Vol.:(0123456789) 1 3 Behavior Genetics https://doi.org/10.1007/s10519-018-9922-2 ORIGINAL RESEARCH Efects of Repeated Treatment with Midazolam in SHR and SLA16 Rat Strains in the Triple Test Lucía Raily Acuña 1  · Renata Cristina Nunes Marchette 1,2  · Natalli Granzotto 1,2  · Paula Gomes Dias 1  · Maria Elisa Corvino 1  · Fernando Gabriel Mazur 1  · Fernanda Junques Corrêa 1,2  · Geison Souza Izídio 1 Received: 26 April 2018 / Accepted: 11 September 2018 © Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract We exposed male and female rats of SHR (Spontaneously Hypertensive Rats) and SLA16 (SHR.LEW-Anxrr16) strains, in a non-drugged state, for fve consecutive days to the Triple Test (experiment 1); or after repeated treatment with midazolam (MDZ), for four consecutive days. The ffth day was performed without treatment (experiment 2). The frst experiment showed that males did not avoid and females increased the exploration of the open arms over the days. In experiment 2, SLA16 from both sexes approached more the open arms than SHR rats. The MDZ anxiolytic-like efect was sustained in both strains and sexes over the days. On the ffth day, SLA16 still approached more the open arms than SHR rats. Data suggest an absence of repeated-trial tolerance to MDZ anxiolytic-like efects. Testing the SHR and SLA16 strains, especially females, could be necessary for the future search for the genes and molecular pathways underlying anxiety/emotionality. Keywords Midazolam · Anxiety · Emotionality · Anxiolytic drugs · Rats Introduction There is a need to improve the interpretation of animal and pre-clinical behavioral tests to evaluate, test and develop new drugs that will be used in psychiatric disorders treatment. The elevated plus-maze (EPM) is one of the most com- monly used animal models of anxiety/emotionality. A naïve rat or mouse, when exposed to the EPM for the frst time, will exhibit avoidance of the open arms that is decreased by classical anxiolytic drugs (i.e., benzodiazepines; BDZs) and increased by anxiogenic substances (Carobrez and Bertoglio 2005; Handley and Mcblane 1993; Pellow et al. 1985). However, the response to anxiolytic drugs has been shown to diminish or disappear when rats are submitted for one single trial on the EPM. This phenomenon is known as “One-Trial Tolerance” (OTT) (File 1990). It seems that rats consolidate some memories related to exploration of the open arms causing long-term changes in their behavioral responses. These memories infuence drug responsiveness in the subsequent trials impairing the search of new anxiolytic in the preclinical research (for a review see Carobrez and Bertoglio 2005). The OTT seems to occur independently of the emotional level of the animals, during the frst expo- sure to the EPM, the time interval between exposures and the material of which EPM was built (Cruz-Morales et al. 2002; File 1990; Rodgers and Shepherd 1993). It has been described not only for benzodiazepines, but also for ethanol, phenobarbital and NMDA/glycine-B receptor ligands (Rodg- ers et al. 1992; File and Zangrossi 1993; Treit et al. 1993; File et al. 1998, 1999; Frussa-Filho et al. 1999; Bertoglio and Carobrez 2002a, b, 2003). As commented before, it is well known that the OTT phe- nomenon involves learning and memory processes and it has been reported that learning impairment caused by adminis- tering amnesic doses of BDZs, scopolamine or propanolol Edited by Stephen Maxson. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10519-018-9922-2) contains supplementary material, which is available to authorized users. * Geison Souza Izídio geisonizidio@gmail.com 1 Laboratório de Genética do Comportamento, Departamento de Biologia Celular, Embriologia e Genética, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, BEG, bloco C, 3° andar, sala 310C, Florianópolis, SC CEP 88.040-900, Brazil 2 Department of Pharmacology, Federal University of Santa Catarina, Florianópolis, Brazil