Body temperature: possible ionic mechanism in the hypothalamus controlling the set point.

The body temperature of many mammals is set at or around 37 degrees C. The mechanism for this set point appears to depend on a constant and inherent balance between sodium and calcium ions within the posterior hypothalamus. When this region is perfused in unanesthetized cats, an extracellular excess or a normal physiological concentration of sodium ions evokes a rise in body temperature if calcium is not in the perfusate. At the same site, an excess or normal concentration of calcium ions causes the temperature to fall when sodium is absent.

Alcohol preference in the rat: reduction following depletion of brain serotonin.

Preference for ethyl alcohol was significantly reduced or totally abolished in rats given orally p-chlorophenylalanine, a tryptophan hydroxylase inhibitor that selectively depletes brain serotonin. Some aversion to alcohol was observed while p-chlorophenylalanine was administered, but the rats' rejection of alcohol was even more marked after the drug was discontinued. Oral administration of alpha-methyl-p-tyrosine, a tyrosine hydroxylase inhibitor that depletes brain catecholamines, slightly reduced selection of alcohol, but preference returned to normal as soon as alpha-methyl-p-tyrosine was terminated.

Vasopressin: a homeostatic effector in the febrile process.

This review compares the physiological changes which accompany infection and fever with the effects of the peptide, arginine vasopressin (AVP). AVP may act as a neuromodulator, a releasing factor, or a hormone to induce responses which are opposite to those homeostatic changes accompanying fever. Since AVP is released into blood and brain during fever, it is hypothesized that AVP contributes to the maintenance of homeostasis in the infected organism.

Thermoregulatory actions of centrally-administered vasopressin in the rat.

Dependent upon the route and/or site of administration, arginine vasopressin (AVP) evoked a number of thermoregulatory actions in the conscious rat. Infused into a lateral cerebral ventricle, arginine vasopressin produced short-lasting hypothermia of rapid onset. Injected into the preoptic area, arginine vasopressin caused long-lasting hyperthermia of rapid onset that was antagonized by the prior administration of a V1 receptor antagonist, [d(CH2)5 Tyr(Me)AVP]. Injections of arginine vasopressin into the nucleus accumbens, ventral septal area, substantia innominata and the dorsomedial hypothalamus were without effect on body temperature. Although the antipyretic action of arginine vasopressin within the ventral septal area has been well documented, these findings provide further evidence that this peptide exerts additional thermoregulatory actions that are both neuroanatomically and functionally specific.

The ventral septal area: electrophysiological evidence for putative arginine vasopressin projections onto thermoresponsive neurons.

The present experiments were conducted to identify thermoresponsive neurons in the ventral septal area and to characterize such units with respect to their connectivity to potential sources of arginine vasopressin in this area (the paraventricular nucleus and the bed nucleus of the stria terminalis) and to other brain regions (fornix and amygdala). Single unit in vivo microelectrode techniques were used to classify warm responsive, cold responsive, dynamic, biphasic and phasically active thermoresponsive neurons in the ventral septal area which altered their spontaneous activity in response to thermal stimulation of the scrotal skin. The fornix provided a large number of primarily inhibitory afferents to ventral septal thermoresponsive neurons while the amygdala projection consisted of approximately equal excitatory and inhibitory inputs. Electrical stimulation of the paraventricular nucleus resulted in orthodromic inhibition in 9 of 12 thermoresponsive units while projections from the bed nucleus of the stria terminalis appeared to preferentially inhibit warm responsive neurons in this area. These findings implicate the ventral septal area in thermoregulatory pathways by identifying neurons in this area responsive to peripheral thermal stimulation. Further, evidence in support of arginine vasopressin acting in this area to influence thermoregulation is provided by the identification of the paraventricular nucleus and bed nucleus of the stria terminalis as possible sources of afferents to the ventral septal area, and the characterization of the influence of this afferent input on thermoresponsive neurons in this region.

Characteristics of pyrogen fevers are altered in the aged rabbit.

The febrile response to both intravenous and intracerebral administration of pyrogens was investigated in young and old male New Zealand White rabbits. Intravenous bacterial pyrogen evoked biphasic fevers in both groups of animals. However, the fevers in the group of older rabbits were significantly less than in younger animals. In contrast, intravenous injection of endogenous pyrogen produced identical fevers in the two groups. Bacterial and endogenous pyrogens injected into a lateral cerebral ventricle evoked marked febrile responses of long duration in both young and old rabbits. The responses of the old rabbits were significantly less than those of the younger ones. Finally, direct microinjection of prostaglandin E1 into tissue sites within the anterior hypothalamic preoptic area elicited short latency hyperthermic responses which were significantly less in the older rabbits. Analysis of ear skin temperatures during fever demonstrated that some of the differences may, in part, be due to altered vasoconstrictor responses in the peripheral vasculature. Thus, these data indicate that the febrile response is altered with increasing age in the rabbit.

