24 Although the results of this control study provide some positive information, we felt that it was far too limited in its design: a single antidepressant was administered IP (instead of orally as in clinical psychiatry) to unstressed control rats, ie, very different conditions from those required to assess the potential psychoneuroendocrine benefit of the psychotropic agent. This is why we performed a second series of experiments with imipramine and desipramine that took into account the limits of the first paradigm.25 Repeated fluoxetine treatment in SHR and WKY receiving imipramine and desipramine In the imipramine and desipramine experiments, it was observed that following a 24-h wash-out period, WKY displayed

higher Inhibitors,research,lifescience,medical plasma antidepressant and antidepressant metabolite levels than SHR. Fluoxetine pretreatment decreased [3H]citalopram binding at midbrain 5-HTTs, whereas tricyclic antidepressants and fluoxetine decreased [3H]ketanserin binding at cortical 5-HT2A receptors, [3H]CGP-12177 binding at cortical β-adrenoceptors, Inhibitors,research,lifescience,medical and [3H]nisoxetine binding at midbrain noradrenaline (NA) transporters in both strains. None of the antidepressants affected [3H]8-OH-DPAT binding at hippocampal 5-HT1A receptors. It was notable that repeated restraint triggered a desipramine-sensitive 140 % increase in hypothalamus [3H [nisoxetine binding in WKY, but not in SHR; moreover, plasma adrenocorticotropin-releasing

hormone Inhibitors,research,lifescience,medical DAPT secretase solubility dmso responses to a 5-min open field test were amplified by prior repeated restraint in both strains, but desipramine Inhibitors,research,lifescience,medical prevented such an amplification in WKY only. However, the elevated

plus-maze and open field behaviors of SHR and WKY were unaffected by desipramine pretreatment. A simple conclusion of these experiments is that they clearly show that the SHR and WKY strains may be useful in understanding how genetic differences in noradrenergic responses to stress and desipramine treatment Inhibitors,research,lifescience,medical impact on adaptive processes. Genetic variability in the rat 5-HTT The experiments described above all focused on one main question: do individuals that differ in their behavioral responses to novel environments also differ with respect to key central monoaminergic responses to stressors and/or antidepressants? The results underline how comparisons between rat strains may allow the detection of models of some value for understanding the basis of the interindividual variability in fear responses, whether these are linked to behavior (eg, the socially below stressed LEW) or neurochemistry (eg, the restrained WKY). The quest for the mechanisms explaining such strain-dependent characteristics undoubtedly require intense effort, at least effort that is beyond the scientific and human capacities of our research group. Accordingly, we recently decided to change our scientific goals by trying to focus on the genetics of central serotonergic systems, leaving behavioral and neuroendocrine research topics aside, at least in the preliminary stages of research.