Serotonin Stimulates Hypothalamic mRNA Expression and Local Release of Neurohypophysial Peptides : 5-HT activation of vasopressin and oxytocin

To investigate the effects of an ethologically-relevant stressor on central and peripheral release of arginine vasopressin and oxytocin, we forced adult male Wistar rats to swim for 10 min and simultaneously measured the release of the two peptides (i) within the hypothalamic supraoptic and paraventricular nuclei (by means of the microdialysis technique) and (ii) into the blood (by chronically-implanted jugular venous catheters). Forced swimming caused a significant rise in the release of arginine vasopressin and oxytocin within both the supraoptic nuclei (four-fold and three-fold, respectively) and the paraventricular nuclei (three-fold and four- to five-fold, respectively). Release patterns measured before, during and after repeated stress exposure on three consecutive days indicated that, at the level of the hypothalamus, the two neuropeptides are critically involved in the rats' stress response in a peptide-, locus- and stress-specific manner. Particularly, despite a general reduction of the recovery of the microdialysis probes over the time, the release of arginine vasopressin within the paraventricular nuclei and of oxytocin within the supraoptic nuclei tended to increase upon repeated stress exposure. Measurement of plasma peptide concentrations revealed that the central release of oxytocin was accompanied by a secretion of this peptide into the systemic circulation. In contrast, arginine vasopressin, assayed in the same plasma samples, failed to respond to the stressor. The latter finding is consistent with a dissociated release of the neuropeptide from different parts of a single neuron (soma/dendrites vs axon terminals). It provides evidence that under physiological conditions plasma hormone levels do not necessarily reflect the secretory activity of central components of the respective neuropeptidergic system.

The release of the nonapeptides oxytocin and vasopressin within the hypothalamic supraoptic and paraventricular nuclei was measured in 30-min microdialysates in conscious female rats in the last three days of pregnancy, during parturition, immediately after parturition and during suckling, all in the same rats, and in virgin controls. Nonapeptide release within the supraoptic and paraventricular nuclei was unchanged during late pregnancy compared to virgin rats, but intranuclear oxytocin and not vasopressin release was elevated during parturition (relative to late pregnancy, supraoptic nucleus: to 254%, paraventricular nucleus: to 300%; P < 0.01) and during suckling also on days 8-10 of lactation (relative to pre-suckling, supraoptic nucleus: to 407%, paraventricular nucleus: to 275%; P < 0.02). Suckling-induced release of oxytocin was significantly reduced using Ca(2+)-free, EDTA-containing (10(-4) M) microdialysis fluid and further stimulated by high K(+)- (56 mM), veratridine-containing (50 microM) microdialysis fluid. The opioid antagonist naloxone whether given by subcutaneous injection (5 mg/kg) or directly into the supraoptic nucleus by microdialysis (5 x 10(-6) M) or microinjection (1.5 microliters, 10(-6) M) did not further enhance oxytocin release within either the supraoptic or paraventricular nuclei during parturition. In contrast to the selective release of oxytocin within the supraoptic and paraventricular nuclei during parturition and suckling, direct osmotic stimulation of the nuclei by microdialysing hypertonic medium (artificial cerebrospinal fluid; 1 M NaCl) increased intranuclear release of both oxytocin and vasopressin which was further enhanced after replacement of hypertonic with isotonic fluid. This rebound phenomenon served to confirm the precise location of the microdialysis probe ante mortem and the ability of the nuclei to adequately respond to the osmotic stimulus at the end of the experiment. The study has shown that oxytocin is released in the supraoptic and paraventricular nuclei during parturition as well as in lactation unrestrained by endogenous opioids during parturition. This intranuclear release of oxytocin may act by local positive feedback stimulation of oxytocin neurons to excite further oxytocin release in the brain and into blood during both parturition and lactation.

This review of the CNS effects of the neurohypophyseal hormones and related neuropeptides discusses recent data illustrating the significance of these principles in brain function, synthesis, distribution, in particular in extrahypothalamic brain structures, binding sites, and signal transduction. Binding sites for vasopressin of the vascular V1a type have been found in the CNS and there is evidence for the existence of a subtype of the antidiuretic V2 receptor in the brain. Also two types of oxytocin binding sites have been detected. One widely distributed throughout the CNS is comparable to the uterine type receptor and a sexually dimorphic slightly different type is found in the ventromedial nucleus. Vasopressin and oxytocin can be converted to highly selective C-terminal fragments as AVP-(4-9) and OXT-(4-9) and shorter fragments. Conversely they can be acetylated. This almost completely blocks intrinsic activity in bioassays for central and peripheral effects. Such modifications are a good example of the plasticity of a neuropeptide system. For a number of CNS effects of the neurohypophyseal hormones, the whole molecule is required, as it is for their endocrine effects. This is the case for the influence of vasopressin on social communication, temperature regulation, epilepsy, and barrel rotation which may be an animal model of febrile convulsions, and some aspects of the central regulation of the cardiovascular system and for oxytocin on sexual behavior, social communication, and grooming. Nonendocrine C-terminal conversion products seem to exert their effects exclusively on the brain. These neuropeptides modulate learning and memory processes, social recognition, and rewarded behavior. The neuroendocrine and neuropeptide effect of vasopressin and oxytocin and related neuropeptides often exert their CNS effects in an opposite way. Neurochemical and electrophysiological studies suggest that norepinephrine, dopamine, serotonin, and glutamate are the neurotransmitters involved in the influence of the neurohypophyseal hormones and related neuropeptides on brain function. It appears that adequate amounts of vasopressin and oxytocin to induce these effects are released at the appropriate sites of action. It is postulated that the mix of neuropeptides released in the brain in response to environmental changes qualifies the behavioral, neuroendocrine, and immune response and the response of the autonomic nervous and vegetative systems of the organism. Although various other neuropeptides, such as those colocalized in vasopressinergic and oxytocinergic neurons, those produced in pro-opiomelanocortin (POMC) systems, and others, play a role in the modulation of adaptive responses, the neurohypophyseal hormones are unique in that their production sites in the hypothalamus serve the periphery, the pituitary, and the brain.