Environmental enrichment and a selective metabotropic glutamate receptor2/3 (mGluR2/3) agonist suppress amphetamine self-administration: Characterizing baseline differences

Abstract

A challenge for developing effective treatments for substance use disorders (SUDs) is understanding how environmental variables alter the efficacy of therapeutics. Environmental enrichment (EC) enhances brain development and protects against behaviors associated with drug abuse vulnerability when compared to rats reared in isolation (IC) or standard conditions (SC). EC rearing enhances the expression and function of metabotropic glutamate receptor2/3 (mGlurR2/3) and activating mGluR2/3 reduces psychostimulant self-administration (SA). However, the ability for mGluR2/3 activation to suppress amphetamine (AMP) SA in differentially reared rats is not determined. Therefore, we tested the hypothesis EC reduces AMP (SA) by augmenting mGluR2/3 function. At postnatal day 21, male Sprague-Dawley rats were assigned to EC, IC, or SC environments for 30 days. Then, they acquired AMP SA and were moved to a progressive ratio (PR) schedule of reinforcement. EC, IC, and SC rats were pretreated with LY379268 (vehicle, 0.3 and 1 mg/kg), a selective mGluR2/3 agonist, before PR behavioral sessions. Linear mixed effects analysis determined EC rats had reduced motivation for AMP SA when compared to IC or SC rats and that LY379268 dose-dependently suppressed AMP SA, but there was no evidence of an interaction. Cumming/Gardner-Altman estimation plots illustrate that the 0.3 mg/kg dose suppressed infusions in EC rats while the 1 mg/kg dose suppressed infusions in SC rats. LY379268 was incapable of suppressing the motivation for AMP SA in IC rats. Controlling for baseline differences in differentially reared rats remains a challenge. Normalizing to a baseline introduced error which is illustrated in the precision of the estimated effect size differences. The data indicate that environmental enrichment enhances the ability of a selective mGluR2/3 agonist to suppress AMP SA and indicates the functional status of the mGluR2/3 is formed during development. Therefore, environmental history must be considered when evaluating pharmacological therapeutics particularly those aimed at the mGluR2/3.