Director's Report to the National Advisory Council on Drug Abuse
May, 1995
Research Findings
Behavioral Research
Effects of Caffeine on Decrements Produced by Benzodiazepines or Alcohol
Researchers at the University of Vermont (Drs. Rush, Higgins, Bickel, and Hughes) have demonstrated in humans that caffeine can attenuate the behavioral performance decrements produced by benzodiazepines or alcohol. Caffeine attenuated learning and performance decrements on the Repeated Acquisition and Performance Procedure and the Digit Symbol Substitution Test produced either by lorazepam, triazolam, or alcohol. Caffeine administered alone did not enhance performance or learning. Caffeine also decreased self-ratings of sedation produced by the benzodiazepines. (Behav. Pharm. 5, 245-254 (1994), Exp. & Clin. Psychopharm. 2, 211-22 (1994), Behav. Pharm. 4, 562-572 (1993) )
Amphetamine and Feeding Behavior
Amphetamine produces marked stereotypy that may interfere with feeding behavior. Dr. David Wolgin of Florida Atlantic University has investigated the factors contributing to the development of tolerance to amphetamine-induced hypophagia. Rats learned to suppress stereotyped head movements produced by amphetamine in order to receive sweetened milk reinforcement. Further analysis of head movements revealed residual behavioral effects of amphetamine even in "tolerant" amphetamine-treated rats. These studies demonstrate that behavioral tolerance may maintain drug abuse by decreasing the disruptive effects of stimulant drugs. Behavioral Pharmacology, in press, 1995.
Concurrent Cocaine/Alcohol Abuse
Dr. Elinore McCance-Katz of Yale University School of Medicine has conducted a placebo-controlled, double-blind study examining the behavioral and physiological effects and pharmacokinetics of intranasal cocaethylene administration in humans using cocaine as a comparator. Cocaethylene is an active metabolite formed as a result of simultaneous use of cocaine and alcohol, a common occurrence which constitutes a major public health problem. The results showed that the concurrent ingestion of cocaine and alcohol is associated with enhanced subjective euphoria, increased heart rate, and increased plasma cocaine concentration. Slow disposition could result in accumulation of cocaethylene and increase the toxic effects of binge use of cocaine and alcohol in humans. These findings suggest that cocaethylene may play a role in the morbidity and mortality associated with concurrent cocaine/alcohol abuse.
Locomotor and Rewarding Effects of Amphetamine in Enriched Social and Isolated Rats
The interactions of novel environments and behavioral responses to drugs have been investigated by Drs. Bowling and Bardo from the University of Kentucky. They examined the influence of environmental enrichment on the behavioral response to amphetamine. Rats were raised in one of three different environmental conditions: a) an enriched condition (EC), b) a social condition (SC), c) an isolated condition (IC). At 53 days, animals were assessed for amphetamine-induced changes in locomotor activity and reward using the conditioned place preference (CPP) paradigm. EC animals exhibited more horizontal and vertical activity following amphetamine than both the SC and IC animals. Similarly, EC animals exhibited a greater magnitude of amphetamine-induced CPP than both the SC and IC animals. It is hypothesized that the EC environment may sensitize the dopaminergic mesolimbic pathway in much the same way as low doses of amphetamine have been shown to; thus, explaining the enhanced effect of amphetamine in these animals. Bowling, S.L., Bardo, M.T. Locomotor and Rewarding Effects of Amphetamine in Enriched, Social and Isolate Reared Rats. Pharmacology, Biochemistry and Behavior, 48, 459-464, 1994.
Conditioned Place Preference Using Opiate and Stimulant Drugs
Bardo and his colleagues conducted a meta-analysis on data obtained from published articles that have used the conditioned place preference (CPP) paradigm to assess the rewarding effects of morphine, heroin, amphetamine and cocaine in rats. Using a histogram analysis of the data, significant dose effect curves were evident with all of the drugs examined except for cocaine. One surprising outcome was the failure to find any significant differences in effect size based upon the number of drug conditioning trials used. The meta-analysis indicates that researchers must consider the risk of introducing variables which confound interpretations of CPP as a measure of drug reward. Bardo, M.T., Rowlett, J.K., Harris, M.J. Conditioned Place Preference Using Opiate and Stimulant Drugs: A Meta-Analysis. Neurosciences and Biobehavioral Review, 18, 1-12, 1995.
