Roles for presynaptic modulation of dopamine neurotransmission in the striatum are implicated in a broad range of behaviors and disorders, including the initiation of drug addiction. In this proposal, we describe how recent advances in electrochemical amperometric and optical fluorescent presynaptic recording now promise direct answers to long-asked questions on the function of synaptic dopamine release in the striatum. In particular, we will study effects of dopamine on the corticostriatal synapse, an extraordinarily controversial area. By elucidating the precise effects of synaptic and psychostimulant-elicited dopamine release on the fundamental striatal microcircuit, we hope to establish how drugs of abuse mimic normal processes to initiate changes in behavior. Dopamine neuron burst firing occurs during paradigms of reward and conditioned learning. The central hypotheses of this application are a) dopamine can either excite or depress corticostriatal transmission, depending on specific kinetic parameters including neuronal firing patterns, b) that psychostimulant drugs mimic the effects of midbrain dopamine burst firing at the corticostriatal synapse. We hypothesize that corticostriatal terminals are depressed at tonic firing rates due to preferential D2 activation, and excited during burst firing due to Dl activation. Psychostimulants essentially mimic burst firing even during tonic activity, thus appropriating the physiological response to rewarding or conditioned behaviors at corticostnatal terminals. This model could provide the initial stage of synaptic rewiring by drugs of abuse.
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