Physiology of midbrain dendritic dopamine transmission

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DESCRIPTION (provided by applicant): Dopamine cells in the ventral midbrain serve a role in a number of critical functions, including motor processes, focused attention, reward and incentive learning. It is not surprising then that the same cells participate as neural substrates of human diseases such as drug addiction, Parkinson's disease, and likely schizophrenia and attention deficit hyperactivity disorder. Dopamine cells exert their main effects distally through projections to brain regions involved in decision making, movement, and emotion. Small amounts of dopamine are also released dendritically near the midbrain nuclei of the ventral tegmental area (VTA) and substantia nigra (SN). Recently it was discovered that this dendritic release may occur through reversal of the dopamine transporter, a widely-distributed membrane-bound protein responsible for the majority of free dopamine uptake from the extracellular space. Dopamine released by this mechanism can activate D2 dopamine receptors on the dopamine cell bodies, inhibiting firing, and thus the release of dopamine in distal brain regions implicated in behavioral processes. While the existence of dopamine transporters and D2 receptors in the VTA and SN suggest a physiological role for dendritic release, the precise synaptic mechanisms have yet to be investigated. This proposal addresses this issue by investigating the mechanisms of dendrodendritic transmission in the VTA. Whole-cell patch clamp electrophysiological technique will be used to record from dopamine neurons in rat midbrain slices. Of particular interest is the elucidation of the role of metabotropic glutamate receptors in the dopamine-induced inhibition of dopamine cell firing. Amphetamine, a drug of abuse known to act on dopaminergic cells, will also be used to attempt to gain and understanding of the importance and role of the dendritic release of dopamine.