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National Institute on Drug Abuse

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

May, 1996

Research Findings

Behavioral Research

Exposure to Pain Modulates Morphine's, But Not Butorphanol's Subjective Effects

In this study with human volunteers, and in contrast to animal research, a painful stressor does attenuate the subjective effects of the mu agonist morphine, but stress does not modulate the effects of the mixed kappa agonist-antagonist butorphanol. These results have clinical implications in that patients receiving morphine under painful, stressful conditions may be less "intoxicated" than those receiving morphine in the absence of stress. In contrast, butorphanol may be a more effective analgesic in patients under stress. Zacny, J. P. Effects of Cold Water Immersion on Subjective and Psychomotor Effects of Opiates in Healthy Volunteers, Experimental and Clinical Psychopharmacology, In Press.

Transnasal Butorphanol Alters Mood and Psychomotor Function in Normal Volunteers: Implications for Ambulatory Patients

Butorphanol is effective in treating migraine headache and post operative pain. Although butorphanol has been reported to have a low potential for abuse in opioid abusers, this study is the first to demonstrate that butorphanol also has significant effects on psychomotor function and mood in normal volunteers. Ambulatory patients, therefore, should use caution when taking this prescribed medication. It is noteworthy, however, that in the present study clinically-relevant doses of butorphanol did not increase drug-liking ratings in normal volunteers. Zacny, J. P. et al., The Effects of Butorphanol on Mood and Psychomotor Functioning in Healthy Volunteers. Anesthesia & Analgesia, In Press.

Food Deprivation Increases Crack Smoking in Rhesus Monkeys

Rhesus monkeys under short-term food deprivation worked harder in an instrumental task to gain access to cocaine base (1 mg/kg per delivery) than when they were food-satiated. These results and others demonstrate that food deprivation increases self-administration for some abusable substances, and may indicate that increasing appetitive motivation may generalize to a variety of reinforcers including drugs of abuse. Comer, S.D., Lac L.T., Wyvell, C.L., Curtis, L.K. & Carroll, M.E. Effects of Food Deprivation on Cocaine Smoking in Rhesus Monkeys. Psychopharmacology, 119, pp. 127-132, 1995.

Amphetamine Alters the Contribution of Macronutrients to Total Caloric Intake

Food intake of research volunteers was measured during lunch after they were administered either amphetamine (30mg/70kg, QID) or placebo. Amphetamine decreased intake of all macronutrients relative to placebo. However, amphetamine resulted in a relative increase in carbohydrate intake and a decrease in fat and protein intake. That is, the relative contribution of macronutrients to total caloric intake was changed following amphetamine ingestion. These results raise issues concerning the effects of phentermine (a new weight-loss drug) on macronutrient selection given it has neurochemical effects that are similar to d-amphetamine. Foltin, R.W., Kelly, T.H. & Fischman, M.W. Effect of Amphetamine on Human Macronutrient Intake. Physiology & Behavior, 58, pp. 899-907, 1995.

Extending the Release of Alprazolam Reduces its Abuse Liability

Researchers at the Johns Hopkins University School of Medicine assessed the behavioral, subjective and stated preference for immediate- (1 and 2 mg) vs extended-release (2 and 3 mg) alprazolam. Subjects with a history of sedative abuse participated. Plasma alprazolam concentrations peaked, on average, 1.7 and 9.2 hours after IR alprazolam and ER alprazolam, respectively. IR alprazolam impaired cognitive and psychomotor function, while ER alprazolam reduced only a single measure of motor performance, and only at the highest dose examined. In terms of subjective effects, IR alprazolam increased all positive drug effect measures, while effects of the higher ER dose on positive effect measures was mixed. Also, subjects were willing to pay significantly more money for either IR alprazolam dose than the ER doses. These data suggest that extended-release alprazolam has a much lower abuse potential then immediate-release alprazolam. Mumford, G.K., Evans, S.M., Fleishaker, J.C. & Griffiths, R.R. Alprazolam Absorption Kinetics Affects Abuse Liability. Clin Pharmacol Ther, 57, pp. 356-365, 1995.

Alcohol Hangover and Managerial Effectiveness

Dr. Siegfried Streufert and colleagues at Pennsylvania State University studied the effects of alcohol hangover on managerial effectiveness in subjects who held managerial positions. Twenty-two male managers who normally drink moderate amounts of alcohol participated in a placebo-controlled, double-blind, cross-over experiment. Subjects consumed either placebo or alcoholic drinks to attain a breath alcohol level of 0.10 during the evening before participation in Strategic Management Simulations. By the time of arrival at the simulation laboratory on the following morning, breath alcohol levels were measured at 0.00. Questionnaire responses indicated considerable hangover discomfort. Responses to semantic differential evaluative scales suggested that research participants evaluated their own managerial performance in the simulation setting as impaired. However, multiple (validated) measures of decision-making performance obtained in the simulation task did not show any deterioration of functioning. Previous research had shown considerable performance decrements in the same task setting, while blood/breath alcohol levels ranged from 0.05 through 0.10%. Apparently, complex decision-making competence by persons who normally consume moderate amounts of alcohol may not be impaired by hangover caused by intoxication during the previous evening that remains at or below a blood alcohol level of 0.10. Streufert et al., Alcohol Hangover and Managerial Effectiveness. Alcohol Clin Exp Res, 19, pp. 1141-1146, 1995.

