Preferential Enhancement of Dopamine Transmission within the Nucleus Accumbens Shell by Cocaine Is Attributable to a Direct Increase in Phasic Dopamine Release Events

Abstract

Preferential enhancement of dopamine transmission within the nucleus accumbens (NAc) shell is a fundamental aspect of the neural regulation of cocaine reward. Despite its importance, the nature of this effect is poorly understood. Here, we used fast-scan cyclic voltammetry to examine specific transmission processes underlying cocaine-evoked increases in dopamine transmission within the NAc core and shell. Initially, we examined altered terminal dopamine concentrations following global autoreceptor blockade. This was the first examination of autoreceptor regulation of naturally occurring phasic dopamine transmission and provided a novel characterization of specific components of dopamine neurotransmission. Comparison of increased dopamine signaling evoked by autoreceptor blockade and cocaine administration allowed robust resolution between increased frequency, concentration, and duration of phasic dopamine release events following cocaine delivery. Cocaine increased dopamine transmission by slowed uptake and increased concentration of dopamine released in the core and shell. However, an additional increase in the number phasic release events occurred only within the NAc shell and this increase was eliminated by inactivation of midbrain dopaminergic neurons. This represents the first evidence that cocaine directly increases the frequency of dopamine release events and reveals that this is responsible for preferentially increased dopamine transmission within the NAc shell following cocaine administration. Additionally, cocaine administration resulted in a synergistic increase in dopamine concentration and sub-region differences were abolished when cocaine was administered in the absence of autoregulation.Together, these results demonstrate that cocaine administration results in a temporally and regionally specific increase in phasic dopamine release that is significantly regulated by dopamine autoreceptors. The reinforcing properties of cocaine are significantly mediated by enhanced dopamine transmission (Kelley, 2004;Wise, 2004;Everitt and Robbins, 2005) and cocaine exerts its greatest increase in extracellular dopamine concentration ([DA]) within the shell sub-region of the nucleus accumbens (NAc) (Di Chiara and Bassareo, 2007). Cocaine increases [DA] by slowing uptake via blockade of dopamine transporters (DAT) (Giros et al., 1996) and by increasing the amount of dopamine exocytosed through mobilization of vesicles normally unavailable for release (Venton et al., 2006). However, neither mechanism can account for preferential enhancement of dopamine transmission within the NAc shell, because both are mediated through terminal DATs and DAT expression is significantly lower in the NAc shell compared to the core (Nirenberg et al., 1997). KeywordsIt has been suggested that this paradox may be explained by an increased number of dopamine release events within the shell following cocaine administration (Di Chiara and Bassareo, 2007). However, this hypothesis cannot be confirmed using microdialysis because it m...

Impairment of acquisition of intravenous cocaine self-administration by RNA-interference of dopamine D1-receptors in the nucleus accumbens shell

“…This preferential action has been initially documented by microdialysis studies in acutely experimenter-administered rats (Aragona et al, 2008;Pontieri et al, 1995) and later demonstrated in rats during acquisition of i.v. cocaine SA (Lecca et al, 2007a).…”

Chemical Gradients within Brain Extracellular Space Measured using Low Flow Push–Pull Perfusion Sampling in Vivo

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