Neurons in V1 display orientation selectivity by responding optimally to a preferred orientation edge when it is presented within their receptive fields. Orientation plasticity in striate cortex occurs either by ocular deprivation or by imposition of a non-preferred stimulus for several minutes. Adaptation of neurons to a non-optimal orientation induces shifts of tuning curves towards the adapting orientation (attractive shift) or away from it (repulsive shift). Here, we investigated the effects of the neurotransmitter serotonin and antidepressant fluoxetine (a selective serotonin reuptake inhibitor) on the modulation of adaptation-induced orientation plasticity. We show that serotonin and fluoxetine promote mostly attractive shifts. Attractive shifts augmented in magnitude towards adapter, whereas repulsive neurons reversed their behavior in the direction of the forced orientation. Furthermore, neurons which retained their original preferred orientation expressed plasticity by shifting their tuning curves after drug administration mostly towards adapter. Our data suggest a pre-eminent role of fluoxetine by inducing and facilitating short-term plasticity in V1.