Acute and chronic effects of gepirone and fluoxetine in rats tested in the elevated plus-maze: an ethological analysis

Abstract

The potential role of 5-hydroxytryptamine (5-HT) in anxiety has been the subject of much research, most of it addressed to the hypothesis that 5-HT promotes anxiety and, therefore, that drugs that reduce 5-HT functions will be effective anxiolytic agents in human anxiety disorders. However, the effects of serotoninergic drugs in different behavioral paradigms have been inconsistent. These inconsistencies have been particularly well illustrated in the elevated plus-maze. In the present study we provided an ethopharmacological analysis (in addition to conventional measures) of the behavior of rats in the elevated plus-maze with transparent walls after acute and chronic treatments with gepirone, an agonist of 5-HT1A receptors, and fluoxetine, a selective inhibitor of serotonin reuptake. Although gepirone has been used to treat anxiety, fluoxetine is a mainstay in the treatment of depression. Acute treatment with gepirone (1, 3, 5.6, and 10 mg/kg, IP) produced an anxiogenic profile with increased risk assessment behaviors (e.g., flat-back approach) and decreased behavioral measures that are inversely related to "anxiety" (e.g., head dipping and end-arm activity). In contrast, chronic gepirone (10 mg/kg day, PO) produced an opposite effect showing an anxiolytic profile that is consistent with the clinical use of this drug, which shows efficacy after 2-4 weeks of treatment. Acute fluoxetine (5.6 and 10 mg/kg, IP) also produced an anxiogenic profile with reduced head dipping and end-arm activity. On the other hand, chronic fluoxetine (10 mg/kg day, PO) had no effect on any of the behavioral measures. These data demonstrate: (a) the anxiogenic and anxiolytic effects of acute and chronic gepirone, respectively, corroborate with the observed effects of these treatments in the clinic; (b) similarly, the anxiogenic effects of acute fluoxetine observed here have also been reported in clinical studies with 5-HT reuptake blockers. This class of compounds has not been systematically used as anxiolytic; (c) the elevated plus-maze with transparent walls shows good sensitivity for evaluating serotonergic drugs with anxiogenic and anxiolytic profile.