Presynaptic plasticity of dopamine release in the cortex and basal ganglia is involved in learning cues thatelicit cocaine self-administration and underlie selective attention by filtering non-salient stimuli. The objectiveof this proposal is to characterize mechanisms that mediate presynaptic plasticity at the level of thedopaminergic synaptic vesicle exocytosis.We recently reported that the fusion pores of small DAergic synaptic vesicles can flicker once or multipletimes as fast as 10 kHz, thus regulating the amount of transmitter released from a vesicle. This provides thebasis for Aim 1, which asks how flickering of fusion pores is regulated.In chromaffin cells, we discovered that the level of vesicle acidification is not invariant but enhanced bycellular activity, which can increase quantal size. In this proposal, we show evidence for enhanced vesicularacidification that may underlie drug actions (e.g., Ritalin), and a means for behavior to feed back to alterlong-term transmission. This provides the basis for Aim 2 explores whether psychostimulants regulatequantal size via rebound of vesicular acidification.Finally, we identified how a variety of presynaptic receptors alter DA transmission at the quantal level(e.g., GDNF, D2, nicotinic, and mGluR activation) and why these factors are important for DA as socialsynapses. Most of the work has been on acute effects of neurotransmitters. New evidence indicates long-lastingeffects of neurotransmitters on DA transmission, particularly on the density/formation of axonalpresynaptic varicosities. Accordingly, Aim 3 will examine how neurotransmitters regulate DAergicpresynaptic varicosity formation.
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