Role of calcineurin in the VTA in rats behaviorally sensitized to methamphetamine

Abstract

Chronic psychostimulant administration increases locomotor activity, which is referred to as locomotor sensitization. Calcineurin has been suggested to participate in psychostimulant-induced sensitization, but the underlying neurobiological mechanism is poorly understood. This study was designed to examine whether calcineurin activity and its substrates participate in methamphetamine (METH)-induced locomotor sensitization in rats. Two weeks daily METH (1 mg/kg, i.p.) was administrated to rats to induce locomotor sensitization, activity of calcineurin and its substrates Synapsin and glycogen synthase kinase-3β (GSK-3β) were detected. The initiation and expression of locomotor sensitization were tested by inhibition of calcineurin activity systematically or locally in the ventral tegmental area (VTA). Expression of the calcineurin A subunit (catalytic subunit) increased in the VTA but not prefrontal cortex, nucleus accumbens, or hippocampus in rats sensitized to METH. The calcineurin inhibitor cyclosporine A, systemically administered or microinfused into the VTA, suppressed the initiation but not expression of METH-induced locomotor sensitization. Chronic METH exposure upregulated the expression of the calcineurin A subunit in the VTA, which was negatively associated with downregulation of the phosphorylation of Synapsin and GSK-3β. Moreover, the related molecular changes were blocked by systemically administered cyclosporine A or microinjections into the VTA. These data elucidate the critical role of calcineurin in the neurobiological mechanism underlying METH-induced locomotor sensitization, suggesting that calcineurin might participate in the initiation of METH-induced locomotor sensitization by negatively regulating the activity of Synapsin and GSK-3β in the VTA.