Developing an Animal Model of Polysubstance Abuse in Adolescence: The Role of NMDA Receptors in Alcohol/Cocaine Reward

Repeated exposure to drugs of abuse conditions individuals to anticipate the behavioral consequences of drug use specifically in the presence of a drug-associated context. In rodents, preferences and aversions for alcohol and cocaine have been conditioned; however, the mechanisms underlying the expression of these conditioned effects remain unknown. Given that alcohol and cocaine polysubstance abuse is prevalent in young individuals, with more than 50% of these polysubstance abusers reporting to be under the age of 21, it is important to understand the mechanisms contributing to the behavioral effects of alcohol and cocaine co-dependency. Aim 1 determined if age differentially impacted the effects of repeated alcohol exposure on conditioned cocaine preferences. Adolescent [postnatal day (PND) 30) and adult (PND 60) male Sprague-Dawley rats were administered ethanol (0.5 or 1.75 g/kg, i.p.) immediately before each cocaine conditioned place preference (CPP) session (20 mg/kg, i.p.; 15 minutes). Aim 2, Experiments 1 and 2, identified the role of NMDA receptors within the nucleus accumbens septi (NAcc) in conditioned ethanol/cocaine behavior. Adolescent and adult rats in Experiment 1 were administered the NMDA antagonist MK-801 (0.1 or 0.2 m/kg, i.p.) 30 minutes prior to cocaine conditioning. Adolescent and adult rats within Experiment 2 underwent bilateral cannulation for chronic implantation of the cannulae into the NAcc of both hemispheres. Rats administered 1mM MK-801 or saline into the NAcc prior to cocaine (20.0 mg/kg, i.p.) conditioning, completed additional testing to determine the role of NAcc NMDA receptors in the consolidation, reconsolidation and expression of cocaine conditioned behavior in a drug-induced reactivation manner. Findings show adolescent and adult rats responded similarly to co-administration of ethanol/cocaine with both ages showing a decrease in the rewarding properties of cocaine. What differed between the age groups were the aversive properties of ethanol, with adolescents being less sensitive to the aversive properties of ethanol and its modulating effects on cocaine reward. A role for the NAcc NMDA receptors was observed in contributing to the modulating effects of ethanol on cocaine reward. Lastly, the reconsolidation of cocaine reward was more sensitive to disruption in adolescent rats, as compared to their adult counterparts. These results suggest an increased vulnerability for adolescents to continue engaging in polysubstance abuse. However, this at-risk age group also appeared to be more responsive to pharmacological treatment in decreasing addictive behavior