Brain oxytocin inhibits the (re)activity of the hypothalamo–pituitary–adrenal axis in male rats: involvement of hypothalamic and limbic brain regions
Introduction
Following their discovery by Bargmann and Scharrer (for a historical overview, see Ref. [1]), the magnocellular neurosecretory cells of the hypothalamus, which synthesize oxytocin (OXT) and vasopressin (AVP), have been the most intensively studied neuropeptidergic neurons in the nervous system. The morphological, electrophysiological and functional properties of these neurons make them an ideal model system for neurobiological research. Beside the well-described functions of OXT released from neurohypophysial terminals into blood during female reproduction (progression of labor, milk ejection), the potential role of OXT as a neurotransmitter/neuromodulator of the brain has recently received increasing attention. Noticeably, the existence of extra-hypophysial Gomori-positive pathways in the brain had already been described in the 1950s [2], and it was in the 1970s when the existence of OXT- and AVP-containing pathways could be demonstrated by immuno-electron microscopy [3]. In the rat, OXT-containing axons arise from small cells (parvocellular neurons) of the hypothalamic paraventricular nucleus (PVN) and project to a variety of extrahypothalamic brain regions including limbic areas and autonomic centers [4], [5]. Ultrastructural studies have demonstrated that these OXT projections make classical synaptic contacts [6], but the neuropeptides can also be released in a paracrine manner, thus functions both as neurotransmitter and neuromodulator can be postulated.. Using intracerebral microperfusion techniques the release of OXT could be monitored in limbic and hypothalamic regions, for example during parturition and lactation in the female [7], [8], [9], [10], [11], but also in the male rat [12], [13], [14] (for a review, see Ref. [15]). In connection with the results presented here, our recent finding of stimulated release of OXT within the septum in response to exposure to a social conflict situation (social defeat) in male rats needs to be mentioned [16]. Such intracerebral neuropeptide release was found to be dependent on extracellular potassium and could be stimulated by depolarizing agents such as veratridine [11], however it was also found to be independent of TTX and, therefore, independent of the generation of action potentials [17], [18]. This finding, together with immunocytochemical studies [19], implied that OXT and AVP neurons are capable of releasing the respective neuropeptide not only from their axon terminals, but also from somata and dendrites into the extracellular fluid of their nuclei of origin, such as the supraoptic nucleus (SON) and PVN. This is further supported by recent microdialysis experiments demonstrating a dissociated release of OXT and/or AVP within the hypothalamus and of terminal, neurohypophysial secretion [13], [20]. For example, exposure of male rats to a social defeat situation, representing a strong emotional stressor, results in a significant release of OXT within the SON, whereas OXT secretion into blood remains unchanged [21]. Therefore, OXT (as well as AVP) neurons are capable of differentially releasing OXT from different parts of their neuronal surface. Once released within a distinct brain area in a rather paracrine manner, OXT acts at specific receptors which have been localized throughout limbic, hypothalamic and brainstem regions [22], [23], [24], [25], [26], [27] and which are subject to dynamical physiological adaptations [28], [29], [30]. For example, repeated exposure to stress and chronic treatment with corticosteroids alters OXT binding in limbic brain areas [28], [31], [32].
Section snippets
Physiological functions of brain OXT — context with stress coping
Functions of OXT released within the brain have mainly been seen in the context of the establishment of maternal behavior, the expression of sexual behavior both in female and male rats as well as the bonding phenomenon in monogamous species (for reviews, see Refs. [33], [34], [35], [36], [37]). Further actions of brain OXT include the regulation of autonomic functions [38], [39], [40], feeding [41], [42] and grooming [43] behavior, analgesia [44], and olfactory memory [45], [46].
Effects of intracerebral OXT on HPA axis activity
In contrast to these rather conflicting data regarding the effect of circulating OXT on corticosteroids, results of preclinical studies largely agree on the involvement of intracerebral OXT in the regulation of basal and stress-induced HPA axis activity.
First indications for an involvement of brain OXT in stress responses were given by Insel and Winslow [66], who described a reduced ultrasonic vocalization emitted by isolated pups after icv infusion of OXT; ultrasonic vocalizations of rat pups
Localization of OXT action within the hypothalamic paraventricular nucleus (PVN)
The hypothalamic paraventricular nucleus (PVN) is regarded as the site of integration of neuroendocrine and autonomic functions. OXT is released within the PVN in response to various stimuli including emotional and physical stressors. Further, neurons synthesizing CRH, OXT and/or AVP are localized within the PVN and send their projections not only to the portal blood system of the pituitary stalk or the neurohypophysis, but also to limbic and brainstem regions. Within the PVN, both OXT receptor
Differential action of OXT on the activity of the HPA axis within the medio-lateral septum and the amygdala
There is considerable evidence that limbic, extrahypothalamic structures contribute to the complex regulation of the HPA axis activity. Among these the septum and amygdala have direct or indirect connections to the PVN [72]. Thus, the parvocellular neurosecretory neurons expressing CRH (and also AVP) can be considered to represent the final common pathway by which the brain controls the stress response. In addition to the finding that OXT receptors are localized in limbic regions, including
Acknowledgements
We thank R. Herschel, P. Lörscher, K. Rosinski and M. Zimbelmann for excellent technical assistance. The oxytocin receptor antagonist was kindly provided by Dr. M. Manning, Toledo, OH, USA. I.D.N. is a recipient of the Heisenberg stipend of the Deutsche Forschungsgemeinschaft (Ne 465); S.K. and N.T. are supported by DFG (Ne 465/4-1, 4-2); L.T. is supported by CONACyT (Mexico).
