We have examined the anxiolytic activity of acute and chronic antidepressant treatment in an animal model of anxiety involving novelty-suppressed feeding. Rats were food deprived for 48 h, placed into a novel environment containing food, and the latency to begin eating was recorded. Chronic (21 days), but not acute injections of desipramine (DMI; 10 mg/kg) and amitriptyline (AMI; 10 mg/kg) significantly reduced the latency to begin eating compared to controls, but the percentage decrease was not as great as that seen with either acute or chronic treatment with diazepam (2 mg/kg) or adinazolam (20 mg/kg). A time course study indicated that at least 2 weeks of treatment was necessary to observe a significant anxiolytic effect of antidepressants. The anxiolytic effect of the antidepressants was specific to the novel environment, as 2 weeks of treatment with either diazepam or DMI did not influence the latency to begin eating in the home cage. Finally, a single dose of the central benzodiazepine receptor antagonist, Ro15-1788 (20 mg/kg), given 15 min prior to testing, did not block the anxiolytic effects of chronic DMI, while it completely eliminated the effect of chronic diazepam treatment. These data suggest that antidepressants acquire anxiolytic properties following chronic administration and that this effect appears to be independent of the benzodiazepine receptor system.

We examined the anxiolytic effects of a variety of anti-depressant drugs, administered either acutely or chronically, in an animal model of anxiety involving novelty-suppressed feeding in food-deprived rats. Following a single injection of desipramine (10 mg/kg) amitriptyline (10 mg/kg), mianserin (10 mg/kg), fluoxetine (10 mg/kg), buspirone (4 mg/kg), gepirone (4 mg/kg) or nomifensine (10 mg/kg), there was no decrease in the latency to begin eating in the novel environment such as occurred with diazepam (2 mg/kg). In fact, an increased latency was observed for desipramine, amitriptyline, fluoxetine, and nomifensine. In contrast, chronic (21 days) treatment with each of the above-mentioned drugs, except nomifensine, significantly reduced the latency to begin eating relative to vehicle controls. These findings suggest that a variety of tricyclic and novel anti-depressant drugs acquire anxiolytic properties following chronic administration.

There is growing evidence that the serotonergic (5-HT) system is involved in the pathogenesis and treatment of major depression. The 5-HT receptor subtype involved in the enhancing effect of antidepressant treatments, however, has not been identified. The present study was undertaken to quantify 5-HT1A sites in the rat brain by autoradiography and membrane binding, using the selective ligand [3H]8-hydroxy-N,N-dipropyl-2-aminotetralin (8-OH-DPAT), following long-term antidepressant treatment. Following a 21-day treatment with amitriptyline (10 mg/kg/day), there was a significant increase of [3H]8-OH-DPAT binding measured by autoradiography in the dorsal hippocampus, but there was no change in the nucleus raphe dorsalis; whole brain membrane binding revealed an increase in the number of binding sites, with no change in the affinity for [3H]8-OH-DPAT. Conversely, fluoxetine (10 mg/kg/day), a selective blocker of 5-HT reuptake, and gepirone (10 mg/kg/day), a 5-HT1A agonist, both administered for 21 days, significantly reduced [3H]8-OH-DPAT binding measured by autoradiography in the nucleus raphe dorsalis without altering hippocampal binding sites. The control active treatment with diazepam (2 mg/kg/day) did not alter [3H]8-OH-DPAT binding in the hippocampus or in the nucleus raphe dorsalis. All groups were compared to a 21-day vehicle-treated control group. These results are fully consistent with previous electrophysiological and behavioral studies and suggest that alterations of 5-HT1A receptors might underlie the enhancement of 5-HT neurotransmission by antidepressant treatments.