Considerable evidence indicates that the acute and chronic actions of psychomotor stimulants (e.g. cocaine andamphetamine), as well as of other drugs of abuse, involve modulation of neurotransmission in mesolimbic andnigrostriatal dopamine systems. Our previous studies have revealed that a family of substrates for cAMP-dependentprotein kinase, including DARPP-32, RCS (Regulator of Calmodulin Signaling, previously termed ARPP-21), andARPP-16, are highly enriched in the basal ganglia, including the neostriatum and nucleus accumbens. Previous studieshave indicated that a critical target for DARPP-32 is the serine/threonine protein phosphatase, PPL In recent studies wehave found that RCS interacts with the Ca2+-binding protein calmodulin and in turn regulates the serine/threonineprotein phosphatase, calcineurin (or PP2B). In other studies, we have found that ARPP-16 is likely to regulate thestability of GAP-43 mRNA. In Project III, we propose to study the role(s) of RCS and ARPP-16 in mediating ormodulating the actions of psychostimulants. In addition, we propose to study the roles of the three isoforms of PP1(PP1alpha, beta and gamma) in the actions of psychostimulants.
The Specific Aims are:
Aim I : Characterization of RCS - We will analyze in RCS knockout mice, several aspects of animal behavior andphysiology that are modulated by psychostimulants. These studies will include acute and chronic motor-stimulantproperties and drug reinforcing properties of cocaine and amphetamine in RCS mutant mice. We will also characterizemolecular targets for RCS that may be involved in mediating the actions of psychostimulants. Studies will includeanalysis of RCS and regulation of calcineurin, and of RCS and regulation of other calmodulin-binding proteins.
Aim II : Characterization of ARPP-16 - We will analyze in ARPP-16 knockout mice, several aspects of animalbehavior and physiology that are modulated by psychostimulants. These studies will include acute and chronic motorstimulantproperties and drug reinforcing properties of cocaine and amphetamine in RCS mutant mice. We will alsocharacterize the regulation of ARPP-16 by phosphorylation at novel sites and study the phosphorylation of these sites inresponse to psychostimulant treatment.
Aim III : Characterization of PP1 isoforms - We will investigate the role of PP1alpha, beta and gamma isoforms in the actions ofpsychostimulants. These will include acute and chronic motor-stimulant properties and drug reinforcing properties ofcocaine and amphetamine in RCS mutant mice.Results from our studies will complement other Projects of this Program Project grant. Together, these studies willhopefully lead to elucidation of the biochemical pathways through which drugs of abuse act in the brain, and to anincreased likelihood that therapeutic agents will be developed that will prevent or reverse molecular adaptations withinthese pathways.
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