Phasic dopamine release: Its origin and function in reward seeking.

摘要

The reinforcing properties of both natural rewards and drugs of abuse are believed to be due to their action on a common neural pathway, the mesolimbic dopamine system. The mesolimbic dopamine system, extending from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and prefrontal cortex, is thought to play a pivotal role in mediating reward-seeking behaviors. Electrophysiological data suggest that midbrain dopamine neurons are activated on a subsecond timescale in response to primary rewards and their associated cues. This transient activation is believed to produce a rapid rise in extracellular dopamine concentration in the NAc that, we hypothesize, modulates goal-directed behavior. Our laboratory has recently demonstrated that subsecond, or phasic, increases in dopamine release are time-locked to key aspects of reward seeking and may be involved in mediating these behaviors. A central question that remains is if phasic activation of dopaminergic neurons in the VTA gives rise to behaviorally related, transient increases of extracellular dopamine levels in the NAc. Furthermore, the precise role of dopamine transients in reward-seeking behavior remains unclear. The experiments discussed in this thesis were designed to elucidate the origin and role of phasic dopamine release in the NAc during reward seeking. The specific behavior examined was intracranial self stimulation (ICSS), a model of reward seeking in which animals press a lever to deliver an electrical stimulation to select brain regions. The first set of experiments in this work revealed that phasic dopamine release is highly dynamic and correlates with reward-related learning. Secondly, these experiments demonstrated that phasic dopamine release in the NAc serves as an adaptable measure of anticipated reinforcer magnitude and is integrally involved in mediating reward-seeking behavior. The third and fourth sets of experiments sought to investigate the origin of phasic dopamine release in the NAc. The results of these experiments provide unequivocal confirmation that phasic dopamine release arises from phasic VTA activity. These experiments also shed light on the afferent modulation of phasic dopamine signaling. Altogether, the work presented here provides unique insight into the plasticity and origin of phasic dopaminergic transmission and its relationship with reward seeking.