Elena Hernández-Hernández, Sandra Ledesma-Corvi, Fernando Yáñez-Gómez, Celia Garau, Laura Gálvez-Melero, Andrea Bagán, Carmen Escolano, M. Julia García-Fuster, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Govern de les Illes Balears, European Commission, Ministerio de Universidades (España), and Universidad de Las Islas Baleares
In searching for novel targets to design antidepressants, among the characterized imidazoline receptors (IR), I2 receptors are an innovative therapeutical approach since they are dysregulated in major depressive disorder and by classical antidepressant treatments. In fact, several I2 agonists have been characterized for their antidepressant-like potential, but the results in terms of efficacy were mixed and exclusively reported in male rodents. Since there are well-known sex differences in antidepressant-like efficacy, this study characterized the potential effects induced by two I2 drugs, CR4056 (i.e., most promising drug already in phase II clinical trial for its analgesic properties) and B06 (a compound from a new family of bicyclic α-iminophosphonates) under the stress of the forced-swim test in male and female rats exposed to early-life stress. Moreover, some hippocampal neuroplasticity markers related to the potential effects observed were also evaluated (i.e., FADD, p-ERK/ERK, mBDNF, cell proliferation: Ki-67 + cells). The main results replicated the only prior study reporting the efficacy of CR4056 in male rats, while providing new data on its efficacy in females, which was clearly dependent on prior early-life stress exposure. Moreover, B06 showed no antidepressant-like effects in male or female rats. Finally, CR4056 increased FADD content and decreased cell proliferation in hippocampus, without affecting p-ERK/t-ERK ratio and/or mBDNF content. Interestingly, these effects were exclusively observed in female rats, and independently of early-life conditions, suggesting some distinctive molecular underpinnings participating in the therapeutic response of CR4056 for both sexes. In conjunction, these results present CR4056 with an antidepressant-like potential, especially in female rats exposed to stress early in life, together with some neuronal correlates described in the context of these behavioral changes in females., This research was partly supported by several grants to MJG-F: PID2020-118582RB-I00 (MCIN/AEI/10.13039/501100011033) and PDR2020/14 (Comunitat Autonoma ` de les Illes Balears through the Direccio ´ General de Política Universitaria ` i Recerca with funds from the Tourist Stay Tax Law ITS 2017–006). Moreover, this study was also funded by PID2019-107991RB-I00 (MCIN/AEI) and PDC2022-133441- I00 (MCIN/AEI/10.13039/501100011033 and by the “European Union NextGenerationEU/PRTR”) to CE. These entities had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. The salaries of personnel were covered by several research programs: predoctoral scholarships to EH-H (FPI/2102/2018) from Consejería de Innovacion, ´ Investigacion ´ y Turismo del Gobierno de las Islas Baleares y del Fondo Social Europeo, who is currently funded by the Margarita Salas Program (Ministerio de Universidades; Plan de Recuperacion, ´ Transformacion ´ y Resilencia; NextGenerationEU) with the participation of the University of the Balearic Islands; JUNIOR Program to SL-C from “TALENT PLUS Construint Salut, Generant Valor” (IdISBa, GOIB); CG is funded by the María Zambrano Program (Ministerio de Universidades; Plan de Recuperacion, ´ Transformacion ´ y Resilencia; NextGenerationEU) at the University of the Balearic Islands; AB received financial support from Institute of Biomedicine UB_2018.