Gail Winger

Cocaethylene: A neuropharmacologically active metabolite assciated with concurrent cocaine-ethanol ingestion

High concentrations of cocaethylene (EC), the ethyl ester of benzoylecgonine, were measured in the blood of individuals who had concurrently used cocaine and ethanol. Since the powerful reinforcing effects of cocaine appear to be dependent on inhibition of dopamine reuptake in brain, we compared the effects of EC on the dopamine uptake system and its behavioral effects with those of cocaine. EC was equipotent to cocaine with respect to inhibition of binding of [3H]GBR 12935 to the dopamine reuptake complex, inhibition of [3H]dopamine uptake into synaptosomes and in its ability to increase extracellular dopamine concentration in the nucleus accumbens following its systemic administration to rats. Moreover, in rats, EC and cocaine each increased locomotor activity and rearing to the same extent following i.p. administration. In self-administration studies in primates, EC was approximately equipotent to cocaine in maintaining responding. The in vivo formation of this active, transesterified ethyl homolog of cocaine may contribute to the effects and consequences of combined cocaine and ethanol abuse.

Current benzodiazepine issues

This article deals with some of the recent evidence bearing on the issues of the liability of benzodiazepines to lead to abuse, dependence, and adverse behavioral effects. Reviews of epidemiological, clinical and experimental literature indicated that the previous conclusion about abuse of these drugs still holds: the vast majority of the use of benzodiazepines is appropriate. Problems of nonmedical use arise nearly exclusively among people who abuse other drugs. Nevertheless, there are reasons for concern about patients who take benzodiazepines regularly for long periods of time. These drugs can produce physiological dependence when taken chronicaly, and although this does not appear to result in dose escalation or other evidence of “psychological dependence,” physiological dependence can result in patient discomfort if drug use is abruptly discontiniued. Also, physicians are currently prescribing shorter-acting benzodiazepines in preference to longer-acting benzodiazepines. The shorter-acting drugs can produce a more intense withdrawal syndrome following chronic administration. Furthermore, rates of use of benzodiazepines increase with age, and elderly patients are more likely than younger ones to take the drug chronically. The clearest adverse effect of benzodiazepines is impairment of memory. This, too, may be particular concern in older patients whose recall in the absence of drug is typically impaired relative to younger individuals, and who are more compromised following drug administration.

Behavioral and Neurochemical Consequences of Long-Term Intravenous Self-Administration of MDMA and Its Enantiomers by Rhesus Monkeys

The effects of self-administered 3,4-methylenedioxymethamphetamine (MDMA) on behavior and neurochemistry have not been previously studied in laboratory primates. We investigated the capacity of MDMA and its enantiomers to maintain contingent responding over an extended duration, whether any decrements in the reinforcing effects of these compounds would be observed over time, whether such decrements would be MDMA-selective, and whether any neurochemical correlates could be identified. Animals were previously trained to self-administer cocaine, then exposed to periodic substitutions of various doses of racemic MDMA and its enantiomers; full dose–effect curves were generated for each MDMA compound repeatedly over the duration of the study. After approximately 18 months of MDMA self-administration, drug exposure was halted and after at least 2 months drug abstinence, animals were scanned using positron emission tomography (PET) with the vesicular monoamine transporter (VMAT) ligand dihydrotetrabenazine (DTBZ). Shortly thereafter, animals were euthanized, brains were dissected, and samples were assayed for brain monoamines and their metabolites using high-performance liquid chromatography (HPLC), and for VMAT using DTBZ binding. The reinforcing effects of racemic and R(−)-MDMA were reduced over a long series (months) of individual self-administration access periods; the reinforcing effects of S(+)-MDMA were more resistant to this effect, but were attenuated for one animal. The reinforcing effects of cocaine were not altered by chronic MDMA self-administration, nor was the VMAT binding potential as assessed by PET. Further, there were no measurable decrements in serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) or VMAT in any brain regions assayed. The reinforcing effects of MDMA are selectively attenuated by chronic MDMA self-administration, although this behavioral change appears to occur in the absence of any frank neurochemical correlates of toxicity.

The Reinforcing Property of Ethanol in the Rhesus Monkey II. Some Variables Related to the Maintenance of Intravenous Ethanol-Reinforced Responding

Rhesus monkeys received intravenous injections of ethanol during daily sessions contingent on their presses on an available lever. Under the standard conditions, when each response on the lever during a 3-h period each day resulted in an i.v. injection of 0.1 g/kg ethanol, the monkeys made between 30 and 50 responses/session and developed blood ethanol levels of approximately 400 mg%. Under this and other conditions of response-contingent delivery of ethanol, a negatively accelerated pattern of self-injection within sessions was demonstrated. Variations in the dose per injection (0.05–0.2 g/kg/injection) resulted in changes in the rate of lever-pressing; the number of self-injections was inversely related to dose. Ethanol intake increased only slightly with increased dose per injection. Noncontingent administration of various doses of i.v. ethanol immediately prior to a daily session decreased the number of responses; the total amount of ethanol administered (contingent plus noncontingent), however, remained constant over a pretreatment dose range of 1 to 3 g/kg. When access time to ethanol was increased from 3 to 6 h/day, the total amount of ethanol taken increased slightly. However, the blood ethanol levels at the end of a 6-h session closely approximated those obtained following 3-h sessions, indicating that during the last 3–4 h of the 6-h sessions, the rate of ethanol intake closely matched the rate of ethanol elimination.

Self-administration of fentanyl, cocaine and ketamine: effects on the pituitary-adrenal axis in rhesus monkeys

RationaleDrugs of abuse can affect the functioning of the hypothalamic–pituitary–adrenal (HPA) axis. Acute administration of drugs that serve as reinforcers have been observed to stimulate the rat HPA axis, leading to the suggestion that these stimulatory effects may contribute to the development of drug-maintained behaviors.ObjectivesTo determine whether reinforcing drugs that are dissimilar with respect to their mechanisms of action have similar effects on HPA axis activity at doses that are self-administered. Rhesus monkeys were randomly assigned to self-administer the μ-opioid agonist fentanyl, the psychomotor stimulant cocaine, or the NMDA antagonist ketamine.MethodsEach monkey was trained to press a lever in order to receive an intravenous injection of drug or saline. Blood samples were obtained before, during, and after the self-administration sessions and assayed for ACTH and cortisol by radioimmunoassay.ResultsFentanyl, cocaine, and ketamine were each self-administered across a range of doses. However, the three drugs differed in their effects on ACTH and cortisol. Cocaine stimulated ACTH and cortisol secretion, a finding that is consistent with previous rat and primate studies. Self-administration of both fentanyl and ketamine inhibited HPA axis activity. HPA inhibition by fentanyl is consistent with other monkey and human studies, and contrasts with the stimulatory effects of μ-opioids in rodents. The inhibitory effect of ketamine on ACTH and cortisol secretion contrasts with findings in the few primate studies that have evaluated NMDA antagonists. Neither fentanyl nor cocaine, at doses that maintained maximum rates of responding, produced significant changes in ACTH and cortisol levels.ConclusionsThere appears to be little commonality between different classes of abused drugs and their effects on the HPA axis, which calls into question the necessity for HPA axis stimulation in the reinforcement of drug-maintained behavior.

Drug-reinforced responding: rapid determination of dose-response functions

Rhesus monkeys were conditioned to press on levers and receive intravenous infusions of cocaine or ketamine. Experimental conditions provided several different doses of drug during each of two daily 130 min sessions; as a result, a dose-response curve relating rate of responding to dose/injection for self-administered drug was obtained within each session. Relative rate-maintaining effects of nomifensine and cocaine in monkeys on baseline conditions of cocaine self-administration, and rate-maintaining effects of ketamine, phencyclidine and MK-801 in monkeys on baseline conditions of ketamine self-administration, compared favorably with relative rate-maintaining effects of these substances obtained in more traditional paradigms.

Naltrexone reduces ethanol- and sucrose-reinforced responding in rhesus monkeys

Abstract These experiments evaluated the ability of naltrexone (NTX) to reduce selectively oral and IV ethanol-reinforced responding, and examined the ethanol-NTX interaction in terms of the competitive opioid antagonist property of NTX. Five rhesus monkeys self-administered ethanol or sucrose and concurrently available water. Ethanol concentration was varied from 0.25% to 8% (w/v). Naltrexone (0.032–0.32 mg/kg) or saline was given IM 30 min prior to some drinking sessions. NTX (0.32 mg/kg) reduced ethanol-reinforced responding at the concentration that maintained the most responding (1% or 2%). NTX (0.1 mg/kg) reduced ethanol-reinforced responding, both at a low ethanol concentration (0.25%) that produced little ethanol intake (g/kg), and at a higher concentration (4%) with an appreciable intake. Thus, NTX (0.1 mg/kg) shifted the ethanol concentration-consumption curve down, in an insurmountable manner. NTX (0.1 and 0.32 mg/kg) also reduced reinforced responding for sucrose 100 g/l. In another experiment, three rhesus monkeys were given opportunities to self-administer ethanol IV. NTX (0.1 mg/kg) reduced the number of ethanol injections obtained by the monkeys at all ethanol doses tested (0.01, 0.032, and 0.1 g/kg per injection).The dose-effect curve was also shifted down. These results showed that NTX reduced behavior maintained by either ethanol or sucrose non-selectively. Furthermore, the ability of NTX to suppress ethanol-reinforced responding did not depend on the route of ethanol administration and was not overcome by increasing the concentration or dose per injection of ethanol.

The effects of chronic morphine on behavior reinforced by several opioids or by cocaine in rhesus monkeys

The reinforcing effects of intravenously delivered cocaine, alfentanil, morphine, heroin, nalbuphine, or buprenorphine were evaluated in four rhesus monkeys before, during, and after daily administration of 3.2 mg/kg morphine. Morphine was given 21 h prior to measures of the reinforcing effects of each of the drugs. No changes in the potency of cocaine or the high efficacy mu agonist alfentanil were detectable during the period of chronic morphine administration. Small (1/2-1) log unit decreases in the reinforcing potency of intermediate efficacy mu agonists morphine and heroin occurred during chronic morphine administration. Larger decreases in both the potency and effectiveness of low-efficacy mu agonists nalbuphine and buprenorphine developed during this time. These data suggest that the amount of tolerance that develops to the reinforcing effects of opioids depends on the efficacy of the drugs used to maintain responding.

Effects of GBR 12909 and cocaine on cocaine-maintained behavior in rhesus monkeys

The reinforcing effect of the high affinity dopamine reuptake inhibitor GBR 12909 (1-[2-[bis(4-fluorophenyl)methoxy]ethyl)-4(3- phenylpropyl)piperazine) was compared with that of cocaine, and the effects of both GBR 12909 and cocaine pretreatments were evaluated on behaviour maintained by cocaine in rhesus monkeys. Increasing dose per injection of intravenously-delivered GBR 12909 or cocaine led to increased rates of lever-press responding. Maximum cocaine-maintained rates were higher and occurred at a smaller dose than maximum rates of GBR 12909-maintained responding. Presession intravenous administration of either GBR 12909 or cocaine (0.32, 1.0 or 3.2 mg/kg) resulted in dose-dependent decreases in rates of cocaine-maintained responding when high doses of cocaine, which engendered high response rates, were available early in the session. Under these conditions, the decrease in response rates was associated primarily with decreases in running rate rather than with a lengthening in post-reinforcement pause times. The decreases in running rate produced by both cocaine and GBR 12909 probably reflect an unconditioned rate-disruptive effect of these drugs on cocaine-reinforced responding rather than a reduction in the reinforcing efficacy of cocaine.

Comparison of fixed-ratio and progressive-ratio schedules of maintenance of stimulant drug-reinforced responding

The effectiveness of doses of i.v. cocaine and nomifensine in maintaining lever-press responding in rhesus monkeys was evaluated under two schedules, fixed- and progressive-ratio (FR, PR). The doses that maintained maximum rates of responding under the fixed-ratio schedule were 0.32 mg/kg per injection cocaine and 0.10 mg/kg per injection nomifensine. The fixed-ratio rates maintained by this dose of nomifensine were slightly lower than those maintained by cocaine. Under the progressive-ratio schedule, the maximum response rates developed with 0.32 mg/kg per injection cocaine and 0.32 mg/kg per injection nomifensine. Maximum performances under the progressive ratio were slightly higher with cocaine than with nomifensine. Taken in conjunction with existing data for other drugs and conditions, these data indicate that progressive-ratio schedules may yield information on the relative reinforcing effects of drugs that differs only slightly from that obtained with fixed-ratio schedules.