Cooperative CRF and α1 Adrenergic Signaling in the VTA Promotes NMDA Plasticity and Drives Social Stress Enhancement of Cocaine Conditioning

Abstract

Summary: Stressful events rapidly trigger activity-dependent synaptic plasticity, driving the formation of aversive memories. However, it remains unclear how stressful experience affects plasticity mechanisms to regulate appetitive learning, such as intake of addictive drugs. Using rats, we show that corticotropin-releasing factor (CRF) and α1 adrenergic receptor (α1AR) signaling enhance the plasticity of NMDA-receptor-mediated glutamatergic transmission in ventral tegmental area (VTA) dopamine (DA) neurons through distinct effects on inositol 1,4,5-triphosphate (IP3)-dependent Ca2+ signaling. We find that CRF amplifies IP3-Ca2+ signaling induced by stimulation of α1ARs, revealing a cooperative mechanism that promotes glutamatergic plasticity. In line with this, acute social defeat stress engages similar cooperative CRF and α1AR signaling in the VTA to enhance learning of cocaine-paired cues. These data provide evidence that CRF and α1ARs act in concert to regulate IP3-Ca2+ signaling in the VTA and promote learning of drug-associated cues. : Tovar-Díaz et al. demonstrate a cellular mechanism in which corticotropin-releasing factor (CRF) and α1 adrenergic receptors act in concert to regulate the induction of synaptic plasticity in VTA dopamine neurons and enhance cocaine place conditioning. Keywords: VTA, dopamine neuron, CRF, α1AR, IP3, Ca2+, stress, cocaine, reward learning