PHOSPHORYLATION IN NEUROADAPTATIONS TO AMPHETAMINES

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DESCRIPTION(Adapted from applicant's abstract): Repeated treatment with psychoactive drugs such as amphetamine (AMPH) resuits in drug experience‑induced neuroadaptations which may have similarities to other models of synaptic plasticity and learning. This application will focus on one late‑developing but long‑lasting neuroadaptation elicited by repeated AMPH: enhanced AMPH‑induced dopamine (DA) release. Following repeated administration of AMPH, three novel phenomena occur: 1) acute DA release by AMPH is increased; 2) AMPH‑stimulated DA release becomes Ca2+ ‑dependent; and 3) A kinase switch in regulation of AMPH‑mediated DA release occurs from protein kinase C to protein kinase A (PKA) and Ca2+ and calmodulin (CaM)‑dependent protein kinase 11 (CaM Kll). The primary objective of this application is to understand the role of protein phosphorylation/dephosphorylation in the enhanced AMPH‑mediated DA release following repeated AMPH. This application will address three aims. 1. To determine whether PKA and CaM Kll activation are functioning in a parallel or linear pathway to enhance AMPH‑mediated DA release in rat striatum. 2. To assess the role of direct DAT phosphorylation by PKA and CaM Kll in the enhanced AMPH‑mediated DA release following repeated AMPH. 3. To determine the regulation of signalling components following repeated. intermittent AMPH. 4. Determine whether the reoulation of DA release in the nucleus accumbens is similar to that in striatum following repeated AMPH. This work wili begin to define the biochemical basis of of neurobiological adaptations following repeated AMPH, which may exhibit similarities to learning models. Because enhanced DA release is elicited by repeated treatment with many drugs of abuse, and may be involved in the incentive motivation to abuse drugs, it is important to understand the biochemical underpinnings of enhanced DA release.