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Director's Report to the National Advisory Council on Drug Abuse
February, 1995

Research Findings

Intramural Research

Neuroimaging Section - Edythe London, Ph.D.

Scientists in NDAS reported that the spontaneous electroencephalogram (EEG) shows specific alterations in response to acute morphine administration. Morphine increased alpha and theta power. Most important was the finding that changes in EEG spectral power predict the subjective response to morphine. Thus, changes in alpha and beta power can predict the magnitude of positive affect, as measured by subjective self-reports. Findings such as these provide a basis for understanding the role of changes in the spontaneous EEG in brain function and behavior. (RL Phillips, R Herning, ED London (1994): Morphine effects on the spontaneous electroencephalogram in polydrug abusers: Correlations with subjective self-reports: Neuropsychopharmacol. 10:171-181.)

The N-methyl-D-aspartate (NMDA) receptor is major excitatory neurotransmitter receptor in the brain. Scientists in NDAS have discovered that a variety of cations, including polyamines that are present in high concentrations in the brain, cause a shift in the affinity state of the NMDA receptor. Understanding factors that modulate this receptor can lead to important advances in therapeutics aimed at drug abuse, epilepsy, and neurodegeneration. (ED London, A Mukhin: Polyamines as endogenous modulators of the N-methyl-D-aspartate receptor. Ann. N.Y. Acad. Sci., in press.)

A major approach to assessment of brain function noninvasively involves measurement of regional cerebral glucose metabolism by positron emission tomography (PET) scanning. Quantitative determinations using this procedure involve repeated sampling of arterial blood. Investigators in NDAS have developed a mathematical model that may revolutionize cerebral metabolic studies using PET scanning by simplifying the procedure. The model requires only four to six samples of venous blood to estimate the integral of the arterial concentration of the radiotracer during the measurement. (RL Phillips, CY Chen, DF Wong, ED London: An improved method to calculate metabolic rates for glucose using PET. J. Nucl. Med., in press.)

Previous work by investigators in NDAS has demonstrated that inhibitors of nitric oxide synthase, the enzyme that catalyzes formation of nitric oxide, ameliorates the opioid withdrawal syndrome in rats. Although most known inhibitors of nitric oxide produce hypertension, that may be an unwanted side-effect in a treatment medication, recent studies by these investigators have shown that 7-nitroindazole, a selective inhibitor of the neuronal form of the enzyme, ameliorates opioid withdrawal without pressor effects. This compound may lead to development of new approaches to treat opioid dependence. (DB Vaupel, AS Kimes, ED London: Comparison of 7-nitroindazole with other nitric oxide synthase inhibitors as attenuators of opioid withdrawal. Psychopharmacol. in press.)

Investigators in NDAS have demonstrated that the pattern of cerebral glucose metabolism is different in polydrug abusers than in control subjects matched for gender, age, and education. The drug abusers have a lower metabolic rate in the visual association cortex and higher metabolism in the orbitofrontal cortex. It is not know to what extent these differences in drug abusers reflect the effects of chronic drug abuse rather than pre-existing differences that may be pre-disposing factors that confer vulnerability to drug abuse. Future studies directed at testing other measures of function in the orbitofrontal cortex in drug abusers are planned. (JM Stapleton, MJ Morgan, RL Phillips, DF Wong, BCK Yung, EK Shaya, RF Dannals, X Liu, RL Grayson, and ED London: Cerebral glucose utilization in polysubstance abuse. Neuropsychopharmacol., in press.)

Psychobiology Section - Jonathan Katz, Ph.D.

A series of benztropine analogs has been prepared as probes for the dopamine transporter. Several of these analogs, most notably the 4',4"-dihalogenated compounds, demonstrate high affinity binding (Ki<30 nM) to the dopamine transporter that is selective (>100-fold) over the other monoamine transporters. These compounds block dopamine uptake in vitro and yet are not efficacious locomotor stimulants nor are they recognized as being cocaine-like in a drug discrimination paradigm. These compounds represent an unprecedented class of dopamine uptake inhibitors that will provide important tools for further exploration into the role of the dopamine transporter in mediating the behavioral effects of cocaine that lead to abuse. One significant question that may be addressed with these compounds is why some dopamine uptake inhibitors are abused and others are not. Further, these compounds may have potential as cocaine-abuse therapeutics.

