Role of Inflammatory Microglia in Mediating Periadolescent Nicotine-Induced Reward Sensitization

Abstract

Nicotine exposure during the onset of adolescence (periadolescence) is demonstrated to sensitize the brain to the rewarding effects of various drugs of abuse. Nicotine enhances the expression of the transcription factor [delta]FosB that may facilitate this process. It is suggested that microglia, the resident immunocompetent cells in the brain, may contribute to this sensitization. This study was conducted to determine whether suppression of inflammatory microglia impacts nicotine's ability at periadolescence to induce sensitization to cocaine in the adult rat. To achieve this, minocycline was administered at a dose of 30 mg/kg, 30 minutes prior to 10 once-daily doses of 0.4 mg/kg nicotine during periadolescence (postnatal days 35-44) in male Sprague Dawley rats. FosB-like immunoreactivity (FosB-ir) in key brain reward and memory areas, and conditioned place preference (CPP) were used to assess changes at the molecular and behavioral levels. Nicotine enhanced FosB-ir the dentate gyrus (DG) of hippocampus by 52% over vehicle control, while minocycline pretreatment attenuated the density of FosB-ir neurons in the DG by 34% compared to nicotine at PND 45. Similar, but not statistically significant reductions were observed in the nucleus accumbens (NAc), and medial prefrontal cortex (mPFC). This trend continued when the rats were allowed to mature into adulthood (PND 80) in both the NAc and mPFC, with minocycline pretreatment showing a significant decrease in FosB-ir by 36.7% compared to nicotine in the mPFC. The significant reduction in FosB-ir observed at PND 45 in the DG with minocycline pretreatment was reversed at PND 80. CPP studies indicated that both nicotine and minocycline-prior-to nicotine enhanced the rat's anticipation for challenge cocaine following adult conditioning by over 100% with no significant difference between the two. These results suggest that nicotine-induced inflammatory (M1) activation of microglia may be important for the induction of FosB protein, but not related to the sensitization of the adult rat to cocaine. The results further suggest a mechanism separate from induction of FosB expression in producing the long-term changes induced by nicotine.