Caffeine Deprivation and Managerial Effectiveness

In another study by Dr. Siegfried Streufert and colleagues, 25 male and female managers who reported an average daily caffeine consumption of 575 mg participated in two complex simulations. A double-blind cross-over design was employed to assess the effects of normal caffeine consumption versus caffeine deprivation upon seven validated measures of managerial effectiveness. Data from a Caffeine Withdrawal Questionnaire indicated discomfort upon deprivation. Systolic blood pressure increased during normal caffeine consumption levels but fell quickly and remained lower during deprivation. Several measures of managerial performance indicated decreased effectiveness upon caffeine deprivation. In contrast to prior research from simpler task settings, cognitive effectiveness during complex task performance was diminished. However, a measure of strategic performance which requires a relatively high level of cognitive effort showed no impact of caffeine deprivation. Streufert S. et al, Effects of Caffeine Deprivation on Complex Human Functioning. Psychopharmacology, 118, pp. 377-84, 1995.

Behavioral Pharmacology of Phencyclidine (PCP)

Dr. Robert Balster of the Medical College of Virginia, has used the drug discrimination procedure and other behavioral measures to evaluate drugs acting on the N-methyl-D-aspartate (NMDA) receptor complex. The NMDA receptor is the target of much pharmaceutical research because compounds acting at this receptor complex have been shown to be useful therapeutically, but the utility of some of these compounds, e.g. phencyclidine (PCP), is limited because of abuse potential. PCP is a non-competitive NMDA antagonist that blocks the calcium channel site of the receptor complex, and Dr. Balster has shown that all compounds acting at the PCP binding site in the NMDA channel produce PCP-like behavioral effects which differ only in potency. For example, memantine, a low potency antagonist at this site, has similar reinforcing and discriminative effects to PCP. Competitive antagonists bind to the NMDA excitatory amino acid binding site and can serve as training drugs in the drug discrimination procedure. Competitive antagonists have been shown to have unique discriminative stimulus effects for which PCP-like non-competitive agents do not fully substitute. Recent studies in rats using NMDA as the training drug in drug discrimination studies indicated that a number of excitatory amino acids (EAA) could partially substitute for NMDA but only the novel EAA agonist LY 285265 fully substituted with a potency 100 times that of NMDA. Thus, LY 285265 should be a useful agent for in vivo studies of the NMDA receptor Discriminative Stimulus Effects of Excitatory Amino Acid Agonists in Rats, Neuropharmacology, 34, pp. 55-62, 1995.

Other studies from Dr. Balster's laboratory demonstrated that two novel agents which act as antagonists at the glycine modulatory site of the NMDA receptor complex differ markedly from PCP in their behavioral actions. These compounds are devoid of PCP-like discriminative stimulus properties, do not antagonize PCP discrimination, and do not serve as a discriminative stimulus. Behavioral Pharmacology of Two Novel Substituted Quinoxalinedione Glutamate Antagonists, Behavioral Pharmacology, 6, pp. 577-589, 1995.

Mu Opioid Agonists and Tolerance

Dr. Linda Dykstra has investigated the role of intrinsic efficacy in determining cross-tolerance to the rate-decreasing effects of mu agonists on food maintained responding. Tolerance and Cross-Tolerance to the Response Rate-Decreasing Effects of Mu Opioids in Morphine-Maintained Squirrel Monkeys, Behavioral Pharmacology, 6, pp. 776784, 1995. Based on a hypothesis proposed by Paronis and Holtzman (Psychopharmacology 114, pp. 601-610, 1994), mu agonists with higher intrinsic activity than morphine such as etorphine, l-methadone, and sufentanil would be expected to exhibit less cross-tolerance to these rate decreasing effects than the tolerance observed with morphine itself. Buprenorphine, a mu agonist with low intrinsic activity would be expected to exhibit greater cross-tolerance. The degree of cross-tolerance between morphine and drugs with high intrinsic efficacy was as predicted. The dose-effect curves of l-methadone, etorphine, and sufentanil were shifted less far to the right than that for morphine itself. However, buprenorphine exhibited smaller than predicted cross-tolerance; the buprenorphine dose-effect curve was shifted rightward to the same degree as high efficacy agonists.

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