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National Institute on Drug Abuse

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

May, 2000

Research Findings

Behavioral Research

A New Rapid Assessment Method for Dopamine Receptor Agonists

Recent studies suggest that dopamine D1-like and D2-like receptor agonists have differing profiles of cocaine-related actions. Dr. Barak Caine and his colleagues at the McLean Hospital-Harvard Medical School sought to develop a procedure for comparing the effects of D-1- and D-2-like agonists on cocaine self-administration in rhesus monkeys using a rapid pre-treatment dose-comparison procedure. Complete inverted U-shaped dose-effect functions for cocaine self-administration were obtained in all monkeys trained with the rapid assessment procedure. Levels of responding, moreover, were associated with the unit dose of cocaine. Pretreatment with D1-like agonists produced downward shifts in the cocaine dose-effect function at doses that also markedly decreased food-maintained responding. In contrast, pretreatment with D2-like agonists shifted the cocaine dose-effect function to the left. D2-like agonists also increased responding maintained by the cocaine-associated cue lights alone, and moderately decreased food-maintained responding. The authors conclude that D1- and D2-like agonists produce qualitatively different effects on cocaine self-administration that may influence their usefulness for the treatment of cocaine abuse and dependence. Caine, S.B., Negus, S.S., and Mello, N.K. Effects of Dopamine D(1-like) and D(2-like) Agonists on Cocaine Self-Administration in Rhesus Monkeys: Rapid Assessment of Cocaine Dose-Effect Functions. Psychopharmacology, 148, pp. 41-51, 2000.

Drug Discrimination: Training Dose Influences Subjective Drug Effects

Drug discrimination studies have found that animals trained with lower doses of a training drug are more sensitive to detecting the subjective ‘cue' properties of that drug on subsequent discrimination tests. These animals are also more sensitive to the subjective, interoceptive cue effects of other drugs as well, when tested with compounds that show generalization to the training drug. Few studies have assessed the effects of training dose on discrimination profiles in human subjects. Kollins and Rush examined the effects of training dose of d-amphetamine (10 mg or 20 mg) in human subjects performing a drug discrimination task. The dose-response curve for detecting amphetamine was shifted to the left in subjects trained with the lower dose of d-amphetamine. Subjects trained with the lower dose also reported greater subjective effects on scales of "like the drug", "stimulated", and "feel like socializing," while other self-reported effects of d-amphetamine, such as "anxious" and "bad effects" did not vary with training dose. The authors conclude that prior experience with the lower dose rendered these subjects more sensitive to the interoceptive cue properties of d-amphetamine and also to some of the positive subjective effects of this drug. These observations are important because detecting interoceptive drug cues may contribute to relapse. Kollins, S.H. and Rush, C.R. Effects of Training Dose on the Relationship Between Discriminative Stimulus and Self-Reported Drug Effects of d-Amphetamine in Humans. Pharmacol. Biochem. Behav., 64, pp. 319-326, 1999.

Dopaminergic Substrates for the Subjective Effects of Caffeine

At low doses, the methylxanthine caffeine acts as a behavioral stimulant in human subjects and induces locomotor activation in the rat. However, higher doses (>300 mg in humans) produce agitation and anxiety on self-report measures and induce a suppression of animal behavior. Recent evidence suggests that the low dose activation may occur, in part, via the same central dopaminergic system that serves as the critical substrate for behavioral effects of other psychostimulants (e.g., amphetamine or cocaine). Little is known about dopaminergic involvement in subjective effects of caffeine. Drs. Powell, Koppelman and Holtzman from Emory University found that D1 and D2 dopamine receptor antagonists completely block the discriminative stimulus effects of low, but not high, caffeine doses in the rat. Animals trained to discriminate a low dose of caffeine from saline did not show generalization to higher doses of caffeine, suggesting that low and high doses induce qualitatively different subjective effects. These findings mimic self-report measures from human subjects and suggest that increasing doses of this stimulant may recruit different transmitter systems or induce behavioral effects through different neurochemical mechanisms. Powell, K.R., Koppelman, L.F. and Holtzman, S.G. Differential Involvement of Dopamine in Mediating the Discriminative Stimulus Effects of Low and High Doses of Caffeine in Rats. Behav. Pharmacol., 10, pp. 707-716, 1999.

d,l-Fenfluramine Decreases Aggressive and Impulsive Responding in Adult Males with a History of Conduct Disorder

