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Director's Report to the National Advisory Council on Drug Abuse
May, 2001

Research Findings

Behavioral Research

How Persistent is the Effect of Smoking Urges on Cognitive Performance?

Recent work from Dr. R. Zwann's program has provided empirical support for the hypothesis that drug urges interfere with cognitive performance. That is, the speed and/or accuracy of cognitive performance deteriorates in the presence of external smoking cues such as the smell of smoke, or of internal cues such as the thought of smoking. There is, however, little information about the time course of these interference effects. Different theoretical formulations predict that the effect of urges on cognitive performance might remain constant, dissipate, or increase over time. The present study was designed to distinguish among these predictions. Smoking urges were elicited by listening to descriptions of smoking-related information and cognitive performance was evaluated using a sentence comprehension task. Exposure to the urge script decreased comprehension accuracy in smokers but not in nonsmokers. This effect was short-lived, appearing only in the first block of 25 trials. Thus, smoking urges interfere with cognitive performance, but the effect dissipates over time. However, it is still not known if dissipation of the urge effect is due to decay of the urge itself, or to an improved ability to perform in the face of a constant urge. Zwann, R.A., Stanfield, R.A. and Madden, C.J. How Persistent is the Effect of Smoking Urges on Cognitive Performance? Experimental and Clinical Psychopharmacology, 8, pp. 518-523, 2000.

Effects of Cocaine Self-Administration in a Complex Behavioral Task

Dr. Peter Winsauer has been using a three-component multiple schedule of reinforcement to assess cocaine's reinforcing effects separately from its effects on learning (acquisition of an operant response), and performance in monkeys. In the first component of the schedule, monkeys respond for intravenous infusions of cocaine. In the second component, monkeys learn a response sequence to receive food reinforcement. The sequence required in the second component changes from day-to-day; thus, animals must learn a new sequence each day (repeated acquisition). In the third component, monkeys also perform a response sequence to receive food reinforcement. However, the sequence required in the third component remains the same each day and thus provides a measure of effects on performance. The effects of 4 doses of cocaine (0.01, 0.032, 0.1, 0.32 mg/kg) on responding under the multiple schedule were studied. Increasing the unit dose of cocaine dose-dependently decreased overall response rates in all three components of the multiple schedule and increased the total amount of drug obtained per session. In addition, increasing the unit dose of cocaine disrupted acquisition but had little effect on performance. These data indicate that learning is generally more sensitive than performance to the disruptive effects of self-administered cocaine. These experiments also demonstrate the utility of multiple schedules for studying effects of self-administered drugs on the acquisition and performance of complex behaviors. Winsauer, P.J., Silvester, K.R., Moerschbaecher, J.M. and France, C.P. Cocaine Self-Administration in Monkeys: Effects on the Acquisition and Performance of Response Sequences. Drug and Alcohol Dependence, 59, pp. 51-61, 2000.

Motivation to Obtain Nicotine Is Higher in Female Rats

Research on smoking behavior and responsiveness to nicotine suggests that nicotine's effects may depend on the sex of the organism. Researchers in the Department of Psychology, University of Pittsburgh, led by Dr. Anthony R. Caggiula allowed male and female rats to self-administer nicotine at one of four doses (0.02-0.09 mg/kg, free base) on both fixed and progressive ratio schedules of reinforcement. Progressive ratio schedules measure how much an animal will work to obtain reinforcement - an infusion of nicotine in this case. Males and females acquired nicotine self-administration across the entire range of doses. Acquisition of self-administration at the lowest dose was faster in females than males. However, few sex differences were found in the number of active responses, number of infusions, or total intake of nicotine during stable fixed ratio self-administration. In contrast, females reached higher break points on the progressive ratio; that is, they worked harder than the males to obtain the same dose of nicotine. For both schedules, females had shorter latencies to earn their first infusion of each session and demonstrated higher rates of both inactive and timeout responding. There was no effect of estrous cycle on self-administration during either fixed or progressive ratio sessions. Self-administered nicotine resulted in average arterial plasma nicotine levels between 53 and 193 ng/ml and left hemi-brain levels between 174 and 655 ng/g, depending on dose. Nicotine self-administration produced similar up-regulation of nicotinic receptor binding sites in males and females, as reflected by increased right hemi-brain binding of [3H]-epibatidine, when compared to the brains of untreated control rats. These results suggest that the motivation to obtain nicotine is higher in females. Donny, E.C., Caggiula, A.R., Rowell, P.P., Gharib, M.A., Maldovan, V., Booth, S., Mielke, M.M., Hoffman, A. and McCallum, S. Nicotine Self-Administration in Rats: Estrous Cycle Effects, Sex Differences and Nicotinic Receptor Binding. Psychopharmacology (Berl) 151(4), pp. 392-405, 2000.

Sex-Related Differences in the Antinociceptive Effects of Opioids

Sex differences in morphine-induced antinociception (reduction of pain) have been described previously using thermal, chemical and electrical stimuli. The present study examined the role of nociceptive stimulus intensity and relative efficacy (magnitude of binding required for effect) of opioids on sex differences in opioid-induced antinociception. Results indicated that sex differences in potency and effectiveness increased with [1] decreases in the opioid's relative efficacy, and [2] increases in the intensity of the nociceptive stimulus. For example, high efficacy opioids were 2.5 times more potent in males than females, whereas low efficacy opioids were 8.9 times more potent in males than females. These findings suggest that the failure to find sex differences in antinociception using high efficacy opioids may not predict whether a sex difference will be found for low efficacy opioids. In fact, the use of lower efficacy opioids may provide a sensitive assay for investigating the role of sex hormones on opioid sensitivity. Cook, C.D., Barrett, A.C., Roach, E.L., Bowman, J.R. and Picker, M.J. Sex-Related Differences in the Antinociceptive Effects of Opioids: Importance of Rat Genotype, Nociceptive Stimulus Intensity, and Efficacy at the _ Opioid Receptor. Psychopharmacology, 150, pp. 430-442, 2000.