Effects of Ethanol on the Acoustic Startle Reflex in Humans
A substudy of research on the specificity of genetic transmission of risk for substance abuse indicates human sensorimotor reactivity among healthy normal subjects (N=12) was significantly affected by the effects of ethanol. The amplitude of the acoustic startle response in a procedure in which a placebo or ethanol were given on separate days was dramatically reduced by acute ethanol. The effects of ethanol on prepulse inhibition could not be assessed because the startle response was too small in the ethanol conditions. The report helps to describe the risk to normal subjects under acute effects of ethanol in terms of safety and other risks, such as continued drug use. (Grillon, C, Sinha, R, and O'Malley, SS. Effects of Ethanol on the Acoustic Startle Reflex in Humans. Psychopharmacology 114:167-171, 1994).
Cocaine and Cigarette Smoking
In a letter in the December issue of JAMA, Dr. Steven Higgins and colleagues at the University of Vermont described data suggesting that cocaine and cigarette smoking may be correlated. For example, they found that cocaine had a facilitative effect upon cigarette smoking in a laboratory study. Further, a study of cocaine-dependent outpatients revealed that the cigarette smokers in this group used more cocaine than nonsmokers and were more likely to use i.v. or smoked cocaine. This finding is of great concern because the cocaine plus nicotine combination produces greater cardiac risk than either drug alone. [Higgins, S.T., Budney, A.J., Hughes, J.R., Bickel, W.K., Lynn, M., & Mortensen, A. (1994), Influence of Cocaine Use on Cigarette Smoking, JAMA, 272, 1724.]
Social Cooperation During Abstinence From Nicotine
In a study conducted by Dr. Ralph Spiga at the University of Texas, Houston Health Science Center, heavy smokers who had abstained from smoking were brought into the laboratory to investigate their level of cooperation in a shared laboratory task. After the 1st daily session subjects smoked ad libitum, received 0, 2, or 4 mg nicotine gum, or abstained from smoking. Indices of cooperation were significantly greater following ad libitum smoking or acute administration of 4 mg nicotine gum. Nicotine abstinence did not alter "independent", non-cooperative responding, but did reduce cooperative responding. Results suggest nicotine use may increase social cooperation during a shared work task, thus potentially motivating relapse in abstinent heavy smokers. Behavioural Pharmacology. Vol 5(3) 337-343, June 1994.
Chronic and Acute Tolerance to Subjective, Behavioral, and Cardiovascular Effects of Nicotine in Humans
In the first study of its kind, Dr. Perkins and his colleagues (Western Psychiatric Institute, Pittsburgh) measured the dose-related subjective, behavioral, cognitive, and cardiovascular effects of acute or chronic exposure to nicotine in smokers and non-smokers. The subjective (e.g., tension, confusion, vigor, fatigue) and cardiovascular measures (heartrate, blood pressure) were obtained over the first 5 min, followed by behavioral (e.g., finger-tapping speed, handsteadiness, tremor), and cognitive tasks (memory recognition, numerical Stroop task) during the next 10 minutes after the exposure to nicotine (administered at 0, 5, 10, or 20 ug/kg, via measured-dose nasal spay, with different doses presented on different days to male and female smokers [n=17] and nonsmokers [n=18]). The acute tolerance was clear and substantial for subjective measures, but was less clear for behavioral or cardiovascular effects. There was substantial chronic tolerance for subjective responses, less for behavioral task performance and little for cardiovascular responses. The regular use of nicotine was associated with chronic functional tolerance, and repeated nicotine exposure during a single episode produced acute tolerance. According to the authors, the differential development of tolerance across response domains suggests differential mechanisms responsible for the different effects of nicotine. (Perkins KA, Grobe JE, Fonte C, Goettler JL, Caggiula AR, Reynolds WA, Stiller RL, Scierka A, and Jacob RG. Journal of Pharmacology and Experimental Therapeutics, 270: 628-638, 1994).
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