Effects of chronic cocaine and ethanol self-administration on brain dopamine receptors in a rhesus monkey model of polysubstance abuse

Abstract

Most individuals with cocaine use disorder also use alcohol; however, little is known about the behavioural and pharmacological mechanisms that promote co-abuse. For example, although studies in humans and animals have documented that chronic use of either alcohol or cocaine alone decreases D2-like receptor (D2R) availability, effects of co-abuse of these substances on dopamine receptor function have not been characterized. These studies examined the effects of long-term cocaine self-administration in 12 male rhesus monkeys who also consumed either ethanol or an ethanol-free solution each day (n = 6 per group). Specifically, all monkeys self-administered cocaine (0.1 mg/kg per injection) 5 days per week in the morning. In the afternoon, six monkeys consumed 2.0 g/kg ethanol over 1 h to model binge drinking and six monkeys drank an ethanol-free solution. Assessment of D2R availability using positron emission tomography (PET) and [¹¹ C]raclopride occurred when monkeys were drug-naïve and again when monkeys had self-administered approximately 400-mg/kg cocaine. D₃ R function was assessed at the same time points by determining the potency of the D₃ R-preferring agonist quinpirole to elicit yawns. Chronic cocaine self-administration decreased D2R availability in subregions of the basal ganglia in control monkeys, but not those that also drank ethanol. In contrast, D₃ R sensitivity increased significantly after chronic cocaine self-administration in ethanol-drinking monkeys but not controls. These results suggest that co-use of ethanol substantially changes the effects of chronic cocaine self-administration on dopamine receptors, specifically implicating D₃ R as a target for medications in these individuals.

Keywords: alcohol; drug self-administration; nonhuman primates; polysubstance abuse.

FIGURE 1

D2R availability in monkeys that self‐administered only cocaine (Control, n = 6 at baseline and n = 5 at 400 mg/kg) or both ethanol and cocaine (EtOH, n = 6) as measured with [¹¹C]raclopride in five brain areas. Bars represent mean ± SEM. Ordinates: time point, baseline (BL) or after ~400‐mg/kg cocaine self‐administration (400 mg/kg). Abscissae: DVR. *, p < 0.05

FIGURE 2

Quinpirole‐induced yawning (left column) and hypothermia (right column) in six monkeys that self‐administered both cocaine and ethanol. Points represent mean ± SD of multiple determinations. Ordinates, dose of quinpirole or same line (S). Abscissae: yawns (left column) or rectal temperature (right column)

FIGURE 3

Quinpirole‐induced yawning (left column) and hypothermia (right column) in monkeys that self‐administered only cocaine. Points represent mean ± SD of multiple determinations. Ordinates, dose of quinpirole or same line (S). Abscissae: yawns (left column) or rectal temperature (right column)