| Many questions still remain regarding the cellular and molecular mechanisms underlying the switch from casual drug use to the compulsive drug-seeking and drug-taking seen in addiction. Brain regions that utilize both dopaminergic and glutamatergic transmission to mediate the actions of drugs of abuse make up the mesolimbic dopamine system. Within this system, the striatum is responsible for some of the motivating aspects of drug-taking as well as motor control changes that underlie the progression to habit formation. Within the striatum, serine/threonine phosphatases are regulated by both dopamine and glutamate signaling and can ultimately affect both synaptic plasticity and transcription. Therefore, an understanding of the role of this family of proteins in mediating the effects of drugs of abuse should provide important information about the mechanisms underlying both short-term and long-lasting effects of drugs of abuse. To begin to examine the regulation of protein phosphatase-2A (PP2A) in the striatum, evidence for direct interaction with the scaffolding A subunit and cAMP regulated phosphoprotein-16kDa (ARPP-16), a striatally enriched protein, was found and further explored by examining changes in basal phosphorylation of PP2A targets as well as behavioral consequences of conditionally knocking out ARPP-16 in the forebrain. In addition, the role of the protein phosphatase-1 (PP1) isoforms, PP1alpha and PP1gamma in behaviors associated with the actions of drugs of abuse were explored. Changes in the responsivity to cocaine in animals with PP1alpha conditionally knocked out in the forebrain provide evidence for an important role of this isoform in the effects of drugs of abuse. In addition, reduced anxiety-related behavior in PP1alpha conditional KOs links this phosphatase with another aspect of addiction, anxiety. Also, animals with PP1alpha, PP1gamma, or both isoforms knocked out in the NAcc using viral-mediated delivery of cre recombinase showed opposing actions in reward learning and motivation. Taken together, these results highlight the importance of serine/threonine phosphatases in the effects of drugs of abuse as well as behaviors associated with addiction. Because structural plasticity also plays an important role in the long-lasting effects of drugs of abuse, changes in the postsynaptic density (PSD) following acute or chronic exposure to cocaine was examined using proteomic approaches. |
