Drug Development Group of the Behavioral Pharmacology and Genetics Section of NIDA IRP was the first group to report a common subjective effect pattern for cocaine and agonists selective for dopamine D3 receptors. D3 receptors have also become a focus of drug abuse researchers due to the reports from Koob's group that this site may be a target for cocaine abuse therapeutics. In the process of discovery of a selective antagonist for the abused drug, phencyclidine (PCP), we have found a selective D3 agonist with an atypical antipsychotic profile like that of the prototype, clozapine. PD-128,907(4aR,10bR-(+)-trans, 3,4,4a,10b-tetrahydro-4-n-propyl-2H,5H[4,3-b]-1,4-oxazin-9-ol) blocked behavioral effects of dizocilpine [(+)-MK-801], a PCP-like antagonist of the NMDA receptor-associated ion channel. Blockade occurred at doses of PD-128,907 that did not affect spontaneous locomotor activity. Like clozapine, PD-128,907 blocked the stereotyped behavior produced by dizocilpine but had minimal effects against apomorphine-induced stereotypies. The dizocilpine-blocking effects of PD-128,907 were not observed with the inactive, minus isomer of PD-128,907. Importantly, PD-128,907, like clozapine, lacked cataleptic effects, predicting an absence of chronic neurological problems associated with typical antipsychotic drugs (e.g., haloperidol). These data are the first to document a common mode of action of a D3 receptor ligand with PCP blockade and psychosis and suggest novel treatment approaches in both areas. Blockade of dizocilpine-induced behaviors may be a valuable preclinical screening device for novel pharmacological therapies for schizophrenia. The comorbidity of psychosis and drug abuse makes these findings additionally compelling. This work was presented at the annual meeting of the American College of Neuropsychopharmacology in December, 1996.

Marjolein Beekman from the University of Groningen, The Netherlands has been a guest scientist working on this project for the past 5 months. She comes from the medicinal chemistry group that synthesized the most selective drug, to date for D3 receptors. Future research will be directed toward definitive identification of D3 receptors as the target for this novel effect. Based upon the linkage with psychosis and with our previous findings on commonalities in the pharmacology of cocaine and D3 receptor ligands, further work will be expanded to identify a role for these compounds in the control of psychomotor stimulant (cocaine, methamphetamine) abuse and toxicity.

Genotype-Dependent Differences in Morphine Self-Administration
The objective of the behavior genetic work in the Behavioral Pharmacology and Genetics Section of the Preclinical Pharmacology Laboratory has been to characterize the behavioral and neural substrates that determine individual differences in the efficacy of morphine as a reinforcer and vulnerability to opioid-reinforced behavior. The specific hypothesis has been that a significant relationship exists between individual differences in mesolimbic-opiate receptor concentration and the efficacy of morphine as a primary reinforcer. In collaboration with Dr. J.L. Cadet of the Molecular Neuropsychiatry Section of the Neuroscience Branch, behavior genetic and neuroanatomical techniques were used to investigate the relationship between regional -opiate receptor concentration and morphine-reinforced behavior. Inherited differences in regional -opiate receptor concentration (genetically engineered and naturally occurring) was used as a means to manipulate regional concentrations of the -opiate receptor. Intravenous morphine self-administration behavior was investigated in two sets of genetically engineered mice that overexpress the -opiate receptor, two commonly used recombinant inbred strains with high and low opiate receptor concentration and two commonly available inbred strains. Multivariate analysis of the relationship between -opiate receptor concentration in specific neuroanatomical regions and self-administration behavior suggest that -opiate receptor concentration in the amygdala can account for 64% of the variance (r2) in self-administration behavior. When -opiate receptor concentration in amygdala, the shell of the nucleus accumbens and ventral tegmental area were considered jointly, these regions accounted for 98% of the variance (r2) in self-administration behavior across genotype. These results suggest that -opiate receptor concentration in one or more regions of the mesolimbic system are predictive of genotype-dependent differences in morphine self-administration behavior and provide a significant step towards identifying specific neural regions involved in the neurobiological substrates underlying vulnerability to opioid addiction.

