Elsevier

Drug and Alcohol Dependence

Volume 153, 1 August 2015, Pages 278-285
Drug and Alcohol Dependence

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

https://doi.org/10.1016/j.drugalcdep.2015.05.016Get rights and content

Highlights

  • Chronic EtOH consumption increased self-administration of low cocaine doses.

  • Self-administration returned to baseline after EtOH drinking was discontinued.

  • EtOH drinking enhanced quinpirole-induced yawning in two of three monkeys.

  • Cocaine self-administration was not increased after acute EtOH exposure.

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-s 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: 1 h, 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 five of six 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 two of three 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.

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.

References (58)

  • J. Masur et al.

    Increased stimulatory effect by the combined administration of cocaine and alcohol in mice

    Alcohol

    (1989)
  • R.C. Pierce et al.

    The mesolimbic dopamine system: the final common pathway for the reinforcing effect of drugs of abuse?

    Neurosci. Biobehav., Rev.

    (2006)
  • R.H. Rech et al.

    Interactions between depressants (alcohol-type) and stimulants (amphetamine-type)

    Pharmacol. Biochem. Behav.

    (1978)
  • P.K. Thanos et al.

    The selective dopamine D3 receptor antagonist SB-277011-A attenuates ethanol consumption in ethanol preferring (P) and non-preferring (NP) rats

    Pharmacol. Biochem. Behav.

    (2005)
  • D. Tziortzis et al.

    The relationship between impulsivity and craving in cocaine- and methamphetamine-dependent volunteers

    Pharmacol. Biochem. Behav.

    (2011)
  • N.D. Volkow et al.

    Effects of alcohol detoxification on dopamine D2 receptors in alcoholics: a preliminary study

    Psychiatry Res.

    (2002)
  • W.L. Woolverton et al.

    The effects of a D1 and a D2 dopamine antagonist on behavior maintained by cocaine or food

    Pharmacol. Biochem. Behav.

    (1989)
  • J.M. Aspen et al.

    Ethanol effects on self-administration of alfentanil, cocaine and nomifensine in rhesus monkeys

    Psychopharmacology

    (1997)
  • S. Aston-Jones et al.

    Cocaine antagonizes the anxiolytic effects of ethanol

    Psychopharmacology

    (1984)
  • J. Bergman et al.

    Antagonism of cocaine self-administration by selective dopamine D1 and D2 antagonists

    Behav. Pharmacol.

    (1990)
  • J. Bergman et al.

    Behavioral effects of histamine H1 antagonists: comparison with other drugs and modification by haloperidol

    J. Pharmacol. Exp. Ther.

    (1988)
  • C.W. Bradberry

    Dose-dependent effect of alcohol on extracellular dopamine in mesolimbic striatum of awake rhesus monkeys: comparison with cocaine across individuals

    Psychopharmacology

    (2002)
  • K.M. Carroll et al.

    Alcoholism in treatment-seeking cocaine abusers: clinical and prognostic significance

    J. Stud. Alcohol

    (1993)
  • D.D. Chitwood

    Patterns and consequences of cocaine use

    NIDA Res. Monogr.

    (1985)
  • G.T. Collins et al.

    Yawning and hypothermia in rats: effects of dopamine D3 and D2 agonists and antagonists

    Psychopharmacology

    (2007)
  • G.T. Collins et al.

    Dopamine agonist-induced yawning in rats: a dopamine D3 receptor-mediated behavior

    J. Pharmacol. Exp. Ther.

    (2005)
  • K.P. Cosgrove

    Imaging receptor changes in human drug abusers

    Curr. Top. Behav. Neurosci.

    (2010)
  • G. Di Chiara et al.

    Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats

    Proc. Natl. Acad. Sci. U.S.A.

    (1988)
  • D. Erritzoe et al.

    In vivo imaging of cerebral dopamine D3 receptors in alcoholism

    Neuropsychopharmacology

    (2014)
  • Cited by (18)

    • Effect of chronic binge-like ethanol consumption on subsequent cocaine reinforcement in rhesus monkeys

      2021, Drug and Alcohol Dependence
      Citation Excerpt :

      Regarding the high prevalence of cocaine-alcohol polysubstance abuse, the present study suggests that it does not result from an increase in sensitivity to cocaine produced by prior alcohol use. Moreover, previous studies in nonhuman primates have indicated that acute administration of ethanol does not increase cocaine reinforcement (Aspen and Winger, 1997; Czoty, 2015; Winger et al., 2007) making it unlikely that co-abuse of these substances is perpetuated by synergy in their reinforcing effects. Future research should examine other phenomena, such as long-term drug interactions on the brain and behavior, as factors that may underlie cocaine-alcohol polysubstance abuse.

    • The importance of considering polysubstance use: lessons from cocaine research

      2018, Drug and Alcohol Dependence
      Citation Excerpt :

      Upon discontinuing daily post-cocaine alcohol access, self-administration of the maintenance dose of cocaine was not affected; however, lower doses of cocaine, which had been reinforcing during the period of concurrent alcohol access, were no longer self-administered. Long-term self-administration of concurrent cocaine and alcohol may also have increased D3 dopamine receptor sensitivity (Czoty, 2015). Thus, simultaneous cocaine and alcohol administration increases the reinforcing qualities of dopamine agonists, potentially through enhancements in dopamine receptor sensitivity.

    • Yawning elicited by intravenous ethanol in rhesus monkeys with experience self-administering cocaine and ethanol: Involvement of dopamine D<inf>3</inf> receptors

      2018, Alcohol
      Citation Excerpt :

      Inspection of individual subject data (Fig. 2, bottom) demonstrated that effects of PG01037 appeared to be dose-dependent in all four monkeys. In a previous study of cocaine-ethanol polysubstance abuse, using adult male rhesus monkeys who had experience self-administering cocaine, yawning elicited by the D3R agonist quinpirole was increased after several weeks of ethanol consumption (Czoty, 2015). In addition, it was observed that monkeys yawned during intravenous ethanol infusions (Czoty, 2015, 2016).

    • Pharmacological Treatments for Alcohol-Cocaine Interactions: A Preclinical Focus.

      2017, The Neuroscience of Cocaine: Mechanisms and Treatment
    View all citing articles on Scopus
    View full text