A Dopamine Agonist Attenuates the Development of Morphine Tolerance but not Physical Dependence in Rats

Chronic administration of mu opioids such as morphine and heroin produces tolerance and physical dependence. In addition to their direct effects on the opioid system, chronic administration of mu opioids affect other neurotransmitter systems, in particular the dopaminergic (DA) system. The present study was undertaken to investigate the effects of a DA D2/D3 receptor agonist, 7-OH-DPAT, on the development of morphine tolerance and physical dependence in the rat. Results indicate that 7-OH-DPAT attenuates the development of morphine tolerance in a time- and dose-dependent manner in both na•ve and morphine-tolerant rats. This effect was not the result of increased sensitivity to morphine. However, 7-OH-DPAT did not attenuate signs of physical dependence to morphine and did not precipitate withdrawal in morphine-dependent rats. Thus, it appears that the effects of 7-OH-DPAT on tolerance versus physical dependence can be pharmacologically dissociated. This study adds to a growing body of literature showing that non-opioid mechanisms can differentially modulate the acute effects of morphine as well as the development of tolerance and dependence. Cook, C.D., Barrett, A.C., Syvanthong, C. and Picker, M.J. The Dopamine 3/2 Agonist 7-OH-DPAT Attenuates the Development of Morphine Tolerance but not Physical Dependence in Rats. Psychopharmacology, 152, pp. 93-104, 2000.

Role of Endogenous Stress Systems in the Acute Effects of Psychostimulants

Animals with experimenter-manipulated or stress-induced increases in corticosterone are more prone to acquire drug self-administration. Both locomotor and reinforcing effects of these drugs are blocked by interfering with the HPA (hypothalamic-pituitary-adrenal) axis or by inhibiting corticosterone synthesis. Stress has also been reported to influence acute responses to psychostimulants in humans and to enhance reports of craving reported by cocaine abusers. NIDA grantee Dr. Stephen Wachtel and colleagues recently evaluated the effects of hydrocortisone (HC) on the effects of acute d-amphetamine in drug experienced human subjects. These investigators pre-treated subjects with 100 mg HC (or placebo) prior to administering either 20 mg d-amphetamine or the amphetamine placebo in a cross-over design. HC by itself produced few subjective effects on the Addiction Research Center Inventory, on visual analog scales (e.g., "stimulated", "sedated", etc.), on a drug effects questionnaire (DEQ, e.g., "do you feel any drug effects", "are you high", etc.) or on a version of the POMS (profile of mood states). The acute physiological (increased heart rate and blood pressure), psychomotor performance (enhanced digit symbol substitution test performance), and subjective effects (stimulation, arousal, and positive mood) of d-amphetamine were not altered by prior HC treatment, with the exception of a decrease in reports of "want more drug" on the DEQ. These observations with human subjects do not parallel the existing body of literature on an importance for endogenous stress systems in the reinforcing effects of psychostimulant drugs. However, this study examined only acute effects of d-amphetamine and did not directly assess choice behavior for the drug. It is also possible that activation of other components of this endogenous HPA system may be involved in vulnerability and relapse, or that a more prolonged activation is required to detect these influences. Wachtel, S.R., Charnot, A. and de Wit, H. Acute Hydrocortisone Administration Does not Affect Subjective Responses to d-amphetamine in Humans. Psychopharmacology, 153, pp. 380-388, 2001.

Behavioral Reactivity to Cocaine as a Predictor of Social Status

Researchers at the Wake Forest University School of Medicine examined a number of variables as potential predictors of social rank in 20 individually-housed Cynomologus monkeys; among them were body weight, serum cortisol and testosterone levels, and locomotor activity in an open-field apparatus following a low dose of cocaine (0.01 mg/kg). Subsequently, the 20 monkeys were placed in social groups (five pens of four monkeys each) and social rank was determined on the basis of dyadic agonistic encounters. Heavier body weight predicted higher social rank and cocaine-induced high locomotor activity predicted subordinance. Social rank was unrelated to serum cortisol and testosterone levels. Morgan, D. Grant, K.A., Prioleau, O.A., Nader, S.H., Kaplan, J.R. and Nader, M. Predictors of Social Status in Cynomolgus Monkeys (Macaca Fascicularis) After Group Formation. American Journal of Primatology, 52, pp. 115-131, 2000.

Increased Sensitivity to Alprazolam in Females with a Paternal History of Alcoholism

In a study of 28 women characterized as light drinkers, the anxiolytic drug alprazolam impaired performance in a dose-related manner on psychomotor, cognitive and memory tasks. At the highest alprazolam dose, women with a paternal history of alcoholism were more impaired on these measures than women without a paternal history of alcoholism. The authors also report greater alprazolam-produced increases in ratings of "difficulty concentrating" and "unmotivated behavior" as well as fewer positive subjective effects (e.g. positive mood, elation, friendliness, "drug liking") and more negative subjective effects (e.g., "bad drug effect") in women with a paternal history of alcoholism. Evans, S.M., Levin, F.R., and Fischman, M.W. Increased Sensitivity to Alprazolam in Females with a Paternal History of Alcoholism. Psychopharmacology, 150, pp. 150-162, 2000.

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