Additive Interactions of Caffeine and Nicotine
Nicotine and caffeine are two of the most widely used licit drugs in society, and they are repeatedly consumed together. Epidemiological reports indicate a correlation between coffee drinking and tobacco smoking and a possible explanation is provided by laboratory studies that indicate these two heavily used drugs interact additively. In a series of studies in the Behavioral Pharmacology and Genetics Section of the Preclinical Pharmacology Laboratory, we have shown that acute or chronic caffeine exposure can alter the reinforcing and other behavioral properties of nicotine. Rats consuming caffeine in their drinking water acquired i.v. nicotine self-administration faster and reached higher levels of intake than controls. Rats trained to discriminate nicotine from saline failed to generalize to other psychomotor stimulant drugs when they were chronically exposed to caffeine during training. Squirrel monkeys showed increases in nicotine self-administration responding and a marked potentiation of other behavioral effects of nicotine after acute or chronic caffeine exposure. Thus, caffeine exposure can markedly alter the reinforcing, discriminative and stimulant properties of nicotine. Such an interaction could be part of the pharmacological basis for nicotine usage and relapse to usage after cessation. Results of this research were presented at the College on Problems of Drug Dependence meeting in June, 1996 and the Society for Neuroscience meeting in November, 1996.

Methamphetamine-Associated Neurotoxicity
Investigators in the Behavioral Pharmacology and Genetics Section and and the Molecular Neuropsychiatry Section of NIDA's IRP have been conducting a series of studies on methamphetamine self-administration and associated neurotoxicity in rats and monkeys. D-methylamphetamine (methamphetamine) and its stereoisomer l-methylamphetamine have been shown to have amphetamine-like abuse liability in rats and monkeys using operant drug-discrimination and intravenous self-administration procedures. Both isomers of methylamphetamine, and l-deprenyl (selegiline), whose major metabolite is l-methylamphetamine, had dose-dependent, d-amphetamine-like, discriminative-stimulus properties in rats and monkeys. Both d-and l-methylamphetamine maintained high rates of self-administration behavior in monkeys and rats. In rats, after 97 d-methylamphetamine self-administration sessions, with total intake of d-methylamphetamine over the 97 sessions ranging from 68 to 116 mg/kg, there were neuroadaptive changes in dopamine uptake sites in the caudate and a small decrease in dopamine transporter levels with corresponding upregulation of dopamine D1 receptors in the nucleus acumbens. There was an indication that opioid systems may be important in the mediation of methamphetamine's reinforcing effects since there was marked upregulation of -opioid receptors in the nucleus acumbens, substantia nigra compacta, ventral tegmental area, prefrontal cortex, anterior caudate and different hippocampus regions. Further studies in rats are underway using yoked control groups of rats that passively receive injections of either methamphetamine or saline whenever test rats self-administer injections of methamphetamine.

Potential Utility of l-deprenyl in Treating Stimulant Abuse
l-deprenyl has been suggested as a potential treatment agent for various types of psychomotor stimulant abuse. l-deprenyl failed to maintain self-administration behavior in monkeys and treatment with l-deprenyl before experimental sessions failed to alter either the discriminative-stimulus actions of d-amphetamine or d-methylamphetamine in rats or monkeys or the self-administration of either d-or l-methylamphetamine in monkeys. Thus, although l-deprenyl had amphetamine-like, discriminative-stimulus properties, it did not appear to have methamphetamine-like reinforcing properties in rats or monkeys and was ineffective in altering established patterns of methamphetamine self-administration behavior. It is possible, however, that l-deprenyl treatment would ameliorate the neurotoxicity seen with extended administration or self-administration of high doses of methamphetamine.

Development of Compound that Binds Irreversibly to the Dopamine Transporter
The Psychobiology Section of NIDA's IRP has developed a drug that binds irreversibly to the dopamine transporter. The drug was derived from a compound that binds to the dopamine transporter and inhibits dopamine uptake but does not have cocaine-like behavioral effects. It is believed that the parent compound acts primarily through a low-affinity binding site on the dopamine transporter, although that is highly speculative. The characterization of the in vitro pharmacology of the compound that binds irreversibly is currently in progress. Studies will more fully characterize the drug in order to assess its suitability for functional characterization of the roles of the high-and low-affinity sites on the dopamine transporter.

