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Preclinical evaluation of pharmacotherapies for treatment of cocaine and opioid abuse using drug self-administration procedures

Drug abuse is a major public health problem, and the relationship between intravenous drug abuse and AIDS underscores the need for more effective treatment medications. Animal models of drug self-administration are useful to systematically evaluate new treatment medications and predict clinical efficacy. This review summarizes the status of preclinical evaluations of medications for treatment of cocaine and opiate abuse. The basic drug self-administration methodology and the rationale for experimental designs and outcome criteria are described. Studies of the effects of dopamine or opioid receptor agonists and antagonists as well as medications used clinically for other indications on drug self-administration are critically examined. Where possible, the degree of concordance between clinical and preclinical studies of drug abuse treatment medications is discussed. We conclude that drug self-administration models are valuable for preclinical assessment of medication efficacy, and we recommend some strategies to further improve evaluation procedures. The discovery of more effective medications for substance abuse treatment should be facilitated by recent advances in behavioral science, pharmacology, neurobiology and medicinal chemistry.

Effect of alcohol and marihuana on tobacco smoking

Tobacco smoking covaried with alcohol consumption in male social drinkers over 15 days of unrestricted alcohol availability. Increased tobacco smoking was associated with alcohol consumption in occasional, moderate, and heavy smokers. Tobacco smoking was not systematically related to marihuana smoking even though both drugs were often smoked at the same time. During ten days of concurrent access to tobacco, alcohol, and marihuana, tobacco smoking continued to covary with alcohol consumption rather than with marihuana smoking. Marihuana smoking appeared to be independent of alcohol consumption patterns.

Self-administration of an enkephalin analog by rhesus monkey

Intravenous injections of a synthetic enkephalin analog, FK-33-824 were found to maintain operant responding under second-order schedule control (FR 4[VR 16:S]) in five, morphine-dependent rhesus monkeys. All monkeys self-administered enkephalin in amounts equivalent to morphine at comparable doses per injection. Each of five doses of enkephalin (0.5, 0.25, 0.125, 0.05 and 0.01 mg/kg/inj) were substituted for morphine during 10 consecutive sessions over a 56 hr period. No monkey developed opiate withdrawal signs during enkephalin substitution except at the lowest enkephalin dose (0.01 mg/kg/inj). Although the number of enkephalin injections self-administered increased as the dose per injection progressively decreased, there was a significant linear decrease (p less than 0.05) in mg/kg/enkephalin per session at doses of 0.25 mg/kg/inj and below. Reductions in morphine dose per injection, over a range of 0.5 to 0.125 mg/kg/inj produced comparable increases in number of injections per session, but no significant changes in morphine intake. The number of food pellets earned on a second order FR 4 (VR 16:S) schedule decreased during enkephalin substitution. These decreases were significant at the highest doses of enkephalin (0.5 to 0.125 mg/kg/inj). These data attest to the reinforcing characteristics of an enkephalin analog in rhesus monkey and suggest that natural polypeptides may contribute to the reinforcing properties of opiate drugs.

Some Behavioral and Biological Aspects of Alcohol Problems in Women

It is generally acknowledged that relatively little is known about alcoholism and problem drinking in women. The origins, expression, and consequences of alcohol abuse for women remain obscure. Although these issues have not been resolved for alcohol problems generally, most of the existing information about alcohol abuse has come from clinical studies of men. The question of possible sex-related differences has seldom been raised explicitly (Edwards et al., 1973; Mulford, 1977; Wanberg and Horn, 1970).

Delta opioid antagonist effects of buprenorphine in rhesus monkeys.

Buprenorphine is an opioid with high affinity for delta, mu and kappa opioid receptors. The delta receptor-mediated effects of buprenorphine in vivo have not been studied. Thus, the present study examined the delta receptor-mediated effects of buprenorphine in rhesus monkeys. In vitro assays of receptor binding and agonist-stimulated GTP &ggr; S binding confirmed that buprenorphine had high affinity for, and low efficacy at, delta receptors. In an assay of schedule-controlled responding for food presentation in four monkeys, buprenorphine produced little effect alone, but it antagonized the effects of the delta agonist SNC80, the mu agonist morphine and the kappa agonist U50,488. Buprenorphine was approximately 30-fold less potent as a delta antagonist than as a mu or kappa antagonist. In three monkeys trained to discriminate SNC80 from saline, buprenorphine alone produced only saline-appropriate responding, and buprenorphine pretreatment antagonized the discriminative stimulus effects of SNC80. In a fourth monkey, buprenorphine produced a partial substitution for SNC80 that could be blocked by the delta-selective antagonist naltrindole but not by the mu-selective antagonist quadazocine. These results indicate that, in rhesus monkeys, buprenorphine has very low efficacy at delta receptors, and that buprenorphine produces delta receptor-mediated effects with lower potency than it produces mu or kappa receptor-mediated effects.

Diurnal patterns of cocaine and heroin self-administration in rhesus monkeys responding under a schedule of multiple daily sessions.

