Differential regulation of locomotor activity to acute and chronic cocaine administration by acid-sensing ion channel 1a and 2 in adult mice.

Acid-sensing ion channels (ASICs) are densely expressed in the brain with ASIC1a and ASIC2 channels being the predominant subtypes. These channels are enriched at synaptic sites and are central for the regulation of normal synaptic transmission. Moreover, increasing evidence links ASICs to the pathogenesis of various neurological and neuropsychiatric disorders. In this study, we explore the putative role of ASIC1a and ASIC2 in the regulation of behavioral sensitivity to the psychostimulant cocaine by utilizing ASIC1a or ASIC2 knockout mice. Acute cocaine injection induced a typical dose-dependent increase in locomotor activities in wild-type (WT) mice. However, in ASIC1a and ASIC2 mutant mice, different motor responses to cocaine were observed. In ASIC1a(-/-) mice, cocaine induced a significantly less motor response at all doses (5, 10, 20, and 30 mg/kg), while in ASIC2(-/-) mice, cocaine (5-20 mg/kg) stimulated locomotor activity to an extent comparable to WT mice. Only at 30 mg/kg, the cocaine-stimulated motor activity was reduced in ASIC2(-/-) mice. In a chronic cocaine administration model (20mg/kg, once daily for 5 days), a challenge injection of cocaine (10mg/kg, after 2-week withdrawal) caused an evident behavioral sensitization in the cocaine-pretreated WT mice. This behavioral sensitization to challenge cocaine was also displayed in ASIC1a(-/-) and ASIC2(-/-) mice. However, ASIC2(-/-) mice showed less sensitization to challenge cocaine when compared to WT and ASIC1a(-/-) mice. Our results demonstrate the important role of ASIC1a and ASIC2 channels in the modulation of behavioral sensitivity to cocaine. The two synapse-enriched ASIC subtypes are believed to play distinguishable roles in the regulation of behavioral responses to acute and chronic cocaine administration.