Cocaine experience abolishes the motivation suppressing effect of CRF in the ventral midbrain

Abstract

Stress affects dopamine-dependent behaviors in part through the actions of corticotropin releasing factor (CRF) in the ventral tegmental area (VTA). In particular, CRF signaling in the VTA mediates how acute stress suppresses the motivation to work for food rewards, as well as how stress promotes drug seeking behavior. These diverging behavioral effects in food-and drug-based tasks could indicate that CRF modulates goal-directed actions in a reinforcer-specific manner. Alternatively, prior drug experience could functionally alter how CRF in the VTA regulates dopamine-dependent behavior. To address these possibilities, we examined how intra-VTA injections of CRF influenced cocaine intake and whether prior drug experience alters how CRF modulates the motivation for food rewards. Our results demonstrate that intra-VTA injections of CRF had no effect on drug intake when self-administering cocaine under a progressive ratio reinforcement schedule. We also found that a prior history of either contingent or non-contingent cocaine infusions abolished the capacity for CRF to reduce the motivation for food rewards. Furthermore, voltammetry recordings in the nucleus accumbens illustrate that CRF in the VTA had no effect on cocaine-evoked dopamine release. These results collectively illustrate that exposure to abused substances functionally alters how neuropeptides act within the VTA to influence motivated behavior. Introduction:Stress induces the release of corticotropin releasing factor (CRF), which is responsible for initiating the hormonal and physiological responses to stress [1]. CRF signaling within the mesocorticolimbic system also mediates the effects of stress on motivation and decision-making processes [2]. For example, CRF receptor activation within the ventral tegmental area (VTA) is required for the stress-induced reduction in the motivation to work for food rewards [3]. Acute stress also decreases the preference for high effort / large reward options in decision making tasks [4]. This alteration in effort-based decision making is blocked by antagonizing CRF receptors and recapitulated by administering CRF directly into the VTA [4]. Therefore, the actions of CRF in the ventral midbrain are critical for how stress regulates behavioral responding for natural rewards.Whereas acute stress reduces the motivation to work for food rewards, stress promotes the reinstatement of drug seeking in a CRF-dependent manner [5]. Antagonizing CRF receptors in the VTA prevents stress-induced cocaine seeking [6,7]. Furthermore, intra-VTA injections of CRF are sufficient to reinstate cocaine seeking in the absence of stress [6,7], which together highlights the involvement of midbrain CRF signaling in how stress promotes drug-dependent behaviors.