A number of non-pharmacological factors have been shown to influence drug self-administration in experimental animals. This report examines diurnal changes in drug self-administration by rhesus monkeys trained to self-administer food (1 gm fruit-flavored pellets) and cocaine (0.01 or 0.032 mg/kg/injection) under a second order FR4 (VR16:S) schedule during four daily food and drug self-administration sessions. Saline, different unit doses of cocaine (0.001–0.1 mg/kg/injection) or different unit doses of heroin (0.0001–0.01 mg/kg/injection) were substituted for the maintenance dose of cocaine during drug sessions. Dose-effect curves relating unit dose of cocaine or heroin to the number of injections per session displayed an inverted U-shape during each of the four daily drug sessions. When 0.032 mg/kg/injection cocaine or 0.0032 mg/kg/injection heroin were available, monkeys usually self-administered the maximum number of injections during all four drug sessions. Substitution of saline or lower unit doses of cocaine (0.001–0.01 mg/kg/injection) or heroin (0.0001–0.001 mg/kg/injection) decreased the number of injections/session; however, these decreases were consistently greater during the evening (20.00 21.00 h) and morning (07,00–08.00 h) sessions than during the afternoon sessions (12.00–13.00 h and 16.00–17.00 h). As a result, the ascending limbs of the cocaine and heroin dose-effect curves for the evening and morning sessions were shifted to the right of the ascending limbs of the dose-effect curves for the afternoon sessions. Moreover, when saline was substituted for cocaine for only two sessions per day, drug self-administration decreased more during the evening and morning sessions even when the cocaine was available during those sessions. These findings suggest a diurnal variation in cocaine and heroin self-administration. Specifically, drug self-administration during the evening and morning sessions appears to be more sensitive to a decrease in reinforcer magnitude than responding during the afternoon sessions. These findings confirm and extend previous reports of the influence of non-pharmacological factors on drug self-administration.

Alcohol use, marihuana smoking, and sexual activity in women.

This report describes a prospective study of social drinking, marihuana smoking, and sexual activity by 26 healthy adult women (mean age 26.8 years). Each subject completed daily questionnaires for 3 consecutive menstrual cycles, and recorded menstrual cycle status, quantities and frequencies of alcohol consumption, marihuana smoking, and sexual activity. Consistent patterns of alcohol consumption, marihuana smoking, and sexual activity were reported across all 3 menstrual cycles. Heavy drinkers (mean greater than or equal to 1.80 drinks per day) were more likely to smoke marihuana than moderate drinkers (mean less than or equal to 1.75 drinks per day) and they also smoked significantly more marihuana (p less than 0.05). Neither age nor frequency of sexual activity were related to patterns of alcohol or marihuana consumption.

Concordant alcohol and marihuana use in women

Alcohol and marihuana use are common among both sexes, but systematic data on drug use patterns by women previously have been unavailable. This report describes the first prospective study of alcohol and marihuana consumption patterns in women, and examines factors that promote or maintain concurrent use. Thirty healthy adult women (mean age = 26.4 years) completed daily questionnaires for 3 consecutive menstrual cycles. Subjects recorded quantities and times of alcohol and marihuana consumption, episodes of sexual activity, and occurrence of unusual life events. Temporal variables significantly affected both alcohol and marihuana consumption. Marihuana use occurred earlier in the day than alcohol use. Significantly greater marihuana consumption and more concordant alcohol and marihuana use occurred on weekends. Older subjects (26 to 30) exhibited more concordant alcohol and marihuana use than younger subjects (21 to 25). Significant differences in alcohol use also distinguished heavy from light marihuana smokers. Neither sexual activity nor unusual events were associated with concordant alcohol and marihuana consumption in all subjects.

Effects of Drugs of Abuse on Reproductive Function in Women and Pregnancy

In the United States, the prevalence of substance use and abuse in women has been increasing over the last 20 yr. According to a 1984 survey in three major metropolitan areas sponsored by the National Institute on Mental Health (NIMH), alcohol abuse and dependence ranked fourth among psychiatric disorders in women aged 18–24, and drug abuse and/or dependence was the second most common psychiatric disorder among women aged 18–241,2In a National Household Survey conducted in 1991, more than half (57.8 and 52.8%, respectively) of all women ages 18–25 and 26–34 yr reported that they had used alcohol during the previous month, and more than 1 in 10 women surveyed in these age groups (13.4 and 11.2%, respectively) had used some illicit drug during the same interval.3Prevalence estimates for alcohol, marijuana, cocaine, and heroin use are presented in Fig. 1. However, these figures may be underrepresented as this was a household survey and the prevalence of substance abuse may indeed be higher in women who have comprised socioeconomic status.

Naloxonazine antagonism of levorphanol-induced antinociception and respiratory depression in Rhesus monkeys

The mu-opioid receptor antagonist effects of naloxonazine on levorphanol-induced thermal antinociception and respiratory depression were examined in rhesus monkeys. Levorphanol (0.032-3.2 mg/kg) produced dose-dependent increases in tail-withdrawal latencies from 50 degrees C water in a warm-water tail-withdrawal assay and dose-dependent decreases in ventilation in both air and 5% CO2 mixed in air. Naloxonazine (0.1-3.0 mg/kg) antagonized both the antinociceptive and ventilatory effects of levorphanol to a similar degree, and the antagonist effects of naloxonazine were greater after 1 h than after 24 h. Under all conditions, the antagonist effects of naloxonazine were fully surmountable. Schild analysis of the antagonist effects of naloxonazine after 1 h pretreatment in the antinociception assay yielded a pA2 value of 7.6 and a slope of -0.50; by comparison, quadazocine yielded a pA2 value of 7.5 and a slope of -1.05. These results suggest that naloxonazine acts as a potent and fully reversible mu-opioid receptor antagonist with a moderately long duration of action in rhesus monkeys. In addition, these results suggest that the antinociceptive and ventilatory effects of mu-opioid receptor agonists in rhesus monkeys are mediated by pharmacologically similar populations of mu opioid receptors.