The effects of acute doses of d,l-fenfluramine (0.2, 0.4, and 0.8 mg/kg) on aggression and impulsivity were examined in ten male subjects with a history of conduct disorder and criminal behavior. Aggression was assessed with a laboratory-based point subtraction aggression procedure that provides subjects with aggressive, escape, or monetary response options. Impulsivity was assessed in a delay of gratification task in which subjects chose between a small reward after a short delay and a larger reward after a longer delay. Impulsivity was measured as frequent choice of the short delayed reward. In the aggression procedure, d,l-fenfluramine produced a dose-related decrease in aggressive responding, but did not alter escape responding, and slightly increased monetary responding. d,l-fenfluramine releases serotonin and the finding that d,l-fenfluramine decreases aggression is consistent with a body of literature relating aggression and serotonin. d,l-fenfluramine also dose-dependently decreased impulsive responding, a finding consistent with published animal data showing a reduction in impulsivity following d,l-fenfluramine administration. Cherek, D.R., and Lane, S.D. Effects of d,l-Fenfluramine on Aggressive and Impulsive Responding in Adult Males with a History of Conduct Disorder. Psychopharmacology, 146, pp. 473-481, 1999.

Methodological Issues: Cumulative Dosing, Progressive Ratio, and Inferential Statistics

Dr. Marc Branch, University of Florida, recently published new data concerning the use of various methodologies in drug abuse research. He found that repeated use of the cumulative dosing procedure produced dose-response curves that were not as reliable as those produced by non-cumulative dosing procedures. He argued for the action of Pavlovian factors in producing the less reliable curves under the cumulative dosing procedure (Walker, D.J. and Branch, M.N. Response Suppression During Cumulative Dosing: A Role for Pavlovian Conditioning. Behavioural Pharmacology, 9, pp. 255-271, 1998). Branch and his colleagues also examined the role of step size in the progressive ratio procedure, a procedure commonly used to assess the reinforcement strength of drugs. Results indicated that step size did not affect the break point, but was inversely related to the average number of completed ratios in a manner well fit by a power function (Stafford, D., and Branch, M.N. Effects of Step Size and Break-Point Criterion on Progressive Ratio Performance. Journal of the Experimental Analysis of Behavior, 70, pp. 123-138, 1998). In a more recent paper, Branch described two things that statistical significance testing does not do: 1) provide a quantitative estimate of the reliability of a result and 2) estimate the probability that the results were due to chance. He argues that significance testing frequently: reduces scientific responsibility; is employed in a poor manner to test theory; emphasizes population parameters over behavior; limits the reasons for doing experiments; and discounts reliability in effects in some types of research. Branch, M.N. Statistical Inference in Behavior Analysis: Some Things Significance Testing Does and Does Not Do. The Behavior Analyst, 22, pp., 87-92, 1999.

Menstrual Cycle Phase Affects the Subjective Effect of d-Amphetamine

Research from the laboratory of Dr. Harriet de Wit at the University of Chicago shows that menstrual cycle phase is a factor in the subjective response to acute d-amphetamine. Sixteen healthy women received oral d-amphetamine during the follicular and mid-luteal phases of the menstrual cycle. Under d-amphetamine, subjective effects were greater during the follicular phase than the luteal. Subjects reported a greater feeling of "high," euphoria (ARCI MBG), and energy and intellectual efficiency (ARCI BG) during the follicular than the luteal phase, and more liking and wanting of the drug. During the follicular phase (when estrogen levels are high and progesterone levels are low), higher estrogen levels were associated with feeling energetic and intellectually efficient. During the luteal phase, when levels of both estrogen and progesterone are relatively high, the response to d-amphetamine was unrelated to estrogen level. Justice, A.J.H. and de Wit, H. Acute Effects of d-Amphetamine During the Follicular and Luteal Phases of the Menstrual Cycle in Women. Psychopharmacology, 145, pp. 67-75, 1999.

Menstrual Cycle Phase Affects Smoking Withdrawal Symptoms and Depressive Symptomatology

Dr. Kenneth Perkins and colleagues at the University of Pittsburgh found that in women who attempt to quit, phase of the menstrual cycle affects withdrawal symptoms. In a study of 78 women enrolled in a smoking cessation trial, women who quit during the luteal phase of their cycle had significantly more withdrawal symptoms and more depressive symptomatology during the week after quitting than women who quit during their follicular phase. These data suggest that women seeking to quit smoking may reduce the adverse effects of cessation by choosing to quit during the follicular phase. Perkins, K.A., Levine, M., and Marcus, M. Tobacco Withdrawal in Women and Menstrual Cycle Phase. Journal of Consulting and Clinical Psychology, 68, pp. 176-180, 2000.

