Reversal of learned helplessness by selective serotonin reuptake inhibitors in rats is not dependent on 5-HT availability.

Serotonin (5-HT) and 5-HT(1A) receptors have been suggested to play a pivotal role in the mechanism of action of antidepressant drugs, particularly in the case of selective serotonin reuptake inhibitors (SSRIs). In the rat learned helplessness (LH) paradigm, a valid animal model of human depression, repeated treatment with the 5-HT(1A) receptor agonist 8-OH-DPAT (0.125 and 0.5mg/kg) and several classes of antidepressants such as the tricyclic agent desipramine (30 and 60mg/kg), the monoamine oxidase inhibitor (MAOI) pargyline (60mg/kg) and the SSRIs fluoxetine (15 and 30mg/kg), paroxetine (15 and 30mg/kg) and sertraline (30mg/kg) improved behavioural deficit in helpless rats. The involvement of serotonergic mechanisms in the antidepressant-like effect of these agents was investigated using the selective 5-HT(1A) receptor antagonist WAY 100,635 and the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA). Pretreatment with WAY 100,635 blocked the 8-OH-DPAT-induced reduction in escape failures, but did not counteract the antidepressant effect of fluoxetine and paroxetine. PCPA given alone did not modify helpless behaviour nor did it affect the behavioural effect of 8-OH-DPAT, fluoxetine and paroxetine. Adaptive changes in 5-HT(1A) receptor function were studied by measuring 8-OH-DPAT-mediated hypothermia and lower lip retraction (LLR) in the animals 24h after LH test session. Fluoxetine and paroxetine treatments caused a marked reduction in agonist-induced responses, an effect completely prevented by WAY 100,635 and PCPA. In conclusion, whereas direct agonist activity at postsynaptic 5-HT(1A) receptors attenuated helpless behaviour, the antidepressant-like effect of SSRIs was found to be independent of their actions on either 5-HT(1A) receptor function or extracellular 5-HT.