PMID- 36937711 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240104 IS - 1664-0640 (Print) IS - 1664-0640 (Electronic) IS - 1664-0640 (Linking) VI - 14 DP - 2023 TI - Individual differences in the effects of midazolam on anxiety-like behavior, learning, reward, and choice behavior in male mice. PG - 1122568 LID - 10.3389/fpsyt.2023.1122568 [doi] LID - 1122568 AB - INTRODUCTION: The aim of the present study was to investigate the behavioral effects of the benzodiazepine midazolam in male mice, in models of anxiolysis, learning, and abuse-related effects. METHODS: In a first set of experiments, male Swiss mice were submitted to the training session of a discriminative avoidance (DA) task on the elevated plus maze to evaluate anxiety-like behavior and learning after vehicle or midazolam (1, 2 or 5 mg/kg, i.g.) administration. The same animals were submitted to a conditioned place preference (CPP) protocol with midazolam (1, 2 or 5 mg/kg, i.g.). In a second experiment, outbred (Swiss) and inbred (C57BL/6) male mice were submitted to a two-bottle choice (TBC) oral midazolam drinking procedure. Animals were exposed to one sucrose bottle and one midazolam (0.008, 0.016 or 0.032 mg/ml) plus sucrose bottle. RESULTS: Midazolam (1 and 2 mg/kg) induced anxiolytic-like effects, and all doses of midazolam prevented animals from learning to avoid the aversive closed arm during the DA training session. Assessment of midazolam reward via the CPP procedure and choice via the TBC procedure showed notable variability. A 2-step cluster analysis for the CPP data showed that midazolam data were well-fitted to 2 separate clusters (preference vs. aversion), albeit with the majority of mice showing preference (75%). Correlational and regression analyses showed no relationship between midazolam reward and anxiolytic-like effects (time spent in the open arms in the DA test) or learning/memory. Two-step cluster analysis of the TBC data also demonstrated that, regardless of strain, mice overall fell into two clusters identified as midazolam-preferring or midazolam-avoiding groups. Both midazolam preference and avoidance were concentration-dependent in a subset of mice. DISCUSSION: Our findings show that midazolam preference is a multifactorial behavior, and is not dependent solely on the emergence of therapeutic (anxiolytic-like) effects, learning impairments, or on genetic factors (inbred vs. outbred animals). CI - Copyright (c) 2023 Jovita-Farias, Follett, Dias-Junior, Serra, Kisaki, Barros-Santos, de Jesus, Rodrigues, Macedo, Malpezzi-Marinho, Oliveira-Lima, Marinho, Rowlett and Berro. FAU - Jovita-Farias, Caio AU - Jovita-Farias C AD - Department of Health Sciences, Universidade Estadual de Santa Cruz, Ilheus, BA, Brazil. FAU - Follett, Meagan E AU - Follett ME AD - Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, United States. FAU - Dias-Junior, Behaim C AU - Dias-Junior BC AD - Department of Health Sciences, Universidade Estadual de Santa Cruz, Ilheus, BA, Brazil. FAU - Serra, Yasmim A AU - Serra YA AD - Department of Health Sciences, Universidade Estadual de Santa Cruz, Ilheus, BA, Brazil. FAU - Kisaki, Natali D AU - Kisaki ND AD - Department of Health Sciences, Universidade Estadual de Santa Cruz, Ilheus, BA, Brazil. FAU - Barros-Santos, Thaisa AU - Barros-Santos T AD - Department of Health Sciences, Universidade Estadual de Santa Cruz, Ilheus, BA, Brazil. FAU - de Jesus, Nailton M S AU - de Jesus NMS AD - Department of Health Sciences, Universidade Estadual de Santa Cruz, Ilheus, BA, Brazil. FAU - Rodrigues, Isa R S AU - Rodrigues IRS AD - Department of Health Sciences, Universidade Estadual de Santa Cruz, Ilheus, BA, Brazil. FAU - Macedo, Larissa E L AU - Macedo LEL AD - Department of Health Sciences, Universidade Estadual de Santa Cruz, Ilheus, BA, Brazil. FAU - Malpezzi-Marinho, Elena L A AU - Malpezzi-Marinho ELA AD - Department of Biological Sciences, Universidade Estadual de Santa Cruz, Ilheus, BA, Brazil. FAU - Oliveira-Lima, Alexandre J AU - Oliveira-Lima AJ AD - Department of Health Sciences, Universidade Estadual de Santa Cruz, Ilheus, BA, Brazil. FAU - Marinho, Eduardo Ary Villela AU - Marinho EAV AD - Department of Health Sciences, Universidade Estadual de Santa Cruz, Ilheus, BA, Brazil. FAU - Rowlett, James K AU - Rowlett JK AD - Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, United States. FAU - Berro, Lais F AU - Berro LF AD - Department of Health Sciences, Universidade Estadual de Santa Cruz, Ilheus, BA, Brazil. AD - Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, United States. LA - eng GR - R01 DA011792/DA/NIDA NIH HHS/United States GR - R01 DA043204/DA/NIDA NIH HHS/United States PT - Journal Article DEP - 20230303 PL - Switzerland TA - Front Psychiatry JT - Frontiers in psychiatry JID - 101545006 PMC - PMC10021295 OTO - NOTNLM OT - benzodiazepine OT - conditioned place preference OT - elevated plus maze OT - mice OT - midazolam OT - self-administration COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2023/03/21 06:00 MHDA- 2023/03/21 06:01 PMCR- 2023/03/03 CRDT- 2023/03/20 04:08 PHST- 2022/12/13 00:00 [received] PHST- 2023/02/13 00:00 [accepted] PHST- 2023/03/20 04:08 [entrez] PHST- 2023/03/21 06:00 [pubmed] PHST- 2023/03/21 06:01 [medline] PHST- 2023/03/03 00:00 [pmc-release] AID - 10.3389/fpsyt.2023.1122568 [doi] PST - epublish SO - Front Psychiatry. 2023 Mar 3;14:1122568. doi: 10.3389/fpsyt.2023.1122568. eCollection 2023.