Clinical Trials Section - Kenzie Preston, Ph.D.

Cocaine use among patients participating in methadone maintenance programs is a widespread problem for which no reliable treatment solutions currently exist. Division of Intramural Research (DIR) scientists evaluated the effectiveness of a novel voucher-based reinforcement contingency in producing sustained cocaine abstinence. A randomized controlled trial compared a voucher-based reinforcement contingency for cocaine abstinence to noncontingent voucher presentation in the treatment research clinic of the NIDA Intramural Research Program, Baltimore, MD. Patients were selected from 52 intravenous heroin abusers in methadone maintenance treatment; thirty seven of the 52 patients who used cocaine consistently during the first 5 weeks of treatment participated. Patients exposed to voucher-based reinforcement received a voucher for each cocaine-free urine sample (i.e., negative for benzoylecgonine) provided during a 12-week period; the vouchers had monetary values that increased as the number of consecutive cocaine-free urines increased. Control patients received noncontingent vouchers that were matched in rate, pattern, and amount to the vouchers received by patients in the contingent group. Primary outcome measures were cocaine abstinence by study week and the longest duration of sustained cocaine abstinence as determined by qualitative urinalysis. Patients receiving voucher reinforcement achieved significantly more weeks of cocaine abstinence (P=.007) and significantly longer durations of sustained cocaine abstinence (P=.001) than controls. Nine patients (47%) receiving voucher reinforcement achieved between 7 and 12 weeks of sustained cocaine abstinence; only 1 control patient (6%) achieved more than 2 weeks of sustained abstinence. Patients receiving voucher reinforcement rated the overall treatment quality significantly higher than controls (P=.002). Decreases in cocaine use were not associated with increases in use of alcohol or other drugs. Voucher-based reinforcement contingencies can produce sustained cocaine abstinence in inner-city intravenous polydrug abusers.

In addition to establishing the efficacy of contingency management procedures for treatment of cocaine abuse, the usefulness of quantitative urinalysis for cocaine metabolite and creatinine correction techniques and the relationship between these data and self-reported drug use were evaluated with data collected in the clinical trial. Rules were developed to differentiate between occasions of new use and carry-over in positive qualitative urine tests. These data were compared to self-reported drug use to evaluate the concordance between objective and subjective measures of drug use. Preliminary analyses suggest: qualitative and quantitative urine testing show greater rates of drug use than that shown by self report; quantitative testing provides a means of differentiating incidences of new drug use from residual carry-over; the identification of new use with quantitative testing may help to reconcile (by elimination of positives due to carry-over) differences between rates of drug use indicated by qualitative urine screens and self-report. In addition, quantitative testing of urine specimens in the contingency management study suggests that individuals who responded to treatment (i.e. stopped their cocaine use) had lower cocaine metabolite concentrations during baseline compared to those who did not respond to treatment. Thus, urine cocaine metabolite concentrations revealed through quantitative testing may be useful for predicting treatment outcome.

This study showed that voucher-based reinforcement of drug abstinence is an effective means of decreasing illicit cocaine use in polydrug abusers. The generalized effects of providing financial support to patients in the form of vouchers was controlled for in the study, clearly establishing the importance of the contingent nature of voucher distribution. It is particularly significant that efficacy was established in the context of otherwise standard methadone treatment, suggesting that this procedure may be readily exportable to community-based treatment programs. The work is further significant in the potential for identification of subject characteristics (e.g., demographic, physiological and behavioral) that are relevant to prediction of treatment outcome.

