{"doi":"10.1177/02698811241292902","title":"Effects of positive mGlu5 modulation on D <sub>2</sub> signaling and nicotine-conditioned place preference: Mechanisms of epigenetic inheritance in a transgenerational model of drug abuse vulnerability in psychosis","abstract":"Background: The metabotropic glutamate type 5 (mGlu5) receptor has emerged as a potential target for the treatment of psychosis that is suggested to have greater efficacy than antipsychotic medications that are currently utilized. Aims: This study sought to elucidate mechanisms of therapeutic action associated with the modulation of the mGlu5 receptor in a disordered system marked by dopamine dysfunction. We further explored epigenetic mechanisms contributing to heritable transmission of a psychosis-like phenotype in a novel heritable model of drug abuse vulnerability in psychosis. Methods: F1 generation male and female Sprague-Dawley rats that were the offspring of two neonatal quinpirole-treated (QQ) or two saline-treated (SS) animals were tested on nicotine-conditioned place preference (CPP). Regulators of G protein signaling 9 (RGS9) and β-arrestin 2 (βA2), which mediate dopamine (DA) D 2 signaling, were measured in the nucleus accumbens shell, prelimbic and infralimbic cortices. Reduced Representation Bisulfite Sequencing (RRBS) was used to analyze the cytosine methylation in these brain regions. Results: Pretreatment with the mGlu5-positive allosteric modulator 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) 20 min prior to conditioning trials blocked enhanced nicotine CPP and mitigated aberrant G protein-dependent and -independent signaling in QQ animals. RRBS analysis revealed region-specific changes in several pathways, including nicotine addiction, dopamine synapses, and neural connectivity. Conclusions: These results reveal an important region-specific mechanism of action for CDPPB in a system marked by enhanced DAD 2 receptor signaling. Results additionally reveal DNA methylation as an epigenetic mechanism of heritability, further validating the current model as a useful tool for the study of psychosis and comorbid nicotine use.","journal":"Journal of Psychopharmacology","year":2024,"id":469629,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9586,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":778300,"name":"Liza J. Wills","orcid":"0000-0003-1698-0448","position":1,"is_corresponding":false},{"id":1140413,"name":"Anthony M. Cuozzo","orcid":null,"position":2,"is_corresponding":false},{"id":1303719,"name":"Cristal D. Ahmed","orcid":null,"position":3,"is_corresponding":false},{"id":1303720,"name":"Samuel R Massey","orcid":null,"position":4,"is_corresponding":false},{"id":271305,"name":"Wanqiu Chen","orcid":"0000-0003-3706-7834","position":5,"is_corresponding":false},{"id":586931,"name":"Zhong Chen","orcid":"0000-0003-4755-9357","position":6,"is_corresponding":false},{"id":24562,"name":"Charles Wang","orcid":null,"position":7,"is_corresponding":false},{"id":369797,"name":"Justin T. Gass","orcid":"0000-0002-6829-6261","position":8,"is_corresponding":false},{"id":447628,"name":"Russell W. Brown","orcid":"0000-0002-6512-7315","position":9,"is_corresponding":false},{"id":778301,"name":"Loren D. Peeters","orcid":"0000-0001-8686-9150","position":0,"is_corresponding":true}],"reference_count":115,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:05:32.241298Z","pmid":"39462877","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}