Abstract
Exposure within an environmental enrichment paradigm results in neurobiological adaptations and decreases the baseline of locomotor activity. The current study determined activation of DARPP-32 (dopamine- and cAMP-regulated phosphoprotein-32) and CREB (cAMP response element binding protein), and locomotor activity in rats raised in enriched (EC), impoverished (IC), and standard (SC) conditions following repeated administration of nicotine or saline. In the saline-control group, the basal phosphorylation state of DARPP-32 at Threonine-34 site (pDARPP-32 Thr34) in the prefrontal cortex (PFC) was lower in EC compared to IC and SC rats, which was positively correlated with their respective baseline activities. While nicotine (0.35 mg/kg, freebase) produced locomotor sensitization across all housing conditions when the nicotine-mediated locomotor activity was expressed as a percent change from their respective saline control, EC rats displayed greater sensitization to nicotine than IC and SC rats. Consistent with the behavioral findings, repeated nicotine injection increased pDARPP-32 Thr34 in PFC of EC and IC rats and in nucleus accumbens of EC rats; however, the magnitude of change from saline control in nicotine-induced enhancement of pDARPP-32 Thr34 in PFC was strikingly increased in EC rats relative to IC rats. Moreover, EC rats had lower basal phosphorylation levels of CREB at serine 133 in PFC and nucleus accumbens compared to IC and SC rats, whereas the nicotine-induced increase in phosphorylated CREB-Ser133 was more pronounced in PFC of EC rats relative to IC and SC rats. Collectively, these findings suggest innovative insights into advancing our understanding of the molecular mechanisms of enrichment-induced changes in the motivational effects of nicotine, and aiding in the identification of new therapeutic strategies for tobacco smokers.
Highlights
Convergent evidence suggests that environmental factors impact individual susceptibility to drugs of abuse [1,2]
To determine whether environmental enrichment regulates DARPP-32 signaling in response to nicotine in a dose-dependent manner, we examined the acute effects of nicotine (0.1, 0.3 and 0.8 mg/kg) on pDARPP-32 Thr34, pDARPP-32 Thr75 and total DARPP-32 in prefrontal cortex (PFC), nucleus accumbens (NAc) and striatum in enriched condition (EC) and impoverished condition (IC) rats (Table 1)
These findings suggest that nicotine dose-dependently increases pDARPP-32 Thr34 levels most prominently in the EC-reared condition and that 0.3 mg/kg acute dose of nicotine is the optimal dose to elicit the most robust changes in pDARPP-32 Thr34 among the measured brain regions of EC and IC rats
Summary
Convergent evidence suggests that environmental factors impact individual susceptibility to drugs of abuse [1,2]. One animal model that addresses environmental factors uses rats raised in one of the three different conditions: an enriched condition (EC), a standard condition (SC), and an impoverished condition (IC). Behavioral sensitization is not a measure of drug reward, this procedure is sensitive to behavioral changes produced by the psychostimulant effects of abused drugs [13,14,15] This procedure was used in the current study to determine whether enriched environmentinduced alterations in locomotor sensitization to nicotine was associated with changes in dopaminergic signaling proteins. EC rats exhibit a reduction in nicotine-mediated locomotor activity compared to IC and SC rats [16], which could be mediated by enriched environment-induced alterations of dopaminergic pathways. EC rats may have lower dopaminergic tone compared to IC rats under basal conditions, which may contribute to differential behavioral responses to psychostimulants
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