In the present study wet-dog shakes in rats were induced by local potassium (K+) depolarization in the dorsal hippocampus. Concurrently, changes in extracellular concentrations of cyclic AMP (cAMP) and serotonin (5-HT) were assessed by microdialysis. It has been well-established that lithium influences the synthesis of cAMP in the brain via effects on adenylate cyclases. In this study, the effect of chronic lithium treatment on the number of wet-dog shakes and the release of 5-HT was investigated. Wet-dog shakes, formation of cAMP and release of 5-HT were induced by perfusing a Ringer solution containing 60 mM K+ through the microdialysis probe for 20 min. Under some conditions, this high K+ solution also contained 20 mu M forskolin. The number of wet-dog shakes and the formation of cAMP induced by K+ depolarization were enhanced by forskolin, while the K+-stimulated release of 5-HT was unaffected by forskolin. Chronic lithium treatment, yielding a plasma lithium level of 0.78+/-0.09 mmol/l, decreased the number of wet-dog shakes but did not affect the extracellular level of 5-HT in the dorsal hippocampus. Chronic lithium treatment may affect the serotonergic wet-dog shake syndrome in the rat partly via the cAMP signalling system but does not seem to influence this syndrome by changing the release of 5-HT from nerve terminals in the dorsal hippocampus. (C) 1998 Elsevier Science B.V./ECNP. All rights reserved.