Impact of environmental enrichment on heroin-induced neuroadaptations in the insula, nucleus accumbens and ventral tegmental area.

The ventral tegmental area (VTA), nucleus accumbens (NAc) and insular cortex (IC) are brain regions implicated in addiction. However, the involvement of heroin-induced neuroadaptations in these regions is not fully uncovered. Here, we used male and female Long Evans rats to investigate the causal roles of two parallel pathways: VTA→IC and VTA→NAc in opioid-driven behaviors, related neuroadaptations and neural mechanisms by which environmental enrichment (EE) attenuates drug taking and seeking. Our findings are: 1) confirmation that the VTA→IC and VTA→NAc pathways consist of dopamine (DA) and nonDA neurons; 2) demonstration that both pathways are involved in heroin intravenous self-administration (IVSA), reinstatement of heroin seeking and conditioned place preference; 3) dopamine D3 receptor (D3R) mRNA is expressed in the IC, predominantly on glutamate and GABA neurons; 4) dopamine D1 receptors (D1Rs), co-localized with D3Rs, are downregulated in IC and upregulated in NAc following heroin IVSA; 5) Heroin IVSA had no significant effect on D3R and mu opioid receptor (MOR) mRNA expression in these regions; 6) EE reversed heroin-induced neuroadaptations in NAc, but not in IC; 7) heroin-seeking reinstating cues activated cFos in VTA DA and nonDA cells and 8) EE attenuated cue-induced cFos in a manner correlated with the cues' ability to reinstate drug seeking. These results indicate that heroin IVSA causes region-specific, bi-directional neuroadaptations of D1Rs and that EE reverses these neuroadaptations in the NAc. This reversal effect, along with the blunting of drug-cue-induced VTA cFos activation in DA and nonDA cells, might constitute mechanisms by which EE reduces relapse.