Differences between first- and second-generation antidepressants and modulation of affective biases in Lister Hooded rats

This study investigated the effects of pharmacologically distinct conventional antidepressants (amitriptyline, moclobemide, sertraline) and modulation of affective biases in rats. We tested each antidepressant in three different affective bias protocols (new learning protocol and modulation of negative affective biases associated with past experiences) and a reward learning assay (RLA) control. The affective bias test (ABT) requires animals to learn two independent and equal reward-value associations following control or drug treatment Any affective bias generated is quantified during a subsequent choice test. Treatments were administered before substrate-reward pairing sessions to test effects on new learning. To test effects on past experiences, we first generated a negative memory bias during pairing sessions (via administration of anxiogenic FG7142), and then administered treatments either acutely or 24-hours before the choice test. The RLA protocol is similar but instead of an affective state-induced bias, a reward-induced bias is generated by pairing one substrate with a higher value reward. All three antidepressants positively biased new learning, but sertraline and moclobemide were only affective at low doses. Amitriptyline and sertraline attenuated previously learnt negative affective biases both acutely and 24-hour post-treatment. None of the antidepressants showed effects in the control RLA, suggesting specific effects on affective-state-induced biases. These findings reveal similar effects of these antidepressants on new learning but suggest difference in whether they also modulate negative biases associated with past experiences. These differences may be important in contributing to their clinical efficacy and time course of effects.