Dissecting motivational circuitry to understand substance abuse

Abstract

SummaryAn important goal of cocaine addiction research is to understand the neurobiological mechanisms underlying this disease state. Here, we review studies from our laboratory that examined nucleus accumbens (NAc) cell firing and rapid dopamine signaling using electrophysiological and electrochemical recordings in behaving rodents. A major advantage of these techniques is that they allow for the characterization of NAc activity and rapid dopamine release during specific phases of motivated behavior. Moreover, each approach enables an examination of the dynamic nature of NAc signaling as a function of factors such as hedonics and associative learning. We show that NAc neurons differentially respond to rewarding and aversive stimuli and their predictors in a bivalent manner. This differential responding is modifiable and can be altered by the presentation of other natural rewards or cocaine. Likewise, the dynamic nature of NAc cell firing is also reflected in the differential activation of distinct populations of NAc neurons during goal-directed behaviors for natural versus drug rewards, and the heightened activation of some NAc neurons following cocaine abstinence. Our electrochemical data also show that rapid dopamine signaling in the NAc reflects primary rewards and their predictors and appears to modulate specific NAc neuronal responses. In some cases, these influences are observed in a regionally specific manner that matches previous pharmacological manipulations. Collectively, these findings provide critical insight into the functional organization of the NAc that can be used to guide additional studies aimed at dissecting the neural code underlying compulsive drug-seeking behavior.

Roles of Nucleus Accumbens CREB and Dynorphin in Dysregulation of Motivation

“…Previous work suggests that the inhibition of this pathway encodes the rewarding effects of DA, and its stimulation may produce anhedonia or dysphoria (Carlezon et al 1995;Durieux et al 2009;Lobo et al 2010). Broad ( 75%) increases in MSN population activity are associated with aversive stimuli (Roitman et al 2005;Wheeler et al 2008;Wheeler and Carelli 2009), as well as behavioral inhibition (Ghazizadeh et al 2012). We propose that activation of CREB following repeated drug exposure or stress results in NAc hyperexcitability.…”

A Brain on Cannabinoids: The Role of Dopamine Release in Reward Seeking

“…In this context, phasic Cheer et al 2007. ) dopamine events are thought to encode conditioned stimuli and promote drug seeking (Wheeler and Carelli 2009). It is possible, therefore, that disrupting endocannabinoid signaling might effectively diminish the influence that environmental cues exert over dopamine transmission during reward-directed behavior.…”

Temporal Pattern of Cocaine Intake Determines Tolerance vs Sensitization of Cocaine Effects at the Dopamine Transporter

“…Cocaine exerts its reinforcing and neurochemical effects by inhibiting the dopamine transporter (DAT), which leads to augmented DA signaling (Ritz et al, 1987;Kristensen et al, 2011). DA elevations in the nucleus accumbens (NAc) core region are critically involved in self-administration behaviors, reinstatement, cue-reward association, assignment of motivational value, and goal-oriented behaviors (for a review, see Wheeler and Carelli, 2009;Kalivas and McFarland, 2003;Aragona et al, 2009;Willuhn et al, 2010).…”