Contribution of a Mesocorticolimbic Subcircuit to Drug Context-Induced Reinstatement of Cocaine-Seeking Behavior in Rats

Abstract

Cocaine-seeking behavior triggered by drug-paired environmental context exposure is dependent on orbitofrontal cortex (OFC)-basolateral amygdala (BLA) interactions. Here, we present evidence supporting the hypothesis that dopaminergic input from the ventral tegmental area (VTA) to the OFC critically regulates these interactions. In experiment 1, we employed site-specific pharmacological manipulations to show that dopamine D1-like receptor stimulation in the OFC is required for drug context-induced reinstatement of cocaine-seeking behavior following extinction training in an alternate context. Intra-OFC pretreatment with the dopamine D1-like receptor antagonist, SCH23390, dose-dependently attenuated cocaine-seeking behavior in an anatomically selective manner, without altering motor performance. Furthermore, the effects of SCH23390 could be surmounted by co-administration of a sub-threshold dose of the D1-like receptor agonist, SKF81297. In experiment 2, we examined effects of D1-like receptor antagonism in the OFC on OFC-BLA interactions using a functional disconnection manipulation. Unilateral SCH23390 administration into the OFC plus GABA agonist-induced neural inactivation of the contralateral or ipsilateral BLA disrupted drug context-induced cocaine-seeking behavior relative to vehicle, while independent unilateral manipulations of these brain regions were without effect. Finally, in experiment 3, we used fluorescent retrograde tracers to demonstrate that the VTA, but not the substantia nigra, sends dense intra-and interhemispheric projections to the OFC, which in turn has reciprocal bi-hemispheric connections with the BLA. These findings support that dopaminergic input from the VTA, via dopamine D1-like receptor stimulation in the OFC, is required for OFC-BLA functional interactions. Thus, a VTA-OFC-BLA neural circuit promotes drug context-induced motivated behavior.

A Cocaine Context Renews Drug Seeking Preferentially in a Subset of Individuals

“…However, in this study, and in a series of studies by Fuchs et al (2008) and Lasseter et al (2014), no discrete CS was associated with drug self-administration. With this procedure, context-induced renewal may occur because the drug context acts as an 'excitor' that arouses a conditioned motivational state ('wanting'), thus instigating instrumental drug-seeking actions (Crombag et al, 2008;Holland and Bouton, 1999).…”

“…This difference may explain why a previous study (Bossert et al, 2007; but see Chaudhri et al, 2009) found D1-receptor antagonism in the shell, but not core, blocked context renewal of heroin seeking in the presence of discrete cues. However, using the same procedure as we did here, Fuchs et al (2007Fuchs et al ( , 2005Fuchs et al ( , 2008 and Lasseter et al (2014) have characterized a network of regions merging on the NAc core, including dorsal hippocampus, basolateral amygdala, and prelimbic cortex, which is necessary for contexts alone to instigate drug seeking. Until now, however, it was unknown if DA signaling within the NAc core was needed for cocaine context renewal.…”

GABAAα1-Mediated Plasticity in the Orbitofrontal Cortex Regulates Context-Dependent Action Selection

“…Specifically, chronic oPFC GABA A a1 silencing impairs the performance of goal-directed response strategies, while M2 GABA A a1 inhibition enhances sensitivity to action-outcome relationships. The effects of oPFC GABA A a1 knockdown are context selective, consistent with evidence that spatial information is represented within the ventrolateral oPFC during appetitive choice tasks (Feierstein et al, 2006), and that the oPFC regulates behavioral sensitivity to rewardassociated contextual cues (Lasseter et al, 2009(Lasseter et al, , 2014.…”

“…Current models suggest that local dopamine D1 receptor stimulation signals the salience of contextual stimuli by interacting with the glutamatergic input to oPFC (Lasseter et al, 2014). In addition, glutamatergic projections from the cortex and dopamine input from the ventral tegmental area converge on dendritic spines within the rodent nucleus accumbens (Bouyer et al, 1984); the targeted medium spiny neurons may then coordinate information being shuttled to the basal ganglia to regulate the expression of instrumental decisionmaking strategies or habits, depending on an animal's drug, stress, or training history.…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…Moreover, the VTA-OFC-BLA forms a functional circuit for contextinduced drug reinstatement. Specifically, contextual reinstatement of cocaine seeking in extinguished rats is dependent on OFC-BLA activity and D 1 R signaling in the OFC (Lasseter et al, 2011(Lasseter et al, , 2014, as demonstrated by local inactivation with microinfusions of GABA A /GABA B agonist cocktail and D 1 R antagonist. 896 7.…”