Cell-Type Specific Deletion of CB2 Cannabinoid Receptors in Dopamine Neurons Induced Hyperactivity Phenotype: Possible Relevance to Attention-Deficit Hyperactivity Disorder.

DAT- mice are conditional knockout (cKO) animals that do not express cannabinoid CB2 receptors (CB2R), in midbrain dopamine neurons. The hyperactivity phenotype of DAT- cKO mice were paradoxically reduced by low dose of amphetamine. Here, we report on the locomotor activity analysis in male and female adolescent (PND 30 ± 2) mice in basal conditions and in response to different doses of amphetamine, using the Open Field (OF), Elevated Plus-Maze (EPM) tests and the Novel Object Recognition (NOR) task as a putative model of attention deficit hyperactivity disorder (ADHD). Results showed that both male and female adolescent DAT- mice displayed significant increases in distance traveled in the OF test compared with WT mice. However, 2 mg/kg dose of amphetamine reduced the distance traveled by the DAT- but was increased in the WT mice. In the EPM test of anxiety-like behavioral responses, DAT- spent more time in the open arms of the maze than the WT mice, suggesting a reduction in anxiety-like response. DAT- mice showed significant increase in the number of unprotected head dips in the maze test and in the cliff avoidance reaction (CAR) test demonstrating impulsivity and risky behavior. DAT- mice also exhibited deficient response in the delay decision making (DDM), with impulsive choice. Both DAT- and WT were able to recognize the new object in the NOR task, but the exploration by the DAT- was less than that of the WT mice. Following the administration of 2 mg/kg of amphetamine, the similarities and differential performances of the DAT- and WT mice in the EPM test and NOR task was probably due to increase in attention. Microglia activation detected by Cd11b immunolabelling was enhanced in the hippocampus in DAT cKO than in WT mice, implicating neuro-immune modulatory effects of CB2R. The results demonstrates that DAT- cKO mice with cell-type specific deletion of CB2R in midbrain dopaminergic neurons may represent a possible model for studying the neurobiological basis of ADHD.