Environmental enrichment attenuates reinstatement of heroin seeking and reverses heroin-induced upregulation of mesolimbic ghrelin receptors

Abstract

We have shown that environmental enrichment (EE) can effectively reduce reinstatement and facilitate true abstinence in animal models of drug use. Here, we investigated whether EE is effective against reinstatement of heroin seeking in long access (LA) model, which has been argued to capture the compulsive features of human drug addiction. We also explored the neurobiology by which EE produces its anti-drug addiction effects. In particular, we focused here on the ghrelin system, which is known for its involvement in reward-motivated behaviors and upregulation following intravenous drug self-administration. Following LA to heroin, rats were housed in either non-EE or EE conditions. During extinction and cue-induced reinstatement test, EE rats showed a significant reduction in active lever responding compared to non-EE rats, suggesting that EE facilitates extinction of drug seeking and reduces the capacity of drug-associated stimuli to elicit and maintain drug seeking. Using Western Blotting, we found that rats with LA to heroin IVSA showed a significant increase in ghrelin receptor (GHS-R1a) expression in the ventral tegmental area and nucleus accumbens, the brain regions implicated in resumption of drug use . Exposure to EE attenuated heroin-induced upregulation of GHS-R1a receptor in these regions but produced no significant changes other brain regions. Our findings suggest that EE can be an effective behavioral approach to diminish drug seeking even following LA to heroin. Compulsive drug taking and seeking seem to be correlated with an upregulation of GHS-R1a expression in the limbic regions, and EE can reverse these neuroadaptations, potentially contributing to a reduction in drug seeking.