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National Institute on Drug Abuse

Director's Report to the National Advisory Council on Drug Abuse
September, 1997

Research Findings

Behavioral Research

Delay Discounting Differs in Opioid-Dependent Persons

Choosing a smaller, immediately available reward could be described as an impulsive behavior if it is chosen over a larger delayed reward. Researchers at the University of Vermont examined opioid-dependent and non-drug dependent volunteers' choices between hypothetical immediate and delayed monetary rewards. The researchers found that opioid-dependent volunteers, in comparison to the controls, chose the smaller more immediate monetary reward more frequently. These results indicate that opioid-dependent subjects were more impulsive than control subjects and were more likely to consider delayed monetary gains to be less valuable ("delay discounting"). Further research is needed to determine whether delay discounting and impulsive behavior precedes or follows drug dependence. Madden, G.J., Petry, N.M., Badger, G.J, and Bickel, W.K. Experimental and Clinical Psychopharmacology, 5(3), pp. 1-7, 1997.

Potential Abuse Liability of Zipeprol

Zipeprol is marketed as a non-opioid antitussive in Europe and Asia, but may have abuse potential and also acute toxicity when taken orally. Laboratory studies indicate that Zipeprol is not discriminable from amphetamine or pentobarbital in a drug discrimination test. Zipeprol has, moreover, suppressed morphine withdrawal in non human primates, and it does substitute for the opioid alfentanil in a drug self-administration procedure. Based on these and other reported observations, the researchers conclude that Zipeprol has significant abuse liability that had not been detected previously. Acteo, M.D., et al., Drug and Alcohol Dependence, 42, pp. 93-104, 1996.

Trazodone May Be a Viable Alternative to Benzodiazepine Hypnotics

Dr. Craig Rush and colleagues at the University of Mississippi compared the acute subject-rated and performance- impairing effects of trazodone and triazolam in research volunteers. Trazodone (50, 100 and 200 mg), triazolam (0.125, 0.25, 0.50 mg) and placebo were administered orally in a double-blind, crossover design. Drug effects were measured before and after dosing for up to 6 hr. Trazodone and triazolam produced dose-related increases in subject- ratings of drug effect and sedation. The absolute magnitude of trazodone's and triazolam's effects was comparable across these measures, which suggests the doses tested were equivalent on some behavioral dimension. By contrast, triazolam, but not trazodone, increased subject ratings of "dizzy", "excited", "nervous", "restless", "stomach turning" and "itchy skin". Triazolam, but not trazodone, significantly impaired learning, recall and performance. Future studies might seek to replicate these results in a clinically relevant population such as individuals with histories of drug abuse. Rush, C.R. et al., Trazodone and Triazolam - Acute Subject Rated and Performance-Impairing Effects in Healthy Volunteers. Psychopharmacology, 131, pp. 9-18, 1997.

Evidence for a Sex-Specific Residual Effect of Cannabis on Visuospatial Memory

Dr. Harrison Pope and his colleagues at Harvard Medical School used a novel computerized battery of neuropsychological tests of attention to assess residual cognitive impairment in 25 college students who were heavy smokers of marijuana (having smoked a median of 29 days in the last 30 days). These were compared with 30 light smokers (having smoked marijuana for one day in the last 30 days). They were assessed after they had abstained from marijuana use for at least 19 hours (monitored by urine toxicology). In the visuospatial tests, the subjects were required to examine a 6x6 'checkerboard' of squares in which certain squares are shaded. The shaded squares were then erased and the subject was required to indicate with the mouse which squares had formerly been shaded. Increasing numbers of shaded squares were presented at each trial. The heavy smoking women performed poorly on the visuospatial memory tasks. They remembered significantly fewer squares and made significantly more errors than the light-smoking women. Authors concluded that it may be important to study the residual effects of marijuana on men and women separately-particularly since women have been greatly underrepresented in previous studies in this area. Pope, H.G., Jacobs, A., Mialet, J.-P. and Gruber, S. Psychother Psychosom, In press.

Effects of Stress Versus Reward on Drug Discrimination

This study was conducted in an attempt to further identify variables that predict individual differences in drug abuse liability. Rats were pretested in several different screens - novelty induced activity, novelty-induced place preference, novel-object interaction, and amphetamine-induced activity. Rats that were more sensitive to the locomotor effects of amphetamine were more active in an escapable novel environment and displayed a greater preference for a novel environment. All animals were trained to discriminate amphetamine (1 mg/kg) from saline in a two-bar discrimination procedure using food maintained responding. Following acquisition of the discrimination, two amphetamine generalization tests (0.0625, 0.125, 0.25, 0.5, 1.0 and 2.0 mg/kg) were conducted. In the second generalization test rats that were more sensitive to the activating effect of amphetamine were also more sensitive to the discriminative stimulus effects of amphetamine. Moreover, high responders in the novelty-induced activity and novelty-induced place preference screens were more sensitive than low responders to the bar-press suppressant effects of amphetamine in the first generalization test. The relations are discussed in terms of identifying processes common to the screens (e.g. stress and reward). Bevins, R.A., Klebaur, J.E. and Bardo, M.T. Individual Differences in Response to Novelty, Amphetamine-Induced Activity and Drug Discrimination in Rats. Behavioral Pharmacology, In press.

Environmental Manipulation Alters Drug Efficacy

To further test the impact of different rearing environments on subsequent behavioral and neurologic response to morphine, rats were raised from weaning to young adulthood in either an enriched-EC (group housed with various novel visual objects) or impoverished-IC (housed individually with no objects). As adults, locomotor activity and reward produced by morphine was assessed using the conditioned place preference paradigm (CPP). On Day 1, rats in both groups showed an inverted U-shaped dose effect curve for locomotor activity though the effect was greater for IC than the EC group. Across days, both groups showed locomotor sensitization; although again, the effect was greatest in the IC group. In contrast, morphine-induced CPP (the measure of 'reward') was attenuated in the IC group when compared to the EC group indicating that the locomotor versus rewarding effects were dependent on different neural substrates. To test this, measurement of mu opioid receptor density and rates of dopaminergic synthesis in the mesolimbic and nigrostriatal systems of rats from each group showed no difference between IC or EC groups. Therefore, it was concluded that while these receptors do modulate mesolimbic dopamine neurotransmission this does not account for the differential behavioral effects seen in the IC group relative to the EC group. Bardo, M.T., Robiner, P.M., and Hammer, R.F. Effect of Differential Rearing Environments on Morphine Induced Behaviors, Opioid Receptors and Dopamine Synthesis. Neuropharmacology, 36, pp. 251-259, 1997.

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