Brain serotonin 1A (5-HT1A) receptors play an important role in mood disorders and can modulate various intracellular signaling mechanisms. We previously reported that systemic administration of either full or partial 5-HT1A agonists increases neuroendocrine responses and that tandospirone, an azapirone partial agonist, can activate (phosphorylate) extracellular signal-regulated kinase (ERK) in the hypothalamic paraventricular nucleus (PVN). In contrast, decreased levels of phosphoERK (pERK) have been reported in hippocampus following in vivo administration of either azapirone or aminotetralin 5-HT1A agonists, such as 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT). The present study investigated the time-dependent activation of MAP kinase in hypothalamus by (+)8-OH-DPAT to determine the regional differences and receptor specificity of the changes in pERK. Adult male rats received a systemic injection of (+)8-OH-DPAT (200 microg/kg, s.c.). The time-dependent changes in ERK activation were examined in hypothalamic nuclei as well as other brain regions associated with modulation of mood. (+)8-OH-DPAT produced a rapid increase (at 5 min) and transient return (at 15 min) of pERK levels in PVN and medial basal hypothalamus. In contrast, pERK levels in hippocampus were reduced at both 5 and 15 min after (+)8-OH-DPAT. Pretreatment with the 5-HT1A receptor-specific antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanec arboxamide (WAY100635) completely blocked the (+)8-OH-DPAT-mediated changes in pERK levels in PVN, medial basal hypothalamus, and hippocampus. No significant (+)8-OH-DPAT-induced changes in pERK were observed in dorsal raphe or amygdala. In conclusion, these results demonstrate that 8-OH-DPAT activation of MAP kinase signaling in vivo is a transient and region-specific phenomenon and in rat hypothalamus and hippocampus is mediated by 5-HT1A receptors.