Prostaglandin fever in rats throughout the estrous cycle late pregnancy and post parturition.

We have examined the influence of natural variations in endocrine status on the ability to generate a prostaglandin-induced fever in virgin female, pregnant and lactating rats and compared responses to those in male rats. Endocrine status of virgin female rats was assessed from examination of vaginal smears and time of parturition noted to enable accurate dating of pre- and postparturient fevers. Unanesthetized rats, previously prepared with intraventricular guide cannulas and intraperitoneal telemetry thermistors, were given intraventricular injections of prostaglandin E1 (2-100 ng/5 microliters) and temperatures monitored for 3 h after injection. Virgin females developed significantly larger fevers than did males at higher doses. There were no significant alterations in either fever height or duration as a function of the phase of the reproductive cycle in the females. Both pregnant and postparturient rats within the several days around birth displayed significantly lower fevers than did virgin females, but there was no further reduction in the immediate periparturient period. These data indicate that there are sex-, and possibly hormone-dependent differences in the central mechanisms involved in fever generation and antipyresis.

Peripheral blood flow during rewarming from mild hypothermia in humans.

During the initial stages of rewarming from hypothermia, there is a continued cooling of the core, or after-drop in temperature, that has been attributed to the return of cold blood due to peripheral vasodilatation, thus causing a further decrease of deep body temperature. To examine this possibility more carefully, subjects were immersed in cold water (17 degrees C), and then rewarmed from a mildly hypothermic state in a warm bath (40 degrees C). Measurements of hand blood flow were made by calorimetry and of forearm, calf, and foot blood flows by straingauge venous occlusion plethysmography at rest (Ta = 22 degrees C) and during rewarming. There was a small increase in skin blood flow during the falling phase of core temperature upon rewarming in the warm bath, but none in foot blood flow upon rewarming at room air, suggesting that skin blood flow seems to contribute to the after-drop, but only minimally. Limb blood flow changes during this phase suggest that a small muscle blood flow could also have contributed to the after-drop. It was concluded that the after-drop of core temperature during rewarming from mild hypothermia does not result from a large vasodilatation in the superficial parts of the periphery, as postulated. The possible contribution of mechanisms of heat conduction, heat convection, and cessation of shivering thermogenesis were discussed.

Central neurohypophyseal peptide pathways: interactions with endocrine and other autonomic functions.

Electrophysiological and pharmacological studies have been carried out in rats and rabbits to attempt to identify possible functional roles for neurohypophyseal peptides in brain. In anesthetized rats, single unit recordings and antidromic activation criteria were utilized to identify projections of the paraventricular nucleus (PVN) to neurohypophysis and to extrahypothalamic areas (amygdala or nucleus tractus solitarius). None of the cells tested innervated more than one of these areas and, when tested for their responses to haemorrhage, increased body osmolarity, or suckling of pups, only the osmotic stimulus caused increased activity in some cells projecting to amygdala or nucleus tractus solitarius. Indirect evidence as well as direct measurement by radioimmunoassay of arginine vasopressin (AVP) in brain perfusates revealed probable central release of AVP in response to stimuli known to activate pituitary secretion of this peptide. These observations raise the possibility that certain brain and pituitary peptidergic systems may function in a co-ordinated manner.

Perfusion of the septum of the rabbit with vasopressin antiserum enhances endotoxin fever.

The septal region of the brains of conscious, adult, male New Zealand White rabbits were perfused by means of a push-pull system before and after an intravenous administration of bacterial pyrogen extracted from Salmonella abortus equi. Perfusion of the septal area with sucrose solution (260 mM) had no significant effect on the resulting fever (1.13 +/- 0.09 degrees C) when compared to a control fever without the push-pull perfusion (1.06 +/- 0.12 degrees C). Arginine vasopressin (AVP) added to the perfusing solution (20 micrograms/ml) caused a significant attenuation of the fever (0.81 +/- 0.20 degrees C). An antiserum specific to AVP when added to the perfusing solution resulted in a fever which was significantly greater (2.38 +/- 0.13 degrees C) than the control. Radioimmunoassay of perfusates collected from the control perfusions before and during fever showed that, as the body temperature rose in response to the pyrogen, the level of AVP in the perfusate collected from the septal area decreased. These results provide further evidence that AVP may act in the septal area of the brain to modulate the febrile response.