Buprenorphine has been reported to have the same efficacy as methadone in the treatment of narcotic abusers, but with lower abuse/dependence liability and greater safety than methadone. Naltrexone has been marketed in the United States for treatment of narcotic addiction; it blocks the euphoriant and analgesic effects of opioids and prevents the development of physical dependence and tolerance in patients who continue to use opioids. Researchers at the NIDA DIR have been working to develop a treatment regimen for short term inpatient detoxification and transition to outpatient naltrexone treatment. The safety and effectiveness of buprenorphine alone or in combination with naltrexone was evaluated in an 8-day inpatient medically supervised withdrawal single-blind study. Naltrexone 12.5, 25 or 50 mg was administered on days 3 & 4, 3 to 8, 5 to 8, or not at all; placebo was given on all days when active naltrexone was not given. All subjects received one sublingual buprenorphine dose daily in the following order: 4 mg (day 1), 6 mg (day 2), 4 mg (day 3), 2 mg (day 4), and 0 mg (day 5 to 8). The study was being conducted under a double-blind, controlled, randomized, parallel group design. The primary outcome variables are: 1) opioid withdrawal; 2) changes in craving for opioids; 3) results from screening of urine samples for opioids and cocaine during outpatient treatment; and 4) outpatient treatment compliance. Forty-five subjects who met DSM-IIIR criteria for opioid dependence consented to be studied. The group on buprenorphine alone (n=33) had equal or less withdrawal from day 2 through 4 compared to the group that started naltrexone on day 2 (n=8). However, from day 5 through day 7 the naltrexone-treated group had less withdrawal than the group with buprenorphine alone. All subjects who started receiving naltrexone on day 5 (n=4) had severe opiate withdrawal and recruitment of subjects for this group was stopped. These results suggest that administration of naltrexone on day 2 may increase opiate withdrawal at the beginning of treatment but lead to decreased withdrawal thereafter, compared to treatment with naltrexone placebo. This result may bear on the hypothesis that antagonists may produce partial resetting of the opiate receptor, resulting in a shorter duration of withdrawal. These data also support the development of cost-effective short-term inpatient opiate detoxification and early transition to opiate-free treatment using naltrexone.

Oral ingestion is the primary route by which cocaine has been used throughout most of history. Cocaine has been self-administered orally for over 3000 years, first by Indians of South America who began the practice of chewing coca leaves, and later by members of a number of cultures who orally ingested cocaine in a variety of vehicles, particularly beverages such as coca tea, soft drinks (i.e., Coca Cola) and coca wine. Recent estimates indicate that today over four million Indians in Peru and Bolivia chew coca leaves regularly, and coca tea is still sold widely and legally in many areas of South America. Despite this remarkable longevity and current-day prevalence, relatively little is known about the behavioral pharmacology of oral cocaine, particularly at low doses that approximate those commonly ingested by the oral route. The study was conducted to characterize the behavioral pharmacology of low-dose oral cocaine in humans as a potential screening tool for identifying pharmacological treatments of cocaine abuse.

Seven volunteers with histories of regular cocaine use were taught to distinguish 50 mg of oral cocaine from placebo using a drug discrimination procedure. During daily training sessions, under double-blind conditions, the volunteers ingested a capsule containing 50 mg cocaine or placebo. For 2 hours after capsule ingestion, subjects guessed whether they had received "Drug" or "Placebo." At the end of each session, subjects were told which compound they had received. Subjects earned money for correct guesses and lost money for incorrect guesses. One subject who quickly acquired the cocaine vs. placebo discrimination was exposed to 3 doses of oral cocaine (6.25 mg, 12.5 mg, and 25 mg) in test sessions in random order across days to determine the lowest doses of cocaine he could detect. No feedback was provided at the end of test sessions. Test sessions were randomly intermixed among training sessions identical to the ones described above in which subjects received either 50 mg cocaine or placebo. Throughout all of these administrations cardiovascular, performance, and self-reported mood measures were collected.

In the last 20 sessions of the initial training condition, 50 mg cocaine produced significant discriminative stimulus and rate increasing performance effects, and increases in "liking" ratings in five of seven subjects. It also produced a profile of mood effects characteristic of cocaine administered by other routes. The onset of the behavioral effects was between 30 and 40 minutes after capsule ingestion. Fifty mg cocaine produced only minor cardiovascular effects. Interestingly, two subjects showed significant behavioral effects without significant tachycardic effects. The subject exposed to 25 mg, 12.5 mg, and 6.25 mg showed clear discriminative stimulus and rate-increasing performance effects at 25 mg and to a lesser extent at 12.5 mg. Cardiovascular effects were minimal or absent at those lower doses.

This study demonstrated the behavioral activity of doses of oral cocaine that are lower than those previously shown to affect human behavior. Oral cocaine produced a similar profile of self-reported mood and performance effects and cocaine administered by other routes. These methods revealed important behavioral effects of oral cocaine at doses that produced minimal or no detectable cardiovascular effects. The results of this study suggest that these procedures may be useful in studying the behavioral pharmacology of cocaine under conditions that minimize risk to subjects.

