1 Stereotaxic lesioning and microiontophoretic techniques were used to study the effects of lesions of the medial forebrain bundle (MFB) on the potentiation by antidepressant drugs of responses to monoamines of cortical neurones.2 Active uptake of noradrenaline (NA) and 5 hydroxytryptamine (5-HT) by synaptosomes from the motor and somatosensory cortex was reduced to approximately 20%, 10 to 14 days following lesion of the MFB in rats.3 Unilateral lesions of the MFB caused changes in responsiveness of neurones to NA and 5-HT, applied by iontophoresis, in the cortex ipsilateral to the lesion. Excitatory responses to both amines were observed less frequently and depression was the predominant response. Excitatory responses on the lesioned side were significantly smaller than on the unlesioned side, but the size of depressant responses was unaltered.4 Viloxazine strongly potentiated responses of cortical neurones to NA and 5-HT on both sides of the brain of MFB-lesioned rats. There were no significant differences in the potentiation of responses to monoamines on the lesioned or unlesioned sides of the brain.5 Desipramine potentiated responses to NA of neurones in the cortex ipsilateral to MFB lesions.6 Chlorimipramine potentiated responses to 5-HT of neurones in the cortex ipsilateral to MFB lesions.7 It is concluded that antidepressants can potentiate responses to monoamines despite a profound reduction in presynaptic terminals. The potentiation is unlikely to be the result of blockade of monoamine uptake into presynaptic terminals, and is probably a postsynaptic effect of the antidepressant drugs.