Human Pharmacokinetics of Intravenous, Sublingual and Buccal Buprenorphine
Buprenorphine is a potent opioid analgesic used in the treatment of moderate to severe pain. At higher doses it has demonstrated potential for treating heroin dependence. Collaborative efforts between scientists from NIDA's IRP and the Armed Forces Institute of Pathology were undertaken to investigate buprenorphine pharmacokinetics by different routes of administration at dosages approximating those used in opioid dependence studies. Six healthy male subjects who were non-dependent but had a history of heroin use were administered buprenorphine in a cross-over design study by intravenous (1.2 mg), sublingual (4.0 mg) and buccal (4.0 mg) routes of administration. Plasma samples were collected up to 96 hours and assayed for buprenorphine and norbuprenorphine by negative chemical ionization tandem mass spectrometry. Plasma concentrations of buprenorphine and norbuprenorphine were analyzed by nonlinear regression analysis with standard non-compartmental methods. Buprenorphine bioavailability by the sublingual and buccal routes was estimated as 51.4% and 27.8%, respectively, although there was considerable inter-subject variability by both routes of administration. The terminal elimination half-lives were longer for the sublingual and buccal routes than the intravenous route. The extended elimination half-lives may be due to a shallow depot effect by sequestration of buprenorphine in the oral mucosa. Norbuprenorphine mean peak plasma concentrations were less than 1 ng/mL and were highly variable between different routes of administration and subjects. The terminal elimination half-life of norbuprenorphine was longer than buprenorphine.

Cocaine Disposition in Meconium from Newborns of Cocaine-Abusing Mothers and Urine of Adult Drug Users
The analysis of meconium for cocaine and other metabolites has proven to be a reliable method for the detection of fetal cocaine exposure. Better sensitivity and a larger gestational window of detection have been demonstrated for meconium testing as compared to neonatal urine testing. Cocaine and cocaine metabolites have been identified in meconium including benzoylecgonine, ecgonine methyl ester, cocaethylene, norcocaine, benzoylnorecgonine, and m-hydroxybenzoylecgonine. The origin of these metabolites, whether maternal or fetal, has not been established. This study was conducted to compare the disposition of cocaine and metabolites in meconium from cocaine exposed fetuses to that of urine from cocaine abusers. Meconium specimens were obtained from 6 neonates of mothers positive for cocaine use by urinalysis and/or self-report during pregnancy. Urine specimens were obtained from 17 adult female and 17 adult male cocaine users enrolled in a treatment program. Specimens were analyzed by GC-MS for cocaine and 12 related analytes. The following analytes were identified and measured in meconium and urine: anhydroecgonine methyl ester; ecgonine methyl ester; ecgonine ethyl ester; cocaine; cocaethylene; benzoylecgonine; norcocaine; norcocaethylene; benzoylnorecgonine; m- and p-hydroxy-cocaine; and m- and p-hydroxybenzoylecgonine. In addition, both m- and p-hydroxy-benzoylecgonine were found to exhibit approximately equal crossreactivity with benzoylec-gonine in the EMIT and TDx assays. The presence of p-hydroxybenzoylecgonine in meconium suggested that this newly identified metabolite, like m-hydroxybenzoylecgonine, might serve as a valuable marker of fetal cocaine exposure during pregnancy. The presence of cocaine and anhydroecgonine methyl ester in meconium was attributed to transfer across the placenta from the mother. However, the origin of the hydrolytic and oxidative metabolites of cocaine could not be established since they were also identified in urine specimens of adult, female cocaine users and could have arisen in meconium from either fetal or maternal metabolism.