Spinal and peripheral modulation of gastric acid secretion and arterial pressure by neuropeptide Y, peptide YY, and pancreatic polypeptide in rats.

Spinal and peripheral modulation of pentagastrin-stimulated gastric acid secretion by the pancreatic polypeptide-fold (PP-fold) peptides, neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP), in urethane-anesthetized rats was evaluated. Neuropeptide Y, PYY, and PP (400 pmol) were administered via intravenous (IV) and intrathecal (IT) injections. The alpha 2 antagonist, yohimbine, was used to evaluate the role of the alpha 2 adrenergic receptors in the modulation of pentagastrin-stimulated gastric acid secretion by NPY, PYY, and PP. Peptide YY and PP (IV) rapidly increased pentagastrin-stimulated gastric acid secretion. Peptide YY and PP (IT) increased pentagastrin-stimulated gastric acid secretion following administration into the thoracic (T8-T10) region of the spinal cord. The alpha 2 adrenergic receptor antagonist, yohimbine, did not modify the increases in pentagastrin-stimulated gastric acid secretion following PYY and PP (IV or IT) administration. Neuropeptide Y (IT) decreased pentagastrin-stimulated gastric acid secretion. However, in the presence of alpha 2 adrenergic receptor blockade, pentagastrin-stimulated gastric acid secretion was potentiated by NPY (IT) administration. Therefore, the inhibitory effect of NPY (IT) on pentagastrin-stimulated gastric acid secretion required the activation of alpha 2 adrenergic receptors in the spinal cord of rats. Mean arterial blood pressure (MAP) was increased immediately following NPY and PYY (IV) administration. During the same time period, PP (IV) decreased MAP in anesthetized rats. Mean arterial blood pressure was rapidly increased by NPY and PYY (IT) in anesthetized rats. The increase in MAP following PYY (IT) was partially attenuated in the presence of yohimbine.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuropeptide Y, peptide YY, and pancreatic polypeptide modulate duodenal and colonic motility at a thoracic spinal site in rats.

Neuropeptide Y, PYY, and PP (200 pmol) alter intraluminal pressure in the duodenum and colon of rats following their administration into the thoracic (T8-T10) region of the spinal cord. Neuropeptide Y decreases the tone of the duodenum and the colon following intrathecal (T8-T10) administration prior to an increase in tone to baseline or greater. There is no effect on intraluminal pressure of either the duodenum or the colon following intrathecal administration of NPY or PP into the lumbar (L4-L5) region of the spinal cord. Following intrathecal (T8-T10) administration of PYY and PP, increases in intraduodenal pressures are observed (+2.1 and +3.0 mmHg from saline baseline). Phasic contractions of the duodenum are increased following intrathecal administration of PYY into the thoracic spinal cord of rats. Neuropeptide Y, PYY, and PP increase intracolonic pressure +2.2, +3.3, and +3.7 mmHg from saline baseline, respectively. Phasic contractions of the colon are increased following PP intrathecal thoracic administration. Responsiveness of the duodenum or colon to the different ligands of the PP-fold peptide family in the absence of alpha-adrenergic blockade did not vary. The increases in intraluminal pressure of the duodenum and colon following intrathecal administration of the PP-fold peptides are attenuated by both alpha-1 adrenergic (prazosin) and alpha-2 adrenergic (yohimbine) blockade. There is a difference in responsiveness of the colon between the ligands of the PP-fold family in the presence of the alpha-2 adrenergic blockade. The findings of this study indicate that duodenal and colonic motility are modulated by the PP-fold peptides at thoracic spinal sites via alteration of sympathetic outflow.

The role of arginine vasopressin in alcohol dependence and withdrawal.

The development and maintenance of tolerance to the physiological and behavioral effects of repeated exposure to ethanol can be altered markedly by the presence of arginine vasopressin (AVP). In addition, AVP has been implicated in the etiology of convulsions, including those induced by exposure to high ambient temperatures. In light of these findings, experiments were conducted to determine the role, if any, that AVP might play in the pathogenesis of alcohol-withdrawal convulsions. Thirty-two male Long Evans (LE) rats and 32 age-matched male homozygous Brattleboro (DI) rats (genetically deficient in AVP) were exposed to ethanol vapor concentrations adjusted to maintain blood alcohol levels of each rat at 150-350 mg/dl. Following at least 5 days of ethanol exposure, the animals were withdrawn. From 3-24 hr after cessation of ethanol administration, withdrawal severity was assessed by observing the response of each animal to a 60-120 sec period of auditory stimulation. No significant differences were observed in either latency to onset or severity of the convulsions in LE and DI rats upon ethanol withdrawal. Thus, alcohol-withdrawal convulsions, unlike hyperthermia-induced convulsions, may be mediated by a neurochemical substrate other than AVP.

