Exposure to environmental enrichment attenuates addiction-like behavior and alters molecular effects of heroin self-administration in rats

Abstract

Environmental factors profoundly affect the addictive potential of drugs of abuse and may also modulate the neuro-anatomical/neuro-chemical impacts of uncontrolled drug use and relapse propensity. This study examined the impact of environmental enrichment on heroin self-administration, addiction-related behaviors, and molecular processes proposed to underlie these behaviors. Male Sprague-Dawley rats in standard and enriched housing conditions intravenously self-administered similar amounts of heroin over 14 days. However, environmental enrichment attenuated progressive ratio, extinction, and reinstatement session responding after 14 days of enforced abstinence. Molecular mechanisms, namely DNA methylation and gene expression, are proposed to underlie abstinence-persistent behaviors. A global reduction in methylation is reported to coincide with addiction, but no differences in total genomic methylation or repeat element methylation were observed in CpG or non-CpG (CH) contexts across the mesolimbic circuitry as assessed by multiple methods including whole genome bisulfite sequencing. Immediate early gene expression associated with drug seeking, taking, and abstinence also were examined. EGR1 and EGR2 were suppressed in mesolimbic regions with heroin-taking and environmental enrichment. Site-specific methylation analysis of EGR1 and EGR2 promoter regions using bisulfite amplicon sequencing (BSAS) revealed hypo-methylation in the EGR2 promoter region and EGR1 intragenic CpG sites with heroin-taking and environmental enrichment that was associated with decreased mRNA expression. Taken together, these findings illuminate the impact of drug taking and environment on the epigenome in a locus and gene-specific manner and highlight the need for positive, alternative rewards in the treatment and prevention of drug addiction.

Have we reproduced Rat Park? Conceptual but not direct replication of the protective effects of social and environmental enrichment in addiction

“…The protective effects of environmental enrichment were further demonstrated in a 2018 study where enriched rats had access to a variety of objects and a running wheel. Animals in the enriched housing condition acquired a similar level of heroin self-administration, but showed reduced motivation to consume heroin and relapse propensity in progressive ratio and reinstatement tests (39). These studies conceptually replicate the key findings of the Rat Park studies and Hill and Powell's experiments, demonstrating that across different opioid reinforcers and research groups, social and environmental enrichment reduce addiction-like behaviours in animals.…”

Global DNA methylation levels in white blood cells of patients with chronic heroin use disorder. A prospective study

“…It could be that transcription start sites and CG islands were hypermethylated and flanking regions were hypomethylated, or vice versa, and thus these two effects cancelled each other out. As Imperio et al [ 5 ] showed, heroin administration to rats revealed no differences in total genomic methylation, but induced site-specific hypo-methylation in EGR1 and EGR2. Moreover, differential methylation was observed in six nuclear-encoded genes in different rat brain regions, following acute and chronic morphine administration [ 4 ].…”

“…Both acute and chronic morphine exposure have been associated with brain region-specific changes in 5-mC and 5-hmC levels [ 4 ]. Moreover, gene specific hypo-methylation has been reported to coincide with heroin use disorder in animal models and has been associated with the treatment and prevention of opioid use [ 5 ]. An epigenome-wide association study that was conducted in 220 European-American women revealed three differentially methylated regions associated with genes PARG, RERE, and CFAP77 [ 6 ].…”

Environmental enrichment decreases chronic psychosocial stress-impaired extinction and reinstatement of ethanol conditioned place preference in C57BL/6 male mice

“…Similarly, the effects of EE on nicotine-induced CPP in male rats were assessed and the results indicated that, in enriched conditions, rats showed extinction of the nicotine-induced CPP response by the 5th extinction session (Ewin et al 2015). Also, while animals in standard and enriched housing conditions intravenously selfadministered similar amounts of heroin over 14 days, EE diminished extinction response in male Sprague-Dawley rats (Imperio et al 2018). In addition, 30 days of EE significantly and consistently reduced cocaine seeking behavior during extinction sessions and significantly reduced cue and stressinduced reinstatement of cocaine self-administration (Chauvet et al 2009).…”