Involvement of hippocampal neuropeptide Y in mediating the chronic actionsof lithium, electroconvulsive stimulation and citalopram

Neuropeptide Y (NPY) has been considered to be involved in the pathogenesis of affective disorders, and chronic treatment with lithium or electroconvu lsive stimuli (ECS) has been shown to increase mRNA and peptide levels of N PY in rat brain tissue. Consequently, parameters reflective of NPYergic neu rotransmission were studied in the hippocampus of rats following chronic tr eatment with lithium, ECS or the selective serotonin re-uptake inhibitor (S SRI), citalopram. Lithium (28 days, diet) and ECS (10 days, once daily) tre atments caused a marked increase in levels of preproNPY mRNA in the CAI are a and dentate gyrus (DG). This increase was accompanied by an increase in e xtracellular 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. I-125-pe ptide YY (PYY) binding was reduced by 40 and 60% respectively in the DG fol lowing the same treatments, showing that the increased release is accompani ed by a down-regulation of corresponding binding sites. In contrast, citalo pram (10 mg/kg i.p., twice daily for 28 days) caused a 100% increase in I-1 25-PYY binding in CA, CA3 and DG while levels of preproNPY mRNA and extrace llular NPY in the hippocampus were unaffected. The results indicate that va rious agents and stimuli exerting antidepressant effects in humans, such as chronic lithium, ECS and citalopram ail increase NPYergic neurotransmissio n in the hippocampus by distinct modes of action. Moreover, NPY (6 mu g) gi ven intracerebroventricularly (i.c.v.) induced an antidepressant-like effec t in the forced swim test. It is hypothesised that the increase in NPYergic neurotransmission may be associated with the mechanism of action of variou s antidepressant treatments in the alleviation of depression. (C) 2000 Else vier Science Ltd. All rights reserved.