Differential patterns of neuronal activation in rostral versus caudal ventral tegmental area involved in behavioral sensitization induced by an escalating-dose morphine administration paradigm

The transition to addiction often involves a gradual process of escalated drug intake. The purpose of the present study was to characterize neuronal activation in the ventral tegmental area (VTA) and substantia nigra (SN) following chronic escalating-dose morphine exposure (days 1-7, 2 mg/kg/d; days 8-21, beginning at 10 mg/kg/d, increasing by 2 mg/kg/d), with steady-dose morphine (2 mg/kg/d, i.p., for 21 days) as the comparison. Using immunohistochemical double-staining for tyrosine hydroxylase (TH) and Fos, we found that the number of Fos+TH+ neurons in the rostral VTA and number of Fos+TH− neurons in the lateral SNr were significantly increased in escalating-dose morphine-treated rats compared with steady-dose morphine-treated rats and acute morphine-treated rats. Meanwhile, this increase was associated with robust expression of behavioral sensitization after a challenge with 10 mg/kg morphine. The number of Fos+TH+ neurons was significantly increased by acute morphine in the caudal VTA and SNc, but this number did not increase further with morphine pretreatment. These results demonstrate that behavioral sensitization was associated with elevated activation of dopaminergic neurons in the rostral VTA and nondopaminergic neurons in the lateral SNr, which could only be induced by chronic escalating-dose morphine rather than chronic steady-dose morphine pretreatment.