Primary cultures of neurons from chick embryo telencephalons were deprived of serum to induce apoptotic cell death. After 24 h of serum withdrawal, we found a reduction in cell viability from 85% to 72% and an increase in the number of apoptotic cells from 12% to 29%. The 5-HT1A receptor agonist 8-OH-DPAT inhibited the decrease in cell viability and reduced the number of apoptotic cells in a concentration-dependent manner. The anti-apoptotic effect of 8-OH-DPAT (1 microM) could be blocked by adding the selective 5-HT1A antagonist MPPI (10 microM), but not in the presence of the dopamine receptor antagonist chlorpromazine (1 microM) and of the beta-receptor blocker propranolol (10 microM). In addition, anti-nerve growth factor (NGF) antibodies inhibited the protective effect of 8-OH-DPAT, suggesting that induction of NGF was involved in the mechanism of action. Serum deprivation alone already induced a release of NGF (10 pg/flask) which protected the neurons from further cell death. Accordingly, the addition of the same amount of exogenous NGF restored cell viability up to control level and addition of anti-NGF antibodies further decreased cell viability to 56%. In the presence of 8-OH-DPAT (1 microM), the level of NGF in the culture medium was only slightly yet consistently increased compared to serum deprivation from 4 h onwards. Thus, our data suggest that the anti-apoptotic effect of 8-OH-DPAT is mediated by the stimulation of 5-HT1A receptors. Furthermore, the induction of neuronal NGF synthesis and secretion contributes to its neuroprotective action.