Recent studies have suggested antidepressant involvement in synaptic plasticity, possibly mediated by neurotrophins and neuropeptides. Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide and neuromodulator. Since its discovery, PACAP has been extensively investigated with regard to its neurotrophic properties including regulation of brain-derived neurotrophic factor (BDNF) expression, a neurotrophin postulated to be involved in the mechanism of antidepressant action and etiology of affective disorders. Using real-time polymerase chain reaction (PCR) technique, we demonstrate in this paper a robust upregulation of BDNF messenger RNA (mRNA) expression in rat primary cortical neurons following a 6-hour incubation with PACAP, and subsequently elevated BDNF expression after prolonged treatment. Additional experiments were conducted to evaluate the effects of antidepressants on the expression of PACAP, its receptors and BDNF. In rat hippocampal neurons, prolonged (72-hour) treatment with selective serotonin reuptake inhibitors paroxetine and citalopram significantly up-regulated BDNF and PACAP expression and down-regulated PACAP receptor (PAC1 and VPAC2) expression; the tricyclic antidepressant imipramine had an opposite effect. These alterations in BDNF expression correlated negatively with PAC1 and VPAC2 expression, and positively with PACAP mRNA levels. Thus, our findings suggest the possible involvement of PACAP signaling in the neuronal plasticity induced by antidepressant treatment.