GABAA receptors mediate the inhibition of somatostatin gene expression and NMDA receptors mediate its stimulation. The aim of this study was to determine whether the two major neurotransmitters in the central nervous system (GABA and glutamate) could interact to control somatostatin mRNA content in primary cultures of hypothalamic neurons. Neurons were incubated for 15 min on days 3, 5, 7 or 11 of culture with Mg2+-free medium containing either NMDA (20 µM) or bicuculline (50 µM) to investigate the ontogenesis of somatostatin secretion in response to NMDA and GABA. We found that NMDA significantly elicited somatostatin release from day 3, and bicuculline-induced release was observed from day 5. An ontogenetic study of somatostatin mRNA levels revealed that it steadily increased up to day 5 (6-fold) and a slight but nonsignificant decrease was observed on day 7 which stabilized until day 13. Experiments were thus carried out on day 11 of culture. Pharmacological manipulations of the two types of receptors (NMDA and GABAA) were performed to study the effect of the interaction on somatostatin mRNA accumulation. Time-course studies revealed the optimal time of action of the neurotransmitters (20 h). Our results demonstrated that bicuculline-induced mRNA accumulation was not additive with that elicited by NMDA after 20 h of incubation. In contrast, (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d’)cyclohepten-510-imine hydrogen (MK-801) at 10 µM completely abolished the stimulatory effect of bicuculline during the same time period. In addition, muscimol was unable to decrease somatostatin mRNA levels when NMDA receptors were blocked by MK-801. These results suggest that bicuculline and NMDA-induced responses share at least one common step in the control of somatostatin mRNA le