Information in neurons flows from synapses, through the dendrites and cell body (soma), and, finally, along the axon as spikes of electrical activity that will ultimately release neurotransmitters from the nerve terminals. However, the dendrites of many neurons also have a secretory role, transmitting information back to afferent nerve terminals. In some central nervous system neurons, spikes that originate at the soma can travel along dendrites as well as axons, and may thus elicit secretion from both compartments. Here, we show that in hypothalamic oxytocin neurons, agents that mobilize intracellular Ca(2+) induce oxytocin release from dendrites without increasing the electrical activity of the cell body, and without inducing secretion from the nerve terminals. Conversely, electrical activity in the cell bodies can cause the secretion of oxytocin from nerve terminals with little or no release from the dendrites. Finally, mobilization of intracellular Ca(2+) can also prime the releasable pool of oxytocin in the dendrites. This priming action makes dendritic oxytocin available for release in response to subsequent spike activity. Priming persists for a prolonged period, changing the nature of interactions between oxytocin neurons and their neighbours.

SUMMARY1. Isolated rat neural lobes were stimulated electrically and the release of vasopressin and oxytocin was measured by radioimmunoassay. The neurohypophyses were stimulated with pulses given at a constant frequency or with a pulse pattern imitating the electrical activity, recorded in vivo, of vasopressin-or oxytocincontaining magnocellular neurones.2. A single burst recorded from a 'vasopressin' cell with an intraburst mean frequency of 13 Hz evoked more vasopressin release than the same number of stimuli delivered at a constant frequency of 13 Hz.3. The amount of vasopressin release per pulse was much higher at the beginning than at the end of the burst.4. Series of bursts given with interburst silent periods released more hormone than bursts delivered without silent periods.5. The amount of hormone released by four 'vasopressin' bursts was significantly larger with silent periods of 21 s than with shorter intervals.6. Four pulses were much more effective in promoting hormone release when given with 60 ms interspike intervals at the beginning of each second than when delivered at a constant frequency of 4 Hz.7. Prolonged stimulation with 'vasopressin' bursts had a greater effect in inducing hormone release than the same number of pulses given in bursts delivered at a constant frequency of 13 Hz. After an initial increase the rate of vasopressin release declined rapidly whereas oxytocin release remained elevated for the first 20 min and only then decreased. The release of both vasopressin and oxytocin remained, however, above the release from unstimulated neurohypophyses.8. 45Ca uptake in the neural lobe was larger when the neurohypophyses were stimulated with vasopressin or oxytocin bursts delivered with silent intervals than when the silent periods were omitted, or when the tissue was stimulated with bursts with the same number of pulses but given at a constant frequency of 13 Hz.9. In conclusion, it is suggested that the interspike intervals in a burst and the silent intervals between bursts are two important determinants of the effectiveness of the burst pattern in promoting neuropeptide release.

Is oxytocin the hormone of happiness? Probably not. However, this small nine amino acid peptide is involved in a wide variety of physiological and pathological functions such as sexual activity, penile erection, ejaculation, pregnancy, uterus contraction, milk ejection, maternal behavior, osteoporosis, diabetes, cancer, social bonding, and stress, which makes oxytocin and its receptor potential candidates as targets for drug therapy. In this review, we address the issues of drug design and specificity and focus our discussion on recent findings on oxytocin and its heterotrimeric G protein-coupled receptor OTR. In this regard, we will highlight the following topics: (i) the role of oxytocin in behavior and affectivity, (ii) the relationship between oxytocin and stress with emphasis on the hypothalamo–pituitary–adrenal axis, (iii) the involvement of oxytocin in pain regulation and nociception, (iv) the specific action mechanisms of oxytocin on intracellular Ca2+ in the hypothalamo neurohypophysial system (HNS) cell bodies, (v) newly generated transgenic rats tagged by a visible fluorescent protein to study the physiology of vasopressin and oxytocin, and (vi) the action of the neurohypophysial hormone outside the central nervous system, including the myometrium, heart and peripheral nervous system. As a short nine amino acid peptide, closely related to its partner peptide vasopressin, oxytocin appears to be ideal for the design of agonists and antagonists of its receptor. In addition, not only the hormone itself and its binding to OTR, but also its synthesis, storage and release can be endogenously and exogenously regulated to counteract pathophysiological states. Understanding the fundamental physiopharmacology of the effects of oxytocin is an important and necessary approach for developing a potential pharmacotherapy.

1. Intracellular Ca2+ concentration ([Ca2+]