References (84)
- et al.
An immuno-electronmicroscopical study comparing vasopressin, oxytocin, substance P and enkephalin containing nerve terminals in the nucleus of the solitary tract of the rat
Brain Res.
(1983) - et al.
Intracranial dialysis measurement of oxytocin, monoamines and uric acid release from the olfactory bulb and substantia nigra of sheep during parturition, suckling, separation from lambs and eating
Brain Res.
(1988) - et al.
Oxytocin and vasopressin release within the supraoptic and paraventricular nuclei of pregnant, parturient and lactating rats: a microdialysis study
Neuroscience
(1993) - et al.
Central and peripheral release of vasopressin and oxytocin in the conscious rat after osmotic stimulation
Brain Res.
(1988) - et al.
Dissociated central and peripheral release of vasopressin, but not oxytocin, in response to repeated swim stress: new insights into the secretory capacities of peptidergic neurons
Neuroscience
(1998) - et al.
Stress increases oxytocin release within the hypothalamic paraventricular nucleus
Brain Res.
(1998) - et al.
Electrical stimulations of perifused magnocellular nuclei in vitro elicit Ca2+-dependent, tetrodotoxin-insensitive release of oxytocin and vasopressin
Neurosci. Lett.
(1987) - et al.
Dendrites of hypothalamic magnocellular neurons release neurohypophysial peptides by exocytosis
Neuroscience
(1989) - et al.
[3H]Oxytocin binding sites in the rat brain demonstrated by quantitative light microscopic autoradiography
Eur. J. Pharmacol.
(1984) - et al.
Pharmacological characteristics and anatomical distribution of [3H]oxytocin-binding sites in the Wistar rat brain studied by autoradiography
Neuroscience
(1987)
The brain oxytocin receptor(s?)
Front. Neuroendocrinol.
Localization and pharmacological characterization of high affinity binding sites for vasopressin and oxytocin in the rat brain by light microscopic autoradiography
Brain Res.
Oxytocin binding sites in rat limbic and hypothalamic structures: site-specific modulation by adrenal and gonadal steroids
Neuroscience
Gonadal steroids regulate oxytocin receptors but not vasopressin receptors in the brain of male and female rats. An autoradiographic study
Brain Res.
Effects of stress and glucocorticoids on CNS oxytocin receptor binding
Psychoneuroendocrinology
Estradiol induces oxytocin binding in the rat hypothalamic ventromedial nucleus
Eur. J. Pharmacol.
Central functions of oxytocin
Neurosci. Biobehav. Rev.
Oxytocin — a neuropeptide for affiliation: evidence from behavioral, receptor autoradiographic, and comparative studies
Psychoneuroendocrinology
Behavioral consequences of intracerebral vasopressin and oxytocin: focus on learning and memory
Neurosci. Biobehav. Rev.
A role of central oxytocin in autonomic function: its action in the motor nucleus of the vagus nerve
Brain Res. Bull.
Oxytocin-induced inhibition of feeding and drinking: no sexual dimorphism in rats
Neuropeptides
Oxytocin potently enhances novelty-induced grooming behavior in the rat
Brain Res.
Oxytocin increases nociceptive thresholds in a long-term perspective in female and male rats
Neurosci. Lett.
Endogenous oxytocin is involved in short-term olfactory memory in female rats
Behav. Brain Res.
Oxytocin inhibits nonphasically firing supraoptic and paraventricular neurons in the virgin female rat
Brain Res. Bull.
Correlation between oxytocin neuronal sensitivity and oxytocin-binding sites in the amygdala of the rat: electrophysiological and histoautoradiographic study
Brain Res.
A possible role for oxytocin in the response to a psychological stressor
Pharmacol. Biochem. Behav.
Immunoneutralization of oxytocin attenuates stress-induced corticotropin secretion in the rat
Regul. Pept.
Oxytocin causes a sustained decrease in plasma levels of corticosterone in rats
Neurosci. Lett.
Central administration of oxytocin modulates the infant rat’s response to social isolation
Eur. J. Pharmacol.
Synaptic associations between oxytocin-containing magnocellular neurons and neurons containing corticotropin-releasing factor in the rat magnocellular paraventricular nucleus
Brain Res.
Limbic pathways and hypothalamic neurotransmitters mediating adrenocortical responses to neural stimuli
Neurosci. Biobehav. Rev.
Oxytocin excites neurones in the bed nucleus of the stria terminalis of the lactating rat in vitro
Brain Res.
A further analysis of physiological changes in rats in the forced swim test
Physiol. Behav.
The origin of the posterior pituitary hormones
Sci. Am.
Neurocrinie et synapses ‘neurosécrétoires’
Arch. Anat. Microsc. Morphol. Exp.
Intra- and extrahypothalamic vasopressin and oxytocin pathways in the rat. Pathways to the limbic system, medulla oblongata and spinal cord
Cell Tissue Res.
Morphology of vasopressin and oxytocin neurons and their central vascular projections
Prog. Brain Res.
Immuno-electron microscopical demonstration of vasopressin and oxytocin in the limbic system
Cell Tissue Res.
Septal and hippocampal release of vasopressin and oxytocin during late pregnancy and parturition in the rat
Neuroendocrinology
Release of oxytocin within the supraoptic nucleus during the milk ejection reflex in rats
Exp. Brain Res.
Septal and hippocampal release of oxytocin, but not vasopressin, in the conscious lactating rat during suckling
J. Neuroendocrinol.
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