Epac2 in midbrain dopamine neurons contributes to cocaine reinforcement via enhancement of dopamine release

Abstract

Repeated exposure to drugs of abuse results in an upregulation of cAMP signaling in the mesolimbic dopamine system, a molecular adaptation thought to be critically involved in the development of drug dependence. Exchange protein directly activated by cAMP (Epac2) is a major cAMP effector abundantly expressed in the brain. However, it remains unknown whether Epac2 contributes to cocaine reinforcement. Here, we report that Epac2 in the mesolimbic dopamine system promotes cocaine reinforcement via enhancement of dopamine release. Conditional knockout of Epac2 from midbrain dopamine neurons (Epac2-cKO) and the selective Epac2 inhibitor ESI-05 decreased cocaine self-administration in mice under both fixed-ratio and progressive-ratio reinforcement schedules and across a broad range of cocaine doses. In addition, Epac2-cKO led to reduced evoked dopamine release, whereas Epac2 agonism robustly enhanced dopamine release in the nucleus accumbens in vitro. This mechanism is central to the behavioral effects of Epac2 disruption, as chemogenetic stimulation of ventral tegmental area (VTA) dopamine neurons via deschloroclozapine (DCZ)-induced activation of Gs-DREADD increased dopamine release and reversed the impairment of cocaine self-administration in Epac2-cKO mice. Conversely, chemogenetic inhibition of VTA dopamine neurons with Gi-DREADD reduced dopamine release and cocaine self-administration in wild-type mice. Epac2-mediated enhancement of dopamine release may therefore represent a novel and powerful mechanism that contributes to cocaine reinforcement.

Activation of Epac in the BLA disrupts reconsolidation and attenuates heroin‐seeking behaviour

“…Epac1 is expressed in various tissues, whereas Epac2 is primarily found in the brain, adrenal gland, pancreas and liver 41 . Interestingly, a recent study by Liu et al 42 demonstrated the contribution of Epac2 to cocaine reinforcement, suggesting a potential role of Epac2 in drug reward effects. They found that down‐regulating Epac2 genetically or pharmacologically impaired the acquisition of cocaine self‐administration, which appears to conflict with our findings where Epac activation reduced heroin‐seeking behaviour.…”

Treadmill Exercise Reduces Neuroinflammation, Glial Cell Activation and Improves Synaptic Transmission in the Prefrontal Cortex in 3 × Tg-AD Mice

“…Mice were anesthetized by isoflurane inhalation and decapitated. The brain was removed, trimmed, and embedded in low-gelling-point agarose, and coronal slices (200 μm thick) containing the prefrontal cortex were cut using a vibrating slicer (Leica VT1200s, Nussloch, Germany), as described in our recent studies [ 62 , 63 ]. Slices were prepared in a cutting solution containing the following (in mM): 110 choline chloride, 2.5 KCl, 1.25 NaH 2 PO 4 , 0.5 CaCl 2 , 7 MgSO 4 , 26 NaHCO 3 , 25 glucose, 11.6 sodium ascorbate, and 3.1 sodium pyruvate.…”