The peripheral modulation of duodenal and colonic motility in rats by the pancreatic polypeptide-fold family: neuropeptide Y, peptide YY, and pancreatic polypeptide.

Neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) altered intraluminal pressure in the duodenum and colon of fasted anesthetized rats following intravenous bolus administration. There were rapid increases in intraluminal pressure of the duodenum and colon of anesthetized rats following peripheral injections of NPY, PYY and PP. Administration (IV) of NPY, PYY, and PP increased intraduodenal pressure +1.8, +3.2, and +3.7 mmHg compared to saline baseline. Prazosin, an alpha-2 adrenergic antagonist, did not alter the response of the duodenum of urethane-anesthesized rats to any of the PP-fold peptides following peripheral administration. Yohimbine, an alpha 2-adrenergic antagonist, attenuated the excitatory response of rat duodenum following NPY (IV) but did not alter the duodenal response to PP (IV). Intravenous NPY, PYY, and PP increased intracolonic pressure +2.0, +3.3, and +6.2 mmHg compared to saline baseline. In the presence of prazosin, an alpha 1-adrenergic antagonist, the intraluminal pressure of the colon increased +2.6, +2.4, and +8.1 mmHg compared to saline baseline by NPY, PYY, and PP (IV), respectively. In the presence of alpha 2-adrenergic blockade by yohimbine, NPY, PYY, and PP (IV) increased intraluminal pressure of the colon +4.2, +2.9, and +2.5 mmHg compared to saline baseline. The response of the duodenum to the excitatory effect of PYY (IV) was enhanced in the presence of yohimbine. Duodenal and colonic tone were modulated by the PP-fold peptides following peripheral administration. The alpha-adrenergic nervous system played only a minor role in the modulation of GI motility by the PP-fold peptides at peripheral sites.

Modulation of brown adipose tissue-mediated thermogenesis by lesions to the nucleus tractus solitarius in the rat.

Given that relatively little is known regarding the central control of brown adipose tissue (BAT)-mediated thermogenesis the present study assessed whether the direct pharmacological stimulation of beta- or alpha-adrenergic receptors located on the brown adipocytes would result in a typical thermogenic response following electrolytic lesions to the nucleus tractus solitarius (NTS). Bilateral electrolytic lesions to the NTS in the rat effectively disrupted the baroreceptor reflex arc. It was observed that the metabolic and temperature responses to either norepinephrine (1, 5, or 25 micrograms/kg/min) or to the beta-agonist isoproterenol (0.5 micrograms/kg/min) were significantly attenuated in the NTS-lesioned rats relative to the control animals with an intact baroreflex. Conversely, the cardiovascular effects of norepinephrine or of the alpha-agonist phenylephrine (10 micrograms/kg/min) were enhanced in the NTS-lesioned animals. The results suggest that the functional capacity of the brown adipocytes was reduced following NTS lesions and points to an alteration in the ability of beta-receptors to respond to pharmacological stimulation with a typical thermogenic response.

Altered sensitivity to arginine vasopressin (AVP) in area CA1 of the hippocampal slice following pretreatment of rats with AVP.

Extracellular recordings from cells in the CA1b region of the in vitro hippocampal slice preparation demonstrate that bath-applied AVP (10(-6)-10(-12) M) frequently results in a decrease in the orthodromically evoked population spike amplitude. This suggests that AVP inhibits CA1 pyramidal cell firing in response to an orthodromic volley. This effect appears to be receptor-mediated, since a potent antagonist of the AVP V1 (vasopressor) receptor and a mixed oxytocin/vasopressin antagonist prevented the decrease in population spike amplitude observed in response to bath application of AVP. Hippocampal slices prepared from rats injected two days earlier with 1.0 micrograms AVP (intracerebroventricular) display increased sensitivity to the depressant effects of AVP at lower doses compared to controls. These results suggest that pretreatment of rats with AVP may alter the sensitivity of hippocampal cells to the depressant effects of this neuropeptide.

Injection of neuropeptide Y into the paraventricular nucleus of the hypothalamus inhibits gastric acid secretion in the rat.

Neuropeptide Y (NPY) was injected into the paraventricular nucleus (PVN) of the hypothalamus of anesthetized rats in order to assess its effect on gastric acid secretion. NPY evoked a dose-dependent decrease of interdigestive gastric acid output when injected directly into the PVN or immediately ventral to it. Intracerebroventricular NPY and saline injections did