Clonidine Blocks Immunosuppressive Effects of Morphine Withdrawal

It is known that morphine depresses immune system function. Changes in immune function during opiate withdrawal are not well understood. Drs. West, Dykstra and Lysle at the University of North Carolina Chapel Hill pretreated rats undergoing opiate detoxification with the drug clonidine, an alpha-2 adrenergic agonist used to alleviate opiate withdrawal symptoms during detoxification. Pretreatment with clonidine prevented opiate withdrawal associated decreases in concanavalin A, toxic shock syndrome toxin, splenic conA-stimulated interferon-gamma production, and splenic natural killer cell activity. Thus, clonidine treatment may be efficacious not only for attenuating withdrawal symptoms during opiate detoxification but may also be protective against withdrawal-induced immunosuppression. West, J.P., Dykstra, L.A. and Lysle, D.T. Immunomodulatory Effects of Morphine Withdrawal in the Rat are Time-Dependent and Reversible by Clonidine. Psychopharmacology, 146, pp. 320-327, 1999.

Role of Glutamatergic NMDA Receptor in Opiate Tolerance Depends on Degree of Tolerance

Recent experimental evidence has implicated central glutamatergic systems in opiate tolerance. The involvement of central glutamatergic NMDA receptors in tolerance has been demonstrated for morphine but not for other opiates with a high intrinsic efficacy, such as fentenyl. Drs. Allen and Dykstra suggest this may indicate that NMDA receptors are involved in only the milder forms of opiate tolerance. They found that rats receiving an NMDA antagonist during chronic opiate treatment showed a blockade of tolerance to antinociceptive effects when the morphine dose was 10 mg/kg, but only an attenuation when the daily dose was 20 or 40 mg/kg. Since the NMDA antagonist had no effect on analgesia in non-dependent rats, and did not affect the acute analgesic effects of morphine, it appears that NMDA receptor systems participate in the development of tolerance rather than in its expression. Their results suggest that different biochemical mechanisms may be involved in the development of tolerance with opiates of varying intrinsic efficacy. Allen, R.M. and Dykstra, L.A. The Role of Morphine Maintenance Dose in the Development of Tolerance and its Attenuation by an NMDA Receptor Antagonist. Psychopharmacology, 148, pp. 59-65, 2000.

Subjective Effects of Nicotine-Containing and De-Nicotinized Cigarettes

Researchers at the University of Vermont compared smokers' preference for nicotine-containing and de-nicotinized cigarettes. In one phase of the experiment, under separate conditions, smokers were given the opportunity to "purchase" cigarette puffs from a nicotine-containing cigarette or a de-nicotinized cigarette. In a second phase of the experiment, both cigarette types were available simultaneously and smokers could choose between a nicotine-containing cigarette and a de-nicotinized cigarette. The researchers found that when the de-nicotinized cigarette was the only cigarette available, the number of puffs taken and the self-reported measure of enjoyment were not different from those measures obtained when the nicotine-containing cigarette was the only cigarette available. When both cigarette types were available simultaneously, however, consumption of the nicotine-containing cigarette was significantly greater. These results suggest that smoking-related factors other than the direct effects of nicotine contribute to smoking and can, in fact, maintain smoking. However, if given a choice, smokers prefer nicotine-containing cigarettes, indicating that the combined effects of nicotine and other smoking-related factors is clearly the preferred option. Shahan, T.A., et al. Comparing the Reinforcing Efficacy of Nicotine and De-Nicotinized Cigarettes: A Behavioral Economic Analysis. Psychopharmacology, 147, pp. 210-216, 1999.

Tolerance to Nitrous Oxide's Hypothermic Effects

Hypothermia is an adverse effect of the abused drug nitrous oxide. Dr. Doug Ramsey at the University of Washington sought to determine whether tolerance to nitrous oxide hypothermia could develop within a single administration of this analgesic gas. Using a rodent model, he found that only a few animals demonstrated evidence of acute hypothermic tolerance over a 120-minute gas administration period. Over the next ten days, the experimental rats received five additional 30-minute exposures to 60 percent nitrous oxide and five 30-minute exposures to placebo, while the control rats received only placebo gas exposures. Chronic tolerance developed to nitrous oxide induced hypothermia over repeated administrations. A test for Pavlovian drug conditioning found no evidence that conditioned temperature effects contributed to chronic tolerance development. In a second experiment, naive rats were given a 380-minute exposure to 60 percent nitrous oxide and a 380-minute exposure to placebo gas in a counterbalanced order. Acute tolerance did develop to nitrous oxide hypothermia, with the recovery of temperature beginning after a mean of 141 minutes of gas administration. Hence, both acute and chronic tolerance developed to nitrous oxide's hypothermic effects in rats. Ramsay, D.S., Omachi, K., Leroux, B.G., Seeley, R.J., Prall, C.W., and Woods, S.C. Nitrous Oxide-Induced Hypothermia in the Rat: Acute and Chronic Tolerance. Pharmacol. Biochem. Behav., 62, pp. 189-196, 1999.

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