Rainer Landgraf

Vasopressin and oxytocin release within the brain: a dynamic concept of multiple and variable modes of neuropeptide communication.

As exemplified particularly with vasopressin and oxytocin, release of neuropeptides within the brain occurs from dendrites, somata, and axons of neurosecretory neurons; mechanisms include activation of intracellular Ca2+ stores, changed strength of synaptic input and altered interaction between transcription factors and gene promoters. Upon demand, both diffuse spread of neuropeptides in the extracellular fluid following dendritic release and focal release from axonal terminals may contribute to regionally and temporally varying combinations of neuromodulator and neurotransmitter actions, thus providing a theoretically unlimited variability in interneuronal signaling. Thus, instead of favoring volume or synaptic transmission following central neuropeptide release, a more dynamic concept is presented with multiple and variable modes of release and communication. This concept considers neuropeptides in the extracellular fluid of the brain rather than those in the cerebrospinal fluid or plasma as primary signals, triggering a variety of receptor-mediated effects, including those underlying behavioral and neuroendocrine regulation and psychopathology.

Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors

Oxytocin and vasopressin are regulators of anxiety, stress-coping, and sociality. They are released within hypothalamic and limbic areas from dendrites, axons, and perikarya independently of, or coordinated with, secretion from neurohypophysial terminals. Central oxytocin exerts anxiolytic and antidepressive effects, whereas vasopressin tends to show anxiogenic and depressive actions. Evidence from pharmacological and genetic association studies confirms their involvement in individual variation of emotional traits extending to psychopathology. Based on their opposing effects on emotional behaviors, we propose that a balanced activity of both brain neuropeptide systems is important for appropriate emotional behaviors. Shifting the balance between the neuropeptide systems towards oxytocin, by positive social stimuli and/or psychopharmacotherapy, may help to improve emotional behaviors and reinstate mental health.

The hypothalamic-neurohypophysial system regulates the hypothalamic-pituitary-adrenal axis under stress: an old concept revisited.

Mammals respond to challenging situations with characteristic changes in their behaviour as well as in autonomic and neuroendocrine parameters aimed at reinstating their disturbed homeostasis. Among such so-called coping strategies, alterations of the hypothalamic-pituitary-adrenal (HPA) axis play a crucial role. Today it is generally accepted that parvocellular neurones of the hypothalamic paraventricular nucleus control the secretion of corticotropin and corticosterone by synthesising and releasing both the corticotropin-releasing hormone and vasopressin (AVP). Recent evidence supports and embellishes the old hypothesis that AVP and the structurally related neuropeptide, oxytocin, originating from the hypothalamic-neurohypophysial system (HNS) might directly affect HPA axis activity. This review presents data supporting the concept of HNS effects on HPA axis activity and outlines their possible impact on some aspects of behavioural regulation and psychopathology.

Attenuated neuroendocrine responses to emotional and physical stressors in pregnant rats involve adenohypophysial changes

1 The responsiveness of the rat hypothalamo‐pituitary‐adrenal (HPA) axis and hypothalamo‐neurohypophysial system (HNS) to emotional (elevated plus‐maze) and physical (forced swimming) stressors and to administration of synthetic corticotrophin‐releasing hormone (CRH) was investigated during pregnancy and lactation. In addition to pregnancy‐related adaptations at the adenohypophysial level, behavioural responses accompanying the neuroendocrine changes were studied. 2 Whereas basal (a.m.) plasma corticosterone, but not corticotrophin (adrenocorticotrophic hormone; ACTH), levels were increased on the last day (i.e. on day 22) of pregnancy, the stress‐induced rise in both plasma hormone concentrations was increasingly attenuated with the progression of pregnancy beginning on day 15 and reaching a minimum on day 21 compared with virgin control rats. A similar attenuation of responses to both emotional and physical stressors was found in lactating rats. 3 Although the basal plasma oxytocin concentration was elevated in late pregnancy, the stress‐induced rise in oxytocin secretion was slightly lower in day 21 pregnant rats. In contrast to vasopressin, oxytocin secretion was increased by forced swimming in virgin and early pregnant rats indicating a differential stress response of these neurohypophysial hormones. 4 The blunted HPA response to stressful stimuli is partly due to alterations at the level of corticotrophs in the adenohypophysis, as ACTH secretion in response to CRH in vivo (40 ng kg−1, i.v.) was reduced with the progression of pregnancy and during lactation. In vitro measurement of cAMP levels in pituitary segments demonstrated reduced basal levels of cAMP and a lower increase after CRH stimulation (10 nM, 10 min) in day 21 pregnant compared with virgin rats, further indicating reduced corticotroph responsiveness to CRH in pregnancy. 5 The reduced pituitary response to CRH in late pregnancy is likely to be a consequence of a reduction in CRH receptor binding as revealed by receptor autoradiography. [125I] CRH binding in the anterior pituitary was significantly reduced in day 11, 17 and 22 pregnant rats compared with virgin controls. 6 Anxiety‐related behaviour of the animals as revealed by the time on and entries into the open arms of the elevated plus‐maze was different between virgin and pregnant rats with decreased number of entries indicating increased anxiety with the progression of pregnancy (except on pregnancy day 18). The emotional behaviour, however, was not correlated with the neuroendocrine responses. 7 The results indicate that the reduced response of the HPA axis to stressors described previously during lactation is already manifested around day 15 of pregnancy in the rat and involves physiological adaptations at the adenohypophysial level. However, alterations in stressor perception at higher brain levels with the progression of pregnancy may also be involved.