Pharmacotherapy Section, David Gorelick, M.D., Ph.D.

Much research on the neuropharmacology of cocaine abuse has focused on brain dopamine systems, but there is growing evidence from animal studies that cocaine also influences brain opiate systems, especially mu-opiate receptors. Researchers at the NIDA DIR, in collaboration with scientists at the Johns Hopkins School of Medicine, recently completed a study showing that chronic cocaine users, compared with healthy controls, have increased mu-opiate receptor binding in certain brain regions, and this increase persists in most subjects even after four weeks of cocaine abstinence. Receptor binding in several brain areas was also significantly correlated with subjects' self-reported craving for cocaine. These findings suggest that brain mu-opiate receptors changes associated with chronic cocaine use may play a role in cocaine abuse, and provide a basis for the study of opiate medications, e.g., buprenorphine, as possible treatments for cocaine abuse.

Numerous animal studies have shown that calorie deprivation increases drug self-administration, but this phenomenon has never been demonstrated in human drug users. Researchers at the NIDA DIR have recently completed a study showing that a 700-calorie deficit diet significantly increased drug self-administration in human subjects, using cigarette smoking as the target drug. This is the first experimental demonstration of this phenomenon in humans, and suggests that dietary changes induced by drug abuse could themselves influence further drug use.

Researchers at the NIDA DIR are exploring several new approaches to the pharmacological treatment of cocaine abuse. One approach is the use of combinations of medications which act on a neurotransmitter system by different mechanisms, thus possibly producing additive or synergistic therapeutic effects while minimizing side-effects. The first such study, recently completed, used two dopaminergic medications, bromocriptine, a dopamine receptor agonist, and bupropion, a presynaptic reuptake inhibitor, in an open-label outpatient clinical trial. The first phase of the study used a very slow dose escalation regimen to establish the safety of this medication combination, even in subjects who use cocaine while in treatment. The second phase used a more rapid dose escalation regimen that achieved putative therapeutic doses earlier in treatment. This phase also established safety, and gave promising efficacy results as compared with the first phase. NIDA DIR now plans a double-blind clinical trial to follow-up this promising approach.

Molecular Neurobiology Section, George R. Uhl, M.D., Ph.D.

Recent studies continuing this laboratory's work characterizing the rat and human mu opiate receptors and their genes have identified surprising findings that add to the diversity of opiate receptor actions in the brain. In studies expressing the rat and human mu receptor genes, sequences were identified that dramatically alter levels of expression of the receptor protein in several model expression systems. These findings, coupled with recent observations of mu receptor gene splice variants, have uncovered, for the first time, a novel mode of possible regulation of the mu receptor's expression. Mechanisms of this regulation and its implications for receptor regulation in brain are currently being explored.

Studying mu receptor localization with selective antisera reveals striking localizations in pathways associated with reward and reinforcement. Densities of mu receptor immunoreactive nerve fibers and terminals patterns in the ventral tegmental area contrast with strongly-immunopositive cell bodies, fibers and terminals in the nucleus accumbens. These studies provide, for the first time, a precise anatomic picture of the ways in which mu opiate activation by morphine and other drugs directly influences both ends of putative dopaminergic reward pathways in the brain.

Recent studies continued this laboratory's work characterizing the rat and human dopamine transporters that form the major brain cocaine receptors. In studies expressing mutants of this transporter, amino acids selectively contributing to cocaine affinity were identified in previous studies. In current work, the exact functional side-chains of these amino acids that contribute to cocaine-selectivity were identified by selective amino acid substitutions. These findings provide new and important clues in efforts to develop dopamine-sparing cocaine antagonist drugs.

Genetics Section, Lucinda Miner, Ph.D. (Acting Chief)

There are large individual differences among humans and animals in behavioral, physiological and toxicological responses to drugs of abuse. Transgenic mouse models with only modest regional overexpression of the dopamine transporter showed greater sensitivity to the rewarding properties of cocaine in the conditioned place preference paradigm.

QTL analyses have located candidate regions for the psychomotor stimulant effects of cocaine to segments of murine chromosomes 4, 5, 9 and 13, several of which have reasonable syntenic matches with human chromosomal segments. This information underscores the possibility that genetic determination of human interindividual differences in drug abuse vulnerability may be oligogenic, caused chiefly by effects of a limited number of genes.

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