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BNST specific mGlu5 receptor knockdown regulates sex-dependent expression of negative affect produced by adolescent ethanol exposure and adult stress.

ABSTRACT: Adolescent alcohol use is one of the strongest predictors for the development of an alcohol use disorder (AUD). Notably, this period of risk coincides with the development of affective disorders, which disproportionately impact and drive problematic drinking behavior in women. Stress is a particularly salient factor that drives relapse during periods of abstinence. Previous work in our lab has shown that adolescent intermittent ethanol vapor (AIE) produces sex-dependent changes in glutamatergic activity in the bed nucleus of the stria terminalis (BNST) and behavioral outcomes following acute restraint stress in adulthood. In females, AIE disrupts group 1 metabotropic glutamate (mGlu1/5) receptor activity and enhances anhedonia-like behavior. The current study site-specifically knocked down mGlu5 receptors in the BNST of male and female Grm5^loxp mice, exposed them to AIE, and observed the interaction of AIE and stress on negative affect-like behaviors in adulthood. These negative affect-like behaviors included the novelty-induced hypophagia task following acute restraint stress, open field activity, and contextual fear conditioning. Overall, we replicated our previous findings that AIE enhanced anhedonia-like activity in the novelty-induced hypophagia task in females and fear acquisition in males. The primary effect of BNST-mGlu5 receptor knockdown was that it independently enhanced anhedonia-like activity in females. Correlation analyses revealed that behavior in these paradigms showed poor interdependence. These results indicate that preclinical models of negative affective-like states encompass distinct features that may have independent, clinically relevant mechanisms. Further, modulating mGlu5 receptors is a prospective treatment target for females experiencing anhedonic-like states that make them susceptible to alcohol relapse.

SUBMITTER: Kasten CR

PROVIDER: S-EPMC7969933 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Adolescent alcohol use is the strongest predictor for alcohol use disorders. In rodents, adolescents have distinct responses to acute ethanol, and prolonged alcohol exposure during adolescence can maintain these phenotypes into adulthood. One brain region that is particularly sensitive to the effects of both acute and chronic ethanol exposure is the hippocampus. Adolescent intermittent ethanol exposure (AIE) produces long lasting changes in hippocampal synaptic plasticity and dendritic morphology, as well as in the susceptibility to acute ethanol-induced spatial memory impairment. Given the pattern of changes in hippocampal structure and function, one potential target for these effects is the ethanol sensitive GluN2B subunit of the NMDA receptor, which is known to be involved in synaptic plasticity and dendritic morphology. Thus we sought to determine if there were persistent changes in hippocampal GluN2B signaling cascades following AIE. We employed a previously validated GluN2B-targeted proteomic strategy that was used to identify novel signaling mechanisms altered by chronic ethanol exposure in the adult hippocampus. We collected adult hippocampal tissue (P70) from rats that had been given 2 weeks of AIE from P30-45. Tissue extracts were fractionated into synaptic and non-synaptic pools, immuno-precipitated for GluN2B, and then analyzed using proteomic methods. We detected a large number of proteins associated with GluN2B. AIE produced significant changes in the association of many proteins with GluN2B in both synaptic and non-synaptic fractions. Intriguingly the number of proteins changed in the non-synaptic fraction was double that found in the synaptic fraction. Some of these proteins include those involved in glutamate signaling cytoskeleton rearrangement, calcium signaling, and plasticity. Disruptions in these pathways may contribute to the persistent cellular and behavioral changes found in the adult hippocampus following AIE. Further, the robust change in non-synaptic proteins suggests that AIE may prime this signaling pathway for future ethanol exposures in adulthood.

Project description:Adolescents and adults vary in sensitivity to many effects of ethanol (EtOH), although it is unknown whether they also differ in their perception of EtOH's subjective cues. This study characterized EtOH discrimination in adolescent and adult male rats using a rapidly acquired Pavlovian conditioned approach procedure.EtOH at 1 of the 3 training doses (0.75, 1.0, or 1.25 g/kg) served as either a positive (POS) or negative (NOS) occasion setter. Each 20-minute training session consisted of eight 15-second presentations of 2 cue lights located on either side of a dipper delivering chocolate Boost(®) . For POS-trained rats, the cue lights reliably predicted 5-second presentations of chocolate Boost during EtOH but not saline sessions, with the opposite contingencies used for NOS-trained rats. Anticipatory approach behavior (head entries into the reward delivery area) in the presence and absence of the cue lights was used to calculate discrimination scores on EtOH and saline sessions. Following acquisition, various doses of EtOH (0 to 1.5 g/kg) were administered to establish generalization curves.Although animals of both ages responded differentially on EtOH and saline sessions by the end of acquisition, adults met criterion more quickly and had higher discrimination scores during reinforced sessions than adolescents. Whereas adolescents failed to demonstrate any dose-dependent responding during testing when trained with the 0.75 or 1.25 g/kg EtOH doses, adults demonstrated broader EtOH generalization during testing sessions following training with all 3 EtOH doses. Among adolescents trained with 1.0 g/kg EtOH, less generalization occurred relative to adults.Adolescents were less sensitive to EtOH's interoceptive effects, indicating that EtOH is likely a more salient cue for adults than for adolescents. These findings contribute to evidence that suggests adolescent-typical insensitivity to internal cues that typically limit EtOH consumption may contribute to the elevated intake commonly reported during this developmental period.

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BNST specific mGlu5 receptor knockdown regulates sex-dependent expression of negative affect produced by adolescent ethanol exposure and adult stress.

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