Effects of chronic binge-like ethanol consumption on cocaine self-administration in rhesus monkeys

Abstract

Background Most cocaine abusers also abuse alcohol, but little is known about interactions that promote co-abuse. These experiments in rhesus monkeys determined the effects of >8 weeks of ethanol (EtOH) consumption on cocaine self-administration (n=6), effects of dopamine (DA) receptor antagonists on cocaine reinforcement (n=3–4 per drug) and the ability of the D2-like DA receptor agonist quinpirole to elicit yawning (n=3). Methods Monkeys self-administered cocaine (0.0–1.0 mg/kg/injection, i.v.) under a 300-second fixed-interval schedule and the above-listed variables were measured before EtOH exposure. Next, monkeys consumed a sweetened, 4% EtOH solution in the home cage under binge-like conditions: one hour, 5 days/week with daily intake equaling 2.0 g/kg EtOH. After approximately 8 weeks, measures were re-determined, then EtOH drinking was discontinued. Finally, acute effects of EtOH on cocaine self-administration were determined by infusing EtOH (0.0–1.0 g/kg. i.v.) prior to cocaine self-administration sessions (n=4). Results In 5 of 6 monkeys, EtOH drinking increased self-administration of low cocaine doses but did not alter reinforcing effects of higher doses. Self-administration returned to baseline after EtOH access was terminated (n=3). Effects of DA receptor antagonists on cocaine self-administration were not consistently altered after EtOH consumption, but the ability of quinpirole to induce yawning was enhanced in 2 of 3 monkeys. Acute EtOH infusions only decreased self-administration of lower cocaine doses. Conclusions Taken together, the data suggest that long-term EtOH exposure can increase sensitivity to cocaine, possibly by increasing D3 receptor sensitivity. Data do not support a role for acute pharmacological interactions in promoting cocaine/EtOH co-abuse.

Effects of ethanol on cocaine self-administration in monkeys responding under a second-order schedule of reinforcement

“…Furthermore, self-administered cocaine did not affect BECs, consistent with human studies (Farré et al 1993, 1997; Higgins et al, 1993; McCance-Katz et al 1993; Perez-Reyes and Jeffcoat 1992). These results extend previous preclinical animal research investigating the interactions of intravenous EtOH and cocaine (Aspen and Winger, 1997; Czoty, 2015, 2016; Winger et al, 2007) to intragastric administration of EtOH and to a schedule of cocaine self-administration that utilized conditioned stimuli to maintain drug seeking.…”

“…Czoty (2015) reported that in monkeys self-administering cocaine under an FI 5-min schedule of reinforcement, 1.0 g/kg EtOH (i.v.) significantly decreased reinforcement frequency when a low dose of cocaine was self-administered.…”

“…In fact, preclinical studies using nonhuman primates have shown that ethanol (EtOH) either has no effect on cocaine self-administration (Czoty, 2015; Winger et al, 2007) or results in an increase in cocaine self-administration in only a subset of subjects (Aspen and Winger, 1997). In contrast, data from studies involving human subjects have shown that the combination of alcohol and cocaine produced more pleasurable subjective effects compared to either drug alone, as well as an increase in cocaine preference over alternative monetary reinforcers (Farré et al, 1997; Higgins et al, 1996).…”

“…Another aim of the present study was to extend the findings of Czoty (2015), which examined the effects of EtOH on cocaine self-administration under a fixed-interval (FI) schedule to include the role of behavior maintained by conditioned stimuli in EtOH-induced changes in cocaine-maintained behavior. To better understand how drugs affect FI responding, investigators can measure pattern of responding by calculating quarter-life (QL) values.…”

Evaluation of the “Pipeline” for Development of Medications for Cocaine Use Disorder: A Review of Translational Preclinical, Human Laboratory, and Clinical Trial Research

“…The effect of other licit and illicit substances on cocaine use has received even less attention. However, those studies that have modeled polysubstance abuse in animals have identified drug interactions that can enhance cocaine reinforcement (e.g., Mattox et al, 1997;Mello et al, 556 2014;Czoty, 2015). Severity of cocaine use (in terms of duration or total lifetime doses) could also be incorporated as an independent variable, particularly in animal laboratory studies where pharmacological variables can be easily controlled.…”