Abstract
Plasticity of neurons in the ventral tegmental area (VTA) is critical for establishment of drug dependence. However, the remodeling of the circuits mediating the transition between positive and negative effect remains unclear. Here, we used neuronal activity-dependent labeling technique to characterize and temporarily control the VTA neuronal ensembles recruited by the initial morphine exposure (morphine-positive ensembles, Mor-Ens). Mor-Ens preferentially projected to NAc, and induced dopamine-dependent positive reinforcement. Electrophysiology and rabies viral tracing revealed the preferential connections between the VTA-projective corticotrophin-releasing hormone (CRH) neurons of central amygdala (CRHCeA→VTA) and Mor-Ens, which was enhanced after escalating morphine exposure and mediated the negative effect during opiate withdrawal. Pharmacologic intervention or CRISPR-mediated repression of CRHR1 in Mor-Ens weakened the inhibitory CRHCeA→VTA inputs, and alleviated the negative effect during opiate withdrawal. These data suggest that neurons encoding opioid reward experience are inhibited by enhanced CRHCeA→VTA inputs induced by chronic morphine exposure, leading to negative effect during opiate withdrawal, and provide new insight into the pathological changes in VTA plasticity after drug abuse and mechanism of opiate dependence.
Highlights
Drugs of abuse trigger the initial acutereward effect, lead to adaptive changes in the brain function following administration [1,2,3], and produce unpleasant physical and negative effects, including dysphoria, depression, irritability, and anxiety after the termination of use [4, 5]
ventral tegmental area (VTA)-projecting corticotrophin-releasing hormone (CRH) neurons tagged with EYFP in the central amygdala (CeA), the bed nucleus of stria terminals (BNST), and the paraventricular nucleus of the hypothalamus (PVN) were detected. c-Fos expression was increased in CRHCeA→VTA and CRHBNST→VTA neurons, while unchanged in CRHPVN→VTA neurons after chronic morphine treatment (Fig. 3a–c), indicating that CRHCeA→VTA and CRHBNST→VTA neurons are activated during opiate withdrawal
We found that chemogenetic activation of Mor-Ens, but not Salof the ensembles labeled by saline (Sal-Ens) during the conditioning sessions, inhibited the development of conditioned aversion induced by optically activating the CRHCeA→VTA terminals (Fig. 5i), and significantly increased the exploration time in the open arms in elevated-plus maze (EPM) test, whereas it had no effect on locomotor activity in open-field test (Fig. 5j and Supplementary Fig. 11f)
Summary
Drugs of abuse (e.g., cocaine, opiates) trigger the initial acutereward effect, lead to adaptive changes in the brain function following administration [1,2,3], and produce unpleasant physical and negative effects, including dysphoria, depression, irritability, and anxiety after the termination of use [4, 5]. Both the reward effect of the drug and the desire to avoid the unpleasant somatic symptoms or emotional feelings drive alternating rounds of positive and negative reinforcement for maintaining drug dependence, respectively [6]. Onto Mor-Ens, and this is involved in the development of the negative effect during opiate withdrawal
Published Version (Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have