The supraoptic nucleus (SON) is well known for its two major roles: 1) the control of blood pressure and water balance through it is synthesis of the neuropeptide, arginine vasopressin (AVP), and 2) the control of milk letdown and facilitation of parturition mediated by the related peptide, oxytocin (OXT). Magnocellular neurons (MCNs) of the SON send projections to the posterior pituitary where the peptide contents are released. In addition, there is now a large body of evidence indicating that these peptides are also released from dendrites of magnocellular neurons. We have used SON slices to investigate the role of AVP and OXT in synaptic transmission in the SON. Stimulation of afferent fibers to MCNs elicits excitatory of inhibitory post synaptic potentials (EPSPs, IPSPs), or, when cells are held under voltage clamp EPSCs or IPSCs. AVP appears to inhibit EPSCs impinging onto AVP neurons through an action at a post synaptic site, in keeping with the known location of AVP receptors on AVP neurons. In putative OXT neurons that bear OXT receptors, OXT enhances post synaptic AMPA receptors, again at a likely postsynaptic site. However, in putative AVP neurons, through analysis of paired pulse facilitation and miniature analysis, we also observed a reduction in EPSCs by OXT through an action at the presynaptic terminal; release of endogenous OXT from MCNs mimicked the effect of exogenous OXT. MCNs, like many peptidergic neurons, also contain a variety of other transmitters and modulators. Thus we have investigated the possible action of these substances. Endogenous cannabinoids (CBs) are now known to be ubiquitously located through many brain structures and CB1 receptors can be localized to presynaptic terminals in the SON. When we applied CB receptor agonists to the SON, we observed a depression in EPSCs and IPSCs similar to what is seen with OXT. Interestingly, the depression of excitatory transmission than can be observed after depolarization of the postsynaptic cell body can be blocked by both CB1 receptor antagonists as well as OXT/AVP receptor antagonists. We believe that excitation of the MCNs causes release of OXT or AVP that, through autocrine actions of the peptides on MCNs, causes synthesis and release of endogenous CBs that act on presynaptic receptors to inhibit afferent transmission. We have also studied other peptides and modulators found in SON MCNs- galanin, pituitary adenylate cyclase activating polypeptide (PACAP), nitric oxide and endothelin. The majority of these substances have potent presynaptic effects, but unlike those elicited by OXT, they do not appear to be mediated via secondary release of endogenous cannabinoids. With respect to galanin and endothelin, we have been unsuccessful in demonstrating that they are released from MCNs, and it appears that the likely source of peptide to influence EPSCs in the SON is from fibers extrinsic to the nucleus. In summary, we are beginning to unravel the receptor location and local circuitry underlying the actions of a number of the neuromodulators and transmitters of the SON; however, little is known at this time of the overall role of these substances in the functioning of the SON.