This study examined the effects of long-term cannabinoid administration on the responsivity of 5-HT1A and 5-HT2A receptors, which have been implicated in depression. Animals received 12 d administration of the potent cannabinoid receptor agonist HU-210 (100 microg/kg), following which they were monitored on their behavioural, physiological and hormonal responses to a single challenge of a 5-HT1A and 5-HT2A receptor agonist, 8-OH-DPAT (0.3 mg/kg) and DOI (1 mg/kg) respectively. Chronic HU-210 treatment lead to a significant enhancement of DOI-induced wet-dog shakes, but a reduction of DOI-induced back muscle contractions. DOI-induced corticosterone release was unaffected by HU-210 treatment. The hyperthermic response to DOI appeared to be potentiated by long-term HU-210 treatment, as 50% of these subjects died from an apparent serotonin syndrome with core temperatures exceeding 43 degrees C. The 8-OH-DPAT-induced hypothermic response and elevation of corticosterone were both significantly attenuated by long- term HU-210 treatment. These data imply that chronic cannabinoid treatment may up-regulate 5-HT2A receptor activity while concurrently down-regulating 5-HT1A receptor activity, a finding similar to that sometimes observed in depression. This may partially explain the association between excessive cannabis consumption and the induction of affective disease.