Thalamocortical mGlu8 Modulates Dorsal Thalamus Excitatory Transmission and Sensorimotor Activity.

Metabotropic glutamate receptor 8 (mGlu8) is a heterogeneously expressed and poorly understood glutamate receptor with potential pharmacological significance. The thalamic reticular nucleus (TRN) is a critical inhibitory modulator of the thalamocortical-corticothalamic (TC-CT) network and plays a crucial role in information processing throughout the brain, is implicated in a variety of psychiatric conditions, and is also a site of significant mGlu8 expression. Using both male and female mice, we determined via fluorescent in situ hybridization that parvalbumin-expressing cells in the TRN core and shell matrices (identified by spp1+ and ecel1+ expression, respectively), as well as the cortical layers involved in CT signaling, express grm8 mRNA. We then assayed the physiological and behavioral impacts of perturbing grm8 signaling in the TC circuit through conditional (adeno-associated virus-CRE mediated) and cell-type-specific constitutive deletion strategies. We show that constitutive parvalbumin grm8 knock-out (PV grm8 knock-out) mice exhibited (1) increased spontaneous excitatory drive onto dorsal thalamus relay cells and (2) impaired sensorimotor gating, measured via paired-pulse inhibition, but observed no differences in locomotion and thigmotaxis in repeated bouts of open field test (OFT). Conversely, we observed hyperlocomotive phenotypes and anxiolytic effects of AAV-mediated conditional knockdown of grm8 in the TRN (TRN grm8 knockdown) in repeated OFT. Our findings underscore a role for mGlu8 in regulating excitatory neurotransmission as well as anxiety-related locomotor behavior and sensorimotor gating, revealing potential therapeutic applications for various neuropsychiatric disorders and guiding future research endeavors into mGlu8 signaling and TRN function.

α2A-adrenergic heteroreceptors are required for stress-induced reinstatement of cocaine conditioned place preference.

The α2a-adrenergic receptor (α2a-AR) agonist guanfacine has been investigated as a potential treatment for substance use disorders. While decreasing stress-induced reinstatement of cocaine seeking in animal models and stress-induced craving in human studies, guanfacine has not been reported to decrease relapse rates. Although guanfacine engages α2a-AR autoreceptors, it also activates excitatory Gi-coupled heteroreceptors in the bed nucleus of the stria terminalis (BNST), a key brain region in driving stress-induced relapse. Thus, BNST α2a-AR heteroreceptor signaling might decrease the beneficial efficacy of guanfacine. We aimed to determine the role of α2a-AR heteroreceptors and BNST Gi-GPCR signaling in stress-induced reinstatement of cocaine conditioned place preference (CPP) and the effects of low dose guanfacine on BNST activity and stress-induced reinstatement. We used a genetic deletion strategy and the cocaine CPP procedure to first define the contributions of α2a-AR heteroreceptors to stress-induced reinstatement. Next, we mimicked BNST Gi-coupled α2a-AR heteroreceptor signaling using a Gi-coupled designer receptor exclusively activated by designer drug (Gi-DREADD) approach. Finally, we evaluated the effects of low-dose guanfacine on BNST cFOS immunoreactivity and stress-induced reinstatement. We show that α2a-AR heteroreceptor deletion disrupts stress-induced reinstatement and that BNST Gi-DREADD activation is sufficient to induce reinstatement. Importantly, we found that low-dose guanfacine does not increase BNST activity, but prevents stress-induced reinstatement. Our findings demonstrate a role for α2a-AR heteroreceptors and BNST Gi-GPCR signaling in stress-induced reinstatement of cocaine CPP and provide insight into the impact of dose on the efficacy of guanfacine as a treatment for stress-induced relapse of cocaine use.