The effects of long-term treatment with the antidepressant drugs, desipramine (DMI) and mianserin (MIA) on neurotransmission in the hippocampal slice were studied by examining the actions of serotonin (5-HT), isoprenaline and (+/-)-baclofen on the population spike in the pyramidal cell layer, recorded in area CA1. The decrease in amplitude of the population spike by 5-HT (1-10 microM) was facilitated by long-term treatment with DMI but not significantly with MIA. Both DMI and MIA depressed the excitatory action of isoprenaline (0.3 microM), whereas the inhibitory responses to (+/-)-baclofen (0.3-3 microM) were unaffected. The results show that significant changes in serotonergic and beta-adrenergic neurotransmission can be demonstrated ex vivo after in vivo treatment with antidepressants and that these changes partly substantiate data measured in vivo.