An investigation of the mechanisms responsible for acute fluoxetine-induced anxiogenic-like effects in mice

Although selective 5-hydroxytryptamine (5-HT) reuptake inhibitors (SSRIs) a re widely used in the chronic treatment of several anxiety disorders, incre ased anxiety has been observed in some patients at the beginning of treatme nt with these compounds. Similar increases in anxiety-related behaviors hav e been observed in animal studies following a single injection with SSRIs. The mechanism underlying this effect is unclear. The aim of the present stu dy was to investigate the effects of a variety of psychoactive compounds on the anxiogenic-like activity of fluoxetine. The drugs used included the be nzodiazepine diazepam, the 5-HT1A receptor partial agonist buspirone, the 5 -HT1A receptor antagonists pindolol and WAY-100635, the non-selective 5-HT2 receptor antagonists methiothepin, mianserin and ritanserin, the non-selec tive dopamine (DA) receptor antagonist haloperidol, the D-1 antagonist SCH2 3390, the selective D-2 antagonist raclopride, the D-2/3 agonist quineloran e, the cholecystokinin(B) (CCKB) receptor antagonist LY 288513, and the cor ticotropin-releasing factor(1) (CRF1) receptor antagonist CP-154,526. Exper iments were performed in the free-exploration test. This model is based on the strong neophobic reactions exhibited by BALB/c mice when confronted sim ultaneously with a familiar and a novel environment. When administered alon e, diazepam (1 and 2 mg/kg), buspirone (1 mg/kg) and mianserin (0.3 mg/ kg) produced anxiolytic-like effects as they significantly increased explorato ry activity of the novel compartment. In contrast, fluoxetine (20mg/kg) alm ost completely suppressed exploration of the novel area. Diazepam reversed the anxiogenic-like as well as the locomotor impairment induced by fluoxeti ne, while quinelorane blocked only the anxiogenic action of fluoxetine. Non e of the other compounds was able to counteract this effect, Taken together , these results suggest that dopaminergic mechanisms may underlie, at least in part, the behavioral effects of fluoxetine in the free-exploration test , whereas 5-HT1A, 5-HT2, CCKB and CRF1 receptors may not be involved primar ily in these effects, (C) 2001 Lippincott Williams & Wilkins.