Drug addiction involves complex interactions between pharmacology and learning in genetically susceptible individuals. Members of the Homer gene family are regulated by acute and chronic cocaine administration. Here, we report that deletion of Homer1 or Homer2 in mice caused the same increase in sensitivity to cocaine-induced locomotion, conditioned reward, and augmented extracellular glutamate in nucleus accumbens as that elicited by withdrawal from repeated cocaine administration. Moreover, adeno-associated virus-mediated restoration of Homer2 in the accumbens of Homer2 KO mice reversed the cocaine-sensitized phenotype. Further analysis of Homer2 KO mice revealed extensive additional behavioral and neurochemical similarities to cocaine-sensitized animals, including accelerated acquisition of cocaine self-administration and altered regulation of glutamate by metabotropic glutamate receptors and cystine/glutamate exchange. These data show that Homer deletion mimics the behavioral and neurochemical phenotype produced by repeated cocaine administration and implicate Homer in regulating addiction to cocaine.

Homer proteins are integral to the assembly of proteins regulating glutamate signaling and synaptic plasticity. Constitutive Homer2 gene deletion [knock-out (KO)] and rescue with adeno-associated viral (AAV) transfection of Homer2b was used to demonstrate the importance of Homer proteins in neuroplasticity produced by repeated ethanol (EtOH) administration. Homer2 KO mice avoided drinking high concentrations of EtOH and did not develop place preference or locomotor sensitization after repeated EtOH administration. The deficient behavioral plasticity to EtOH after Homer2 deletion was paralleled by a lack of augmentation in the rise in extracellular dopamine and glutamate elicited by repeated EtOH injections. The genotypic differences in EtOH-induced change in behavior and neurochemistry were essentially reversed by AAV-mediated transfection of Homer2b into accumbens cells including, differences in EtOH preference, locomotor sensitization, and EtOH-induced elevations in extracellular glutamate and dopamine. These data demonstrate a necessary and active role for accumbens Homer2 expression in regulating EtOH-induced behavioral and cellular neuroplasticity.

No abstract

Rationale This study examined the relationship between voluntary ethanol consumption and ethanol concentrations measured in the nucleus accumbens of ethanol dependent and non-dependent C57BL/6J mice. Method Mice were offered ethanol in a 2-bottle choice, limited access paradigm and consummatory behavior was monitored with lickometers. After baseline intake stabilized, mice received chronic intermittent ethanol (EtOH group) or air (CTL group) exposure by inhalation (16 hr/day for 4 days) and then resumed drinking. Brain ethanol levels during voluntary drinking were measured by microdialysis procedures and compared to brain ethanol concentrations produced during chronic intermittent ethanol vapor exposure. Results Voluntary ethanol consumption progressively increased over repeated cycles of chronic intermittent ethanol exposure but remained unchanged in CTL mice. Analysis of lick patterns indicated EtOH mice consumed ethanol at a faster rate compared to CTL mice. The greater and faster rate of ethanol intake in EtOH mice produced higher peak brain ethanol concentrations compared to CTL mice and these levels were similar to levels produced during chronic intermittent ethanol exposure. Conclusions These results show that in this model of dependence and relapse drinking, dependent mice exhibit enhanced voluntary ethanol consumption relative to non-dependent controls, which consequently produces blood and brain ethanol concentrations similar to those experienced during chronic intermittent ethanol exposure.

No abstract