Hypocretin (orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system.

Hypocretin has been identified as a regulator of metabolic and endocrine systems. Several brain regions involved in the central regulation of autonomic and endocrine processes or attention are targets of extensive hypocretin projections. The most dense arborization of hypocretin axons in the brainstem was detected in the locus coeruleus (LC). Multiple labeling immunocytochemistry revealed a massive synaptic innervation of catecholaminergic LC cells by hypocretin axon terminals in rats and monkeys. In both species, all tyrosine hydroxylase-immunopositive cells in the LC examined by electron microscopy were found to receive asymmetrical (excitatory) synaptic contacts from multiple axons containing hypocretin. In parallel electrophysiological studies with slices of rat brain, all LC cells showed excitatory responses to the hypocretin-2 peptide. Hypocretin-2 uniformly increased the frequency of action potentials in these cells, even in the presence of tetrodotoxin, indicating that receptors responding to hypocretin were expressed in LC neurons. Two mechanisms for the increased firing rate appeared to be a reduction in the slow component of the afterhyperpolarization (AHP) and a modest depolarization. Catecholamine systems in other parts of the brain, including those found in the medulla, zona incerta, substantia nigra or olfactory bulb, received significantly less hypocretin input. Comparative analysis of lateral hypothalamic input to the LC revealed that hypocretin-containing axon terminals were substantially more abundant than those containing melanin-concentrating hormone. The present results provide evidence for direct action of hypothalamic hypocretin cells on the LC noradrenergic system in rats and monkeys. Our observations suggest a signaling pathway via which signals acting on the lateral hypothalamus may influence the activity of the LC and thereby a variety of CNSfunctions related to noradrenergic innervation, including vigilance, attention, learning, and memory. Thus, the hypocretin innervation of the LC may serve to focus cognitive processes to compliment hypocretin-mediated activation of autonomic centers already described.

Social recognition in male rats: age differences and modulation by MIF-I and Alaptide.

Social investigatory behaviour was used as a measure of olfactory recognition in two experiments to assess social memory in adult male rats. In Experiment 1, time spent in social investigation of juvenile males by 3-month-old adults was significantly higher than time spent by 7- and 11-month-old animals. Furthermore, a reexposure to the same juvenile male 30 min after the initial exposure elicited significantly less social investigation in adult males aged 7 and 11 months but not in those aged 3 months. If the reexposure occurs 2 h later, the same juvenile is thoroughly investigated by adult males irrespective of the age. The age-related differences in social recognition are discussed in terms of the internal readiness of adult males. While the social recognition was confirmed in older adult males, it is suggested that an ability to recognize the same juvenile may be masked in young animals by a high sexual arousal. Behavioural phenomenon of the social recognition was used in Experiment 2. An administration of hypothalamic MIF-I or its synthetic derivative Alaptide to adult males 7 or 11 months old immediately after their 1st exposure to a juvenile male resulted in decreasing the time spent in social investigation of the same juvenile during a reexposure performed 120 min later. Both drugs were ineffective if adult males were reexposed to a novel juvenile. The results suggest that both MIF-I and Alaptide improved an animal's capacity to store information received through olfactory cues.

Existence of antiopiate systems as illustrated by MIF-1/Tyr-MIF-1.

Evidence is presented that the small peptides MIF-1/Tyr-MIF-1 are part of an endogenous antiopiate system that may function to balance the opiate system. We review the biological activity, behavioral activity, and functional effects of this proposed opiate antagonist system. In addition, we suggest, based on antinociceptive mechanisms, that the individual components of the antiopiate system might function differently from naloxone.

Possible aminergic mediation of MSH release and of the CNS effects of MSH and MIF-I.

It is well known that the release of melanocyte-stimulating hormone (MSH) from the pituitary gland is mainly controlled by an inhibitory influence from the hypothalamus. In addition to this inhibitory control, there may also be a stimulatory influence. Most, but by no means all, of the evidence is compatible with the possibility that inhibition is mediated by dopaminergic and/or alpha-adrenergic receptors. Gamma-aminobutyric acid also has been shown to have an inhibitory role in some studies. beta-Adrenergic receptors, serotonin, and acetylcholine may be involved in the stimulation of MSH release. Interaction of hypothalamic peptides like Pro-Leu-Gly-NH2(MIF-I) with biogenic amines, however, has not been excluded as a factor in the control of the release of MSH from the pituitary. Just as the evidence for the involvement of amines in the control of MSH release is somewhat puzzling and contradictory, conflicting evidence concerning their involvement in mediating the specific effects of MSH and MIF-I on the CNS remains unresolved.

The behavioural actions of the hypothalamic peptides: a review.

Recent work has shown that the hypothalamic peptides commonly associated with the control of pituitary function have important behavioural actions of possible psychiatric significance. Thus, vasopressin, ACTH and like peptides may influence memory processes, and ACTH and MSH given intracranially induce a peculiar stretching and yawning syndrome accompanied by penile erection and ejaculation. Thyrotrophic hormone-releasing factor potentiates behavioural excitation, somatostatin is depressive, while luteinizing hormone-releasing hormone facilitates sexual behaviour and the newly identified endorphins are markedly opioid in character. These and other activities of the hypothalamic peptides are reviewed and assessed alongside the clinical information available.