Homer2: A Negative Regulator of Methamphetamine Reward Sensitivity

Abstract

Homer2 is a post‐synaptic scaffolding protein involved in regulating glutamate receptor function that has been highly implicated in drug‐induced neural plasticity. Withdrawal from repeated methamphetamine injections increases Homer2 protein expression within the nucleus accumbens (NAC). Moreover, both idiopathic & genetic vulnerability to high MA reward is associated with elevated Homer2 expression within NAC subregions. The present series of studies were designed to examine the functional relevance of NAC Homer2 expression for methamphetamine reward and reinforcement. Under place‐conditioning procedures [4 pairings of 0.5–2 mg/kg], the dose‐response function for a methamphetamine‐conditioned place‐preference was shifted upwards and to the right in Homer2 KO mice, relative to their wild‐type counterparts. A follow‐up study using shRNA‐mediated knock‐down of Homer2b within the NAC core of C57BL/6J mice recapitulated the KO effect upon the expression of a methamphetamine‐conditioned place‐preference (2 mg/kg) and shifted the dose‐response function for methamphetamine reinforcement upwards of controls. Together, these results provide novel evidence that Homer2 expression, particularly that within the NAC core, normally functions to dampen the reinforcing/rewarding properties of methamphetamine, posing an inhibitory role for Homer2‐dependent regulation of glutamate transmission within the NAC as a neurobiological substrate in the etiology of MA addiction.Support or Funding InformationThis work was funded by NIDA grant R01DA039168. The authors thank Drs. Matthias Klugmann and von Jonquires for constructing the AAVs.