Environmental enrichment (EE) introduced during abstinence from cocaine self-administration is protective in reducing cue-elicited incentive motivation for cocaine in rats. This study examined neural activation associated with this protective effect of EE using Fos protein expression as a marker. Rats were trained to press a lever reinforced by cocaine (0.75 mg/kg/0.1 ml infusion) and light and tone cues across 15 consecutive days during which they were all housed in isolated conditions (IC). Rats were then assigned to either remain in IC, or to live in pair-housed conditions (PC) or EE for 30 days of forced abstinence from cocaine. Subsequently, cocaine-seeking behavior (lever presses without cocaine reinforcement) elicited by response-contingent cue presentations was assessed for 90 min, after which the rats' brains were immediately harvested for Fos protein immunohistochemistry. EE attenuated, whereas IC enhanced, cue-elicited cocaine-seeking behavior relative to PC. Also, within the prelimbic and orbitofrontal cortices and basolateral amygdala, IC enhanced, whereas EE reduced, Fos expression relative to PC. Furthermore, EE attenuated Fos expression in the infralimbic and anterior cingulate cortices, the nucleus accumbens (core and shell), bed nucleus of the stria terminalis, and ventral tegmental area, evident as a reduction relative to both PC and IC. In contrast, IC enhanced Fos expression in the dorsal caudate putamen, substantia nigra, and central amygdala, evident as an increase relative to both PC and EE. These results suggest that EE blunts neural activation throughout the mesocorticolimbic circuitry involved in cue-elicited incentive motivation for cocaine, whereas IC enhances activation primarily within the nigrostriatal dopamine pathway. These findings have important implications for understanding and treating drug-conditioned craving in humans.
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