Excitatory action of vasopressin in the brain of the rat: role of cAMP signaling.

Brain vasopressin plays a role in behavioral and cognitive functions and in pathological conditions. Relevant examples are pair bonding, social recognition, fear responses, stress disorders, anxiety and depression. At the neuronal level, vasopressin exerts its effects by binding to V1a receptors. In the brainstem, vasopressin can excite facial motoneurons by generating a sustained inward current which is sodium-dependent, tetrodotoxin-insensitive and voltage-gated. This effect is independent of intracellular calcium mobilization and is unaffected by phospholipase Cß (PLCß) or protein kinase C (PKC) inhibitors. There are two major unsolved problems. (i) What is the intracellular signaling pathway activated by vasopressin? (ii) What is the exact nature of the vasopressin-sensitive cation channels? We performed recordings in brainstem slices. Facial motoneurons were voltage-clamped in the whole-cell configuration. We show that a major fraction, if not the totality, of the peptide effect was mediated by cAMP signaling and that the vasopressin-sensitive cation channels were directly gated by cAMP. These channels appear to exclude lithium, are suppressed by 2-aminoethoxydiphenylborane (2-APB) and flufenamic acid (FFA) but not by ruthenium red or amiloride. They are distinct from transient receptor channels and from cyclic nucleotide-regulated channels involved in visual and olfactory transduction. They present striking similarities with cation channels present in a variety of molluscan neurons. To our knowledge, the presence in mammalian neurons of channels having these properties has not been previously reported. Our data should contribute to a better knowledge of the neural mechanism of the central actions of vasopressin, and may be potentially significant in view of clinical applications.

Oxytocin and vasopressin enhance synaptic transmission in the hypoglossal motor nucleus of young rats by acting on distinct receptor types.

Hypoglossal (XII) motoneurons innervate extrinsic and intrinsic muscles of the tongue and control behaviors such as suckling, swallowing, breathing or chewing. In young rats, XII motoneurons express V1a vasopressin and oxytocin receptors. Previous studies have shown that activation of these receptors induces direct powerful excitation in XII motoneurons. In addition, by activating V1a receptors vasopressin can also enhance inhibitory synaptic transmission in the XII nucleus. In the present work, we have further characterized the effect of these neuropeptides on synaptic transmission in the XII nucleus. We have used brainstem slices of young rats and whole-cell patch clamp recordings. Oxytocin enhanced the frequency of spontaneous inhibitory postsynaptic currents by a factor of two and a half. GABAergic and glycinergic events were both affected. The oxytocin effect was mediated by uterine-type oxytocin receptors. Vasopressin and oxytocin also increased the frequency of excitatory synaptic currents, the enhancement being sixfold for the former and twofold for the latter compound. These effects were mediated by V1a and oxytocin receptors, respectively. Miniature synaptic events were unaffected by either vasopressin or oxytocin. This indicates that the peptide-dependent facilitation of synaptic currents was mediated by receptors located on the somatodendritic membrane of interneurons or premotor neurons, and not by receptors sited on axon terminals contacting XII motoneurons. Accordingly, recordings obtained from non-motoneurons located near the border of the XII nucleus showed that part of these cells possess functional V1a and oxytocin receptors whose activation leads to excitation. Some of these neurons could be antidromically activated following electrical stimulation of the XII nucleus, suggesting that they may act as premotor neurons. We propose that in young rats, oxytocin and vasopressin may function as neuromodulators in brainstem motor circuits responsible of tongue movements.

Action of tachykinins in the hippocampus: facilitation of inhibitory drive to GABAergic interneurons.

By acting on neurokinin 1 (NK1) receptors, neuropeptides of the tachykinin family can powerfully excite rat hippocampal GABAergic interneurons located in the CA1 region and by this way indirectly inhibit CA1 pyramidal neurons. In addition to contact pyramidal neurons, however, GABAergic hippocampal interneurons can also innervate other interneurons. We thus asked whether activation of tachykinin-sensitive interneurons could indirectly inhibit other interneurons. The study was performed in hippocampal slices of young adult rats. Synaptic events were recorded using the whole-cell patch clamp technique. We found that substance P enhanced GABAergic inhibitory postsynaptic currents in a majority of the interneurons tested. Miniature, action potential-independent inhibitory postsynaptic currents were unaffected by substance P, as were evoked inhibitory synaptic currents. This suggests that the peptide acted at the somatodendritic membrane of interneurons, rather than at their axon terminals. The effect of substance P was mimicked by a selective NK1 receptor agonist, but not by neurokinin 2 (NK2) or neurokinin 3 (NK3) receptor agonists, and was suppressed by a NK1 selective receptor antagonist. In contrast to substance P, oxytocin, another peptide capable of activating hippocampal interneurons, had no effect on the inhibitory synaptic drive onto interneurons. We conclude that tachykinins, by acting on NK1 receptors, can influence the hippocampal activity by indirectly inhibiting both pyramidal neurons and GABAergic interneurons. Depending on the precise balance between these effects, tachykinins may either activate or depress hippocampal network activity.

Abnormal inspiratory depth in Phox2a haploinsufficient mice.

Mutations of genes encoding Phox2a or Phox2b transcription factors induce modifications of different brainstem neuronal networks. Such modifications are associated with defects in breathing behavior at birth. In particular, an abnormal breathing frequency is observed in Phox2a-/- mutant mice, resulting from abnormal development of the locus coeruleus (LC) nucleus. However, the role of Phox2a proteins in the establishment of respiratory neuronal pathways is unknown, largely because mutants die shortly after birth. In the present study, we examined the effects of a haploinsufficiency of the Phox2a gene. Phox2a heterozygotes survive and exhibit a significantly larger inspiratory volume both during normoxic breathing and in response to hypoxia and a delayed maturation of inspiratory duration compared to wild-type animals. This phenotype accompanied by an unaltered frequency is evident at birth and persists until at least postnatal day 10. Morphological analyses of Phox2a+/- animals revealed no anomaly in the LC region, but highlighted an increase in the number of cells expressing tyrosine hydroxylase enzyme, a marker of chemoafferent neurons, in the petrosal sensory ganglion. These data indicate that Phox2a plays a critical role in the ontogeny of the reflex control of inspiration.

The Shrugged-Off Shoulder: A Comparison of Patients With Recurrent Shoulder Subluxations and Dislocations.

In brief: Patients with recurrent anterior shoulder subluxations and dislocations are compared in terms of recurrences, delays in diagnoses, and treatments. Based on these criteria, the subluxers experienced substantially more disability than the dislocators. Since shoulder instability is such a frequent problem in athletes (sports caused the initial episode in nearly 70% of the patients), professionals who deal with athletic injuries must be aware of the shoulder subluxation syndrome, recognize It early, and quickly initiate appropriate treatments.