Rapid dopamine signaling in the nucleus accumbens during cocaine administration.

摘要

The dopaminergic projection from the ventral tegmental area in the midbrain to forebrain structures such as the prefrontal cortex, basolateral amygdala, and the nucleus accumbens has been highly implicated in subserving brain reward function for both natural rewards and drugs of abuse. Electrophysiological studies have demonstrated that DA transmission occurs on two distinct timescales. Tonic DA signaling occurs over minutes and is hypothesized to result in ambient low-levels of neurotransmitter release for extended periods of time in the terminal fields. In contrast, phasic DA release is thought to be the results of burst firing of DAergic neurons and result in transient high levels of DA that can escape the synapse. While in vivo microdialysis experiments have characterized the dynamics of tonic DA release (over minutes) during cocaine self-administration behavior, the work presented in this dissertation characterizes phasic DA release with much greater temporal resolution using in vivo fast-scan cyclic voltammetry during cocaine self-administration and noncontingent administration of the drug. During cocaine self-administration behavior, two distinct DAergic signals are seen timelocked to the operant response for the drug. A smaller pre-response increase in DA occurs in the seconds leading up to the lever-press response, promotes the seeking or goal-directed behavior to obtain the drug. Immediately after the lever-press response a larger, postresponse increase in DA is observed, which codes for learned associations between drug associated cues and cocaine. In addition to DA signals timelocked to the operant response for cocaine, 'spontaneous' DA transients also occur, which are not timelocked to any overt behavior or environmental stimuli. These 'spontaneous' transients increase in frequency following administration of cocaine in both drug-naive animals and animals with a history of cocaine self-administration and were shown to be a pharmacological effect of the drug. These data suggest DA signaling in the NAc is composed of multiple, functionally distinct signals which code for different aspects of cocaine self-administration behavior.