Brain oxytocin inhibits basal and stress-induced activity of the hypothalamo-pituitary-adrenal axis in male and female rats: partial action within the paraventricular nucleus.

Oxytocin is a classic reproductive neuropeptide in the female mammal, but its functions in the brain of the male have been less well studied. As stress induces intracerebral oxytocin release independently of gender, we postulated that central oxytocin may play a role in the control of stress responses. In both male and virgin female rats, oxytocin receptor blockade in the brain by intracerebral infusion of a selective oxytocin antagonist (des Gly‐NH2 d(CH2)5 [Tyr(Me)2, Thr4] OVT; 0.75 μg/5 μl increased the activity of the hypothalamo‐pituitary‐adrenal (HPA) axis as indicated by a significantly enhanced basal and stress‐induced (exposure to the elevated plus‐maze, forced swimming) secretion of corticotropin (ACTH) and corticosterone into blood. The anxiety‐related behaviour on the plus‐maze was not altered by the antagonist in either males or females. Infusion of the oxytocin antagonist into the hypothalamic paraventricular nucleus by reversed microdialysis resulted in a significant increase in basal release of ACTH in both male and virgin female rats. These results demonstrate a novel, gender‐independent physiological function of endogenous brain oxytocin in the regulation of neuroendocrine stress responses. Under basal conditions, the inhibition of the HPA axis occurs, at least in part, within the paraventricular nucleus.

Oxytocin and vasopressin release within the supraoptic and paraventricular nuclei of pregnant, parturient and lactating rats: A microdialysis study

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.

Increased brain and plasma oxytocin after nasal and peripheral administration in rats and mice.

The possibility to improve socio-emotional behaviors in humans by intranasal administration of synthetic oxytocin (OXT) attracts increasing attention, but its uptake into the brain has never been demonstrated so far. Here we used simultaneous microdialysis in both the dorsal hippocampus and amygdala of rats and mice in combination with concomitant blood sampling from the jugular vein to study the dynamics of the neuropeptide in brain extracellular fluid and plasma after its nasal administration. OXT was found to be increased in microdialysates from both the hippocampus and amygdala with peak levels occurring 30-60min after nasal administration. Despite a similar temporal profile of OXT concentrations in plasma, peripheral OXT is unlikely to contribute to dialysate OXT as calculated from in vitro recovery data, indicating a central route of transport. Moreover, intraperitoneal administration of synthetic OXT in identical amounts caused rapid peak levels in brain dialysates and plasma during the first 30min after treatment and a subsequent return toward baseline. While the precise route(s) of central transport remain to be elucidated, our data provide the first evidence that nasally applied OXT indeed reaches behaviorally relevant brain areas, and this uptake is paralleled by changes in plasma OXT.

Intracellular calcium stores regulate activity-dependent neuropeptide release from dendrites

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 Ca2+ 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 Ca2+ 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.

Reduced anxiety, conditioned fear, and hippocampal long-term potentiation in transient receptor potential vanilloid type 1 receptor-deficient mice

The transient receptor potential vanilloid type 1 channel (TRPV1) (formerly called vanilloid receptor VR1) is known for its key role of functions in sensory nerves such as perception of inflammatory and thermal pain. Much less is known about the physiological significance of the TRPV1 expression in the brain. Here we demonstrate that TRPV1 knock-out mice (TRPV1-KO) show less anxiety-related behavior in the light–dark test and in the elevated plus maze than their wild-type littermates with no differences in locomotion. Furthermore, TRPV1-KO mice showed less freezing to a tone after auditory fear conditioning and stress sensitization. This reduction of conditioned and sensitized fear could not be explained by alterations in nociception. Also, tone perception per se was unaffected, as revealed by determination of auditory thresholds through auditory brainstem responses and distortion-product otoacoustic emissions. TRPV1-KO showed also less contextual fear if assessed 1 d or 1 month after strong conditioning protocols. These impairments in hippocampus-dependent learning were mirrored by a decrease in long-term potentiation in the Schaffer collateral–commissural pathway to CA1 hippocampal neurons. Our data provide first evidence for fear-promoting effects of TRPV1 with respect to both innate and conditioned fear and for a decisive role of this receptor in synaptic plasticity.

Behavioural profiles of two Wistar rat lines selectively bred for high or low anxiety-related behaviour

Over the past years, two breeding lines, derived originally from outbred Wistar rats, have been established that differ markedly and consistently in their anxiety-related behaviour in the elevated plus-maze. At the age of ten weeks, rats were tested once on the elevated plus-maze and the males and females displaying the most anxious and the least anxious behaviour were sib-mated to start a new generation of the high anxiety-related behaviour (HAB) and the low anxiety-related behaviour (LAB) lines, respectively. The resulting difference in emotionality between these two lines was also evident in an open field test and correlated with differences in the forced swim test. In the open field, the HAB rats tended to be less active and explored the central zone of the open field much less than the LAB animals. In the forced swim test, HAB rats started floating earlier, spent significantly more time in this immobile posture and struggled less than LAB rats. However, in an olfactory-cued social discrimination task there was no difference between male and female animals from either line. The overall performance in these various behavioural tests suggests that selective breeding has resulted in rat lines not only differing markedly in their innate anxiety-related behaviour in the plus-maze, but also in other stress-related behavioural performances, suggesting a close link between the emotional evaluation of a novel and stressful situation and an individuals coping strategy.