Activation of dendritic voltage-dependent calcium (Ca2+) conductances in neuroendocrine cells of the hypothalamus may underlie previously documented Ca2+ spikes in these cells. The present study, in which whole-cell recordings were obtained from paraventricular nucleus neurons in a hypothalamic slice preparation, addresses this issue by directly activating dendritic N-methyl-D-aspartate receptors in the presence of tetrodotoxin. Application of tetrodotoxin abolished spontaneous action potentials in all paraventricular nucleus neurons tested (n = 27). Following tetrodotoxin, spikes were evoked by depolarizing current pulses, in an all-or-none fashion in the majority of cells (n = 20). Removal of extracellular Ca2+ (n = 6) or addition of 500 microM CdCl2 (n = 4) abolished the spikes in response to pulses. Repetitive spiking activity (in tetrodotoxin) was also observed following N-methyl-D-aspartate agonist application in 75% of the cells tested (n = 15). The spikes, underscored by a slow membrane depolarization, were abolished by the administration of CdCl2 (n = 4). N-Methyl-D-aspartate agonist elicited a slow inward current in cells voltage-clamped at -60 mV (n = 5). Additionally, larger amplitude, transient inward currents were observed near the onset of the response. The activation threshold to elicit spikes following N-methyl-D-aspartate agonist application was significantly more negative (-54.6+/-3.6 mV) than the potential at which spikes were initiated as a result of depolarizing current injection (-32.3+/-1.8 mV; Student's t-test: P < 0.0001). In contrast to this, Na+ spikes in control solution had an invariable threshold (-49.6+/-0.7 mV vs -51.5+/-1.2 mV; P > 0.05), regardless of the stimulus used to initiate the spikes. These observations suggest that direct activation of N-methyl-D-aspartate receptors located on the dendrites of paraventricular nucleus neurons triggers Ca2+ spikes. Although the precise function of these spikes is unclear, previous data reporting dendritic neuropeptide release in the paraventricular nucleus raise the possibility that dendritically initiated spikes may serve as a local signal to trigger such release.