Melanin and Lipids on Cocaine Binding to Caucasoid and Africoid Hair

Although the mechanism(s) of drug deposition in hair are unknown, there is evidence which suggests that the amount and type of melanin present is a major factor in determining how much drug enters hair following exposure. Divided hair specimens (N=7) from male and female Caucasoids (black/brown and blond colored) and Africoids (black colored) were exhaustively extracted to remove lipid components (lipid-extracted hair). Separate portions were bleached to denature or alter melanin content. Experiments with radiolabeled cocaine were performed on untreated, lipid-extracted and bleached portions of hair from different groups. Cocaine binding was significantly higher (p<0.01) to male Africoid hair compared to other groups. The amount of drug binding was similar among specimens from female Africoids and male and female black/brown Caucasoids. The lowest amount of binding was observed with blond, female Caucasoid specimens. Binding experiments also revealed that specific cocaine binding generally did not differ significantly between lipid-extracted hair and untreated hair, but bleaching of most hair specimens resulted in significant (p < 0.01) decreases in specific binding compared to untreated hair. In separate experiments with cocaine-treated hair specimens, digested samples were evaluated to determine if removal of the insoluble melanin fraction from soluble hair components provided a means of normalization of drug content and elimination of color bias. Removal of the insoluble melanin fraction was not effective in removal of significant amounts of cocaine indicating that the digestion process released bound cocaine into the digest solution. Overall, these experiments suggested that lipids in hair play a minor role in drug binding, whereas melanin functions as a major binding site for cocaine. Natural (ethnic) or artificial differences (bleaching) in melanin content may determine the extent of cocaine entrapment in hair after drug exposure. Further, digestion of hair samples with removal of insoluble melanin failed to be effective in removal of hair color bias.

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, we hypothesized that phentermine might attenuate the effects of cocaine on DA transmission. We 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. Our findings 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. Neuroreport, In Press.

Sustained Decrease in Cocaine-Maintained Responding in Rhesus Monkeys with
1-[2-[bis-(4-fluorophenyl)methoxy]ethyl]-4-[3-hydroxy-3-phenylpropyl] piper-azinyl decanoate, a Long-Acting Ester Derivative of GBR 12909

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, we 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. Glowa, J.R., Fantegrossi, W.E., Lewis, D.B., Matecka, D.M., Rice, K.C., and Rothman, R.B. J. Med. Chem. 39(24): pp. 4689-4691, 1996.

Serotonin-4 Receptor Antagonists Reverse Cocaine-Induced Cardiac Arrhythmia
The effect of 5-HT4 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. Pretreatment with 2mg/kg of either drug increased the dose of cocaine required to induce arrhythmia by 168 and 286 percent respectively. This effect was dose dependent. The antagonists were ineffective when given intraperitoneally in rats. The results of this study indicate that 5-HT4 antagonist can reverse cocaine-induced arrhythmias.
The clinical implication of these findings 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. Submitted to NeuroReport.

Therapeutic Potential of Enhancing Cocaine Metabolism
Scientists from the Preclinical Pharmacology, Clinical Pharmacology, and Treatment Branches of the Division of Intramural Research, in collaboration with scientists at the Drug Development Program of the Gerontology Research Center of NIA, recently completed a study providing the first experimental demonstration that enhancing the metabolism of cocaine could significantly reduce the acute behavioral effects of a cocaine challenge. Cocaine metabolism in rats was increased several-fold by IV administration of exogenous butyrylcholinesterase (extracted from horse serum), the major cocaine-metabolizing enzyme in primates. Thirty minutes later, the rats were challenged with IP cocaine or saline and their locomotor activity measured for 2 hours. The rats receiving enzyme pretreatment had a significantly blunted response to cocaine (i.e., less of an increase in distance traveled and stereotypy) compared to those receiving saline pretreatment. Rats receiving only butyrylcholinesterase had the same locomotor activity as those receiving saline, indicating that the enzyme by itself did not influence this behavior. These findings, presented at the Society for Neuroscience annual meeting in November 1996, suggest that enhancement of cocaine metabolism by increasing metabolizing enzyme activity may have therapeutic potential.

Chronic Cocaine Exposure Influences Mu-Opiate Receptor Function
Scientists from the Treatment Branch, Division of Intramural Research, in collaboration with scientists at the Johns Hopkins Medical Institutions, recently published a study showing that chronic, heavy cocaine users have increased mu-opiate receptor binding in selected brain areas, and that this increased binding correlates with self-reported cocaine craving. Binding was measured by positron emission tomography (PET) scanning using 11C-carfentanil, a potent synthetic mu-opioid agonist drug. This finding is the first confirmation in humans of the previously reported finding in animals that chronic cocaine exposure influences mu-opiate receptor function, and suggests a possible mechanism for the reported therapeutic effect of buprenorphine, a partial mu-opioid agonist, in reducing cocaine use by cocaine addicts in treatment. Nature Medicine, 2: pp. 1225-1229, 1996.

Cocaine Use Early In Treatment Predicts Outcome In A Behavioral Treatment Program
To evaluate baseline drug use as a predictor of treatment outcome, cocaine use (qualitative and quantitative urinalysis and self-report) during baseline was compared in methadone patients who had <5 weeks of abstinence (n = 10) during a 12-week experimental voucher-based cocaine abstinence reinforcement treatment. Baseline cocaine use was evaluated at the first and last clinic visit and first and last week of baseline and as a mean across the 5-week baseline; treatment response was calculated as a mean across 12-weeks of treatment. Those who had successful outcomes (Abstainers) used significantly less cocaine in the 5-week baseline than those with less successful outcomes (Nonabstainers). Differences in cocaine use were not evident in the first baseline visit or week, but Abstainers used significantly less cocaine in the last visit and week of baseline compared to Nonabstainers. Cocaine use during baseline provided critical predictors of response to the experimental treatment.

Assessment of Cocaine Use With Quantitative Urinalysis
Measures of cocaine use are pivotal both in treatment and in clinical trials of new cocaine abuse treatments. Current qualitative urinalysis methods of monitoring cocaine use may over-detect frequency of use because of carryover from previous cocaine administrations, masking effective treatments and decreasing the sensitivity of clinical trials. This study assessed the value of quantitative urinalysis and a newly developed measure of cocaine use. Urine specimens collected in a cocaine dosing study in non-treatment-seeking subjects (N=5) and a clinical trial of a behavioral treatment for cocaine abuse (N=37) were analyzed for the cocaine metabolite, benzoylecgonine (BE), with qualitative and quantitative methods. Pharmacokinetic criteria ("New Use" rules) were developed and applied to quantitative data to identify occasions of new cocaine use. Results were compared to known cocaine administrations in the laboratory study and to self-reported drug use, qualitative urinalysis and treatment response for subjects in the treatment trial. New Use criteria correctly identified cocaine administrations in the cocaine dosing study in all but a small number of specimens. In the clinical trial, urine BE concentrations and estimated New Uses were more sensitive to differences in cocaine use in statistical analyses than qualitative urinalysis. Interpretation of quantitative urinalysis with New Use rules appears to be a useful method for monitoring treatment outcome and may be more accurate than traditional qualitative urinalysis in estimating frequency of cocaine use. Methamphetamine-Associated Neurotoxicity Investigators in the Behavioral Pharmacology and Genetics Section and the Molecular Neuropsychiatry Section of NIDA's IRP have been conducting a series of studies on methamphetamine self-administration and associated neurotoxicity in rats and monkeys. D-methylamphetamine (methamphetamine) and its stereoisomer l-methylamphetamine have been shown to have amphetamine-like abuse liability in rats and monkeys using operant drug-discrimination and intravenous self-administration procedures. Both isomers of methylamphetamine, and l-deprenyl (selegiline), whose major metabolite is l-methylamphetamine, had dose-dependent, d-amphetamine-like, discriminative-stimulus properties in rats and monkeys. Both d-and l-methylamphetamine maintained high rates of self-administration behavior in monkeys and rats. In rats, after 97 d-methylamphetamine self-administration sessions, with total intake of d-methylamphetamine over the 97 sessions ranging from 68 to 116 mg/kg, there were neuroadaptive changes in dopamine uptake sites in the caudate and a small decrease in dopamine transporter levels with corresponding upregulation of dopamine D1 receptors in the nucleus acumbens. There was an indication that opioid systems may be important in the mediation of methamphetamine's reinforcing effects since there was marked upregulation of -opioid receptors in the nucleus acumbens, substantia nigra compacta, ventral tegmental area, prefrontal cortex, anterior caudate and different hippocampus regions. Further studies in rats are underway using yoked control groups of rats that passively receive injections of either methamphetamine or saline whenever test rats self-administer injections of methamphetamine.


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