Leptin, an anorexigenic hormone synthesized in the adipose tissue, acts centrally to control food intake and body weight. Oxytocin acts as an anorectic peptide centrally and is involved in the regulation of electrolyte balance peripherally. Most supraoptic nucleus (SON) neurones are strongly immunoreactive for leptin receptor (1). Leptin interacts with acute satiety signals such as cholecystokinin (CCK) to regulate appetite (2). Here we investigated whether leptin can excite oxytocin neurones, and whether there are interactions between leptin and CCK, since systemic CCK excites oxytocin neurones. Leptin potentiates the anorectic and Fos expression responses to CCK (3,4). Hence, we hypothesized that leptin also potentiates the CCK-induced excitatory electrophysiological responses of SON oxytocin neurones. The electrical activity of single identified oxytocin neurones in the SON was recorded extracellularly through a glass 0.9% NaCl-filled microelectrode, via a ventral surgical approach in urethane-anaesthetised (1.25g/kg, i.p.) unfasted virgin female rats (n=19). SON oxytocin neurones (n=19) were identified antidromically, by stimulating the neurohypophysial stalk, and by their excitatory response to CCK (20 µg/kg; i.v). The effect of systemic leptin (100µg; i.v) was predominantly excitatory. The firing rate (3.40 ± 0.37 spikes/s, group mean + s.e.m.) was increased by 0.31 ± 0.09 spikes/s two minutes after leptin injection (100µg; i.v). The rate returned to basal within 10min. The mean change in firing rate during the 10min after leptin injection was significantly greater (P=0.013, t-test) than in the 10 min before leptin injection. In the next experiment, an initial CCK response was recorded and then leptin (100µg; i.v) was injected followed by CCK after 20min. Hence, CCK responses were analysed with and without leptin treatment in the same neurones (n=8). The first injection of CCK increased the firing rate from 2.64 ± 0.59 spikes/s by 0.24 ± 0.07 spikes/s in the following 10 min, and after leptin a repeat injection of CCK raised the firing rate from 2.61 ± 0.58 spikes/s by 0.4 ± 0.1 spikes/s; a significant enhancement (P<0.05, one-tailed paired t-test). Hence, in contrast with a report of inhibitory leptin actions on SON neurones in vitro (5), in vivo leptin excited oxytocin neurones. This could result from leptin actions on inputs to oxytocin neurones. Excitation of oxytocin neurones by CCK was slightly enhanced by prior leptin injection. Oxytocin may be involved in central appetite regulation by CCK and leptin.