Effects of chronic binge-like ethanol consumption on cocaine self-administration in rhesus monkeys
Introduction
Despite decades of research, cocaine abuse persists as a major public health problem and no pharmacotherapy has proven suitable for widespread clinical use (Kampman, 2010, Karila et al., 2011). The lack of success in translating preclinical hypotheses to effective medications indicates that significant barriers remain, but reasons for the disconnect between preclinical and clinical results are poorly understood. One clinical reality rarely incorporated into animal models is co-abuse of other substances. Humans who use or are dependent on multiple substances are typically excluded from clinical studies, and nearly all studies in laboratory animals limit exposure to a single drug of interest. This is understandable because characterizing the effects of two substances in combination is complex. In the case of alcohol and cocaine, however, such studies are critical. Estimates indicate that up to 90% of cocaine abusers also abuse alcohol (Grant and Harford, 1990, Helzer and Pryzbeck, 1988, Kampman et al., 2013, Tziortzis et al., 2011). Importantly, individuals who co-abuse alcohol commonly have more severe cocaine dependence, are more adversely affected by their drug use and are less likely to remain in treatment (Carroll et al., 1993, Heil et al., 2000, Higgins et al., 1994). Alarmingly, alcoholic cocaine users also report greater rates of unwanted sexual encounters and suicidal and homicidal behavior (Heil et al., 2000, Salloum et al., 1996).
The mechanistic basis for the pervasive co-abuse of alcohol and cocaine is incompletely understood, and studies characterizing the interactions between the drugs have produced mixed results. Enhancement of cocaine's abuse-related effects by EtOH would be expected based on its ability to increase striatal dopamine (DA) concentrations (e.g., Bradberry, 2002, Di Chiara and Imperato, 1988, Yoder et al., 2009). Moreover, similar alterations in brain DA systems – particularly D2 receptors – have been observed in alcoholics and cocaine abusers (e.g., Cosgrove, 2010, Volkow et al., 1996, Volkow et al., 1999, Volkow et al., 2002). When combined, cardiovascular effects of cocaine and EtOH can be enhanced, while effects on cognitive performance may be attenuated (Farre et al., 1993, Foltin and Fischman, 1988, Foltin et al., 1993, Higgins et al., 1992). Experiments in laboratory animals have also indicated that co-administration of cocaine and EtOH can produce more pronounced effects than either drug alone. These studies have primarily focused on motor endpoints such as locomotion and rates of lever pressing under schedules of reinforcement (Aston-Jones et al., 1984, Masur et al., 1989, Misra et al., 1989, Rech et al., 1978) rather than variables that more directly reflect cocaine's abuse-related effects. Only two studies have examined the effects of EtOH on cocaine self-administration in laboratory animals. In the first (Aspen and Winger, 1997), EtOH increased self-administration of cocaine and another DA uptake blocker, but not a mu opioid receptor agonist, in some monkeys. In the second (Winger et al., 2007), demand functions for cocaine/EtOH combinations were intermediate to those of either drug alone. In contrast, studies in humans demonstrate that alcohol can increase cocaine's reinforcing and pleasurable subjective effects (Farre et al., 1993, Higgins et al., 1996). Thus, although there is some evidence to suggest that EtOH can enhance some effects of cocaine, the data addressing this critical question are limited and involve only acute EtOH exposure. Due to limitations of studies with human drug abusers, including unknown extent of past and current drug use, unknown durations of abstinence, comorbid psychiatric disorders and inability to collect pre-drug “baseline” data, well-controlled, longitudinal experiments in animals are a critical step in understanding the causes and effects of polysubstance abuse.
The present studies were designed to assess two potential mechanisms by which long-term binge-like EtOH consumption may increase cocaine use. One possibility is that chronic exposure to EtOH results in enhancement of the reinforcing effects of cocaine. To address this possibility, dose–effect curves for cocaine self-administration were determined prior to EtOH exposure and again after monkeys had consumed EtOH 5 days per week for 8 weeks. Bottles containing a sweetened 4% EtOH solution were hung on monkeys’ home cages for 1 h; monkeys could consume up to 2.0 g/kg per day. This regimen is consistent with the definition of “binge drinking” promulgated by the National Institute on Alcohol Abuse and Alcoholism: “a pattern of drinking that brings blood alcohol concentration (BAC) levels to 0.08 g/dl…in about two hours;” http://www.niaaa.nih.gov/alcohol-health/overview-alcohol-consumption/moderate-binge-drinking. Because the reinforcing effects of cocaine have been associated with DA D1-like and D2-like receptors, the sensitivity of cocaine self-administration to antagonists of these receptors was determined under both conditions. In addition, the ability of the D2-like DA receptor agonist quinpirole to elicit yawning was examined before and during the period of EtOH drinking. Although it interacts with all D2-like receptor subtypes, yawning elicited by quinpirole has been thoroughly characterized as an effect mediated by the D3 receptor subtype of the D2-like family of DA receptors in rodents and monkeys (e.g., Collins et al., 2005, Collins et al., 2007, Martelle et al., 2007). Finally, after daily EtOH drinking was discontinued, the possibility that acute pharmacological interactions could increase cocaine reinforcement was tested by infusing EtOH intravenously just prior to self-administration sessions.
Section snippets
Subjects
Eight adult male rhesus monkeys (Macaca mulatta) served as subjects. Each monkey was fitted with an aluminum collar (Primate Products, Redwood City, CA) and trained to sit calmly in a standard primate chair (Primate Products). Monkeys were housed individually in stainless steel cages in which water was available ad libitum. Monkeys were weighed weekly and fed enough food (Purina LabDiet Chow, St. Louis, MO), fresh fruit and vegetables daily to maintain healthy body weights without becoming
Initial EtOH drinking
In the first group of three monkeys exposed to this procedure (Cohort 1), as the EtOH concentration and maximum dose was increased over the first 12 days, two monkeys reliably consumed all available EtOH and the third (R-1608) approached maximum intake (Fig. 1, top). On day 13 the EtOH concentration was increased to 6% and the maximum allowed EtOH consumption continued to be increased every three days (see Table 1). Access to this EtOH concentration disrupted EtOH consumption in all monkeys.
Discussion
The primary finding of these studies is that chronic (∼8-week) binge-like consumption of EtOH by rhesus monkeys resulted in increased reinforcing effects of cocaine. Responding during availability of low cocaine doses, which was not different from responding for saline injections prior to EtOH consumption, was robustly increased in most animals. That the change in cocaine reinforcement over time was due to EtOH exposure, rather than a drift in cocaine's effects over time, was confirmed in three
Role of funding source
Funding for these studies was provided by the National Institute on Drug Abuse, Public Health Service grant DA 021658. NIDA had no further role in any aspect of the studies.
Contributors
P.W.C. was responsible for all aspects of this research including study concept and design, acquisition of data, data analysis, interpretation of findings and preparation of the manuscripts for publication.
Conflict of interest
No conflict declared.
Acknowledgements
Michelle Bell, Phillip Epperly and April Davenport provided technical assistance for these studies. The author is grateful to Dr. Michael A. Nader and Sarah A. Kromrey for helpful comments on an earlier version of this manuscript.
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