Effects of repeated fluoxetine on anxiety-related behaviours, central serotonergic systems, and the corticotropic axis in SHR and WKY rats

In keeping with the anxiolytic property of selective serotonin reuptake inh ibitors (SSRIs) in humans, we have examined in the spontaneously hypertensi ve rat (SHR) and the Wistar-Kyoto (WKY) rat, which display low and high anx iety, respectively, some psychoneuroendocrine effects of a repeated treatme nt with the SSRI fluoxetine (5 or 10 mg/kg daily, for 3 weeks). Two days af ter the last injection, plasma levels of fluoxetine were not detectable whe reas those of its metabolite, norfluoxetine, were present to similar extent s in both strains. By means of the elevated plus-maze test (29-30 h after t he 13th administration of fluoxetine) and an open field test (48 h after th e last injection of fluoxetine), it was observed that fluoxetine pretreatme nt did not yield anxiolysis; hence, some, but not all, behaviours were indi cative of anxiety and hypolocomotion las assessed through principal compone nt analyses and acute diazepam studies). In both strains, the 10 mg/kg dose of fluoxetine decreased hypothalamus 5-HT and 5-HIAA levels, and reduced m idbrain and/or hippocampus [H-3]citalopram binding at 5-HT transporters, bu t did not affect [H-3]8-hydroxy2-(di-N-propylamino)tetralin binding at hipp ocampal 5-HT1A receptors. However, the fluoxetine-elicited reduction in hip pocampal 5-HT transporter binding was much more important in WKY than in SH R rats, this strain-dependent effect being associated in WKY rats with a re duction in cortical [H-3]ketanserin binding at 5-HT2A receptors. Lastly, in WKY rats, repeated fluoxetine administration increased adrenal weights and the plasma corticosterone response to open held exposure, but did not affe ct the binding capacities of hippocampal mineralocorticoid and glucocortico id receptors. These data show that key psychoneuroendocrine responses to re peated fluoxetine administration may be strain-dependent, and that repeated fluoxetine administration does not yield anxiolysis, as assessed by two st andard tests of emotivity. (C) 1999 Elsevier Science Ltd. All rights reserv ed.