Neuropeptide Y (NPY) has been considered to be involved in the pathogenesis of affective disorders, and chronic treatment with lithium or electroconvulsive stimuli (ECS) has been shown to increase mRNA and peptide levels of NPY in rat brain tissue. Consequently, parameters reflective of NPYergic neurotransmission were studied in the hippocampus of rats following chronic treatment with lithium, ECS or the selective serotonin re-uptake inhibitor (SSRI), citalopram. Lithium (28 days, diet) and ECS (10 days, once daily) treatments caused a marked increase in levels of preproNPY mRNA in the CA1 area and dentate gyrus (DG). This increase was accompanied by an increase in extracellular levels of NPY in the dorsal hippocampus of freely moving rats as determined by microdialysis, suggesting that lithium and ECS treatments lead to an increased biosynthesis and release of NPY in this area. (125)I-peptide YY (PYY) binding was reduced by 40 and 60% respectively in the DG following the same treatments, showing that the increased release is accompanied by a down-regulation of corresponding binding sites. In contrast, citalopram (10 mg/kg i.p., twice daily for 28 days) caused a 100% increase in (125)I-PYY binding in CA, CA3 and DG while levels of preproNPY mRNA and extracellular NPY in the hippocampus were unaffected. The results indicate that various agents and stimuli exerting antidepressant effects in humans, such as chronic lithium, ECS and citalopram all increase NPYergic neurotransmission in the hippocampus by distinct modes of action. Moreover, NPY (6 microg) given intracerebroventricularly (i.c.v.) induced an antidepressant-like effect in the forced swim test. It is hypothesised that the increase in NPYergic neurotransmission may be associated with the mechanism of action of various antidepressant treatments in the alleviation of depression.