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

Serotonin (5-HT) and 5-HT1A 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-HT1A receptor agonist 8-OH-DPAT (0.125 and 0.5 mg/kg) and several classes of antidepressants such as the tricyclic agent desipramine (30 and 60 mg/kg), the monoamine oxidase inhibitor (MAOI) pargyline (60 mg/kg) and the SSRIs fluoxetine (15 and 30 mg/kg), paroxetine (15 and 30 mg/kg) and sertraline (30 mg/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-HT1A 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-HT1A receptor function were studied by measuring 8-OH-DPAT-mediated hypothermia and lower lip retraction (LLR) in the animals 24 h 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-HT1A receptors attenuated helpless behaviour, the antidepressant-like effect of SSRIs was found to be independent of their actions on either 5-HT1A receptor function or extracellular 5-HT.