Behavioural pharmacologyAltered phosphorylation of GluA1 in the striatum is associated with locomotor sensitization induced by exposure to increasing doses of morphine

Escalation of drug consumption is involved in the transition from drug use to addiction. Our previous study demonstrated that neuronal activation in ventral tegmental area (VTA) and substantia nigra (SN) was associated with behavioral sensitization induced by increasing doses of morphine. Here we sought to characterize the molecular mechanism underlying this behavioral sensitization. We compared mitogen-activated protein kinase (MAPK) signaling following pretreatment with either increasing doses or fixed doses of morphine before and after behavioral sensitization. We found phospho-MAPK markedly increased in ventral striatum and decreased in dorsal striatum after either pretreatment group, but no further change after sensitization induced by 10 mg/kg morphine challenge. Furthermore, we also evaluated the level of phospho-glutamate receptor 1 at serine 845 (pSer845-GluA1) and 831 (pSer831-GluA1) sites in ventral striatum and dorsal striatum. The results showed a significant increase in pSer845-GluA1/GluA1 ratio in ventral striatum but not dorsal striatum after pretreatment with increasing doses of morphine but not after fixed-dose or saline pretreatment. Importantly, pSer845-GluA1/GluA1 ratio was increased exclusively in dorsal striatum and not ventral striatum following acute morphine challenge specifically paired with increasing-dose pretreatment and not fixed-dose or saline. These findings indicate that behavioral sensitization-induced by chronic pretreatment with increasing doses of morphine might be more closely associated with the dynamic GluA1 activity in the striatum rather than the modulation of MAPK signaling. These findings also indicate that GluA1 phosphorylation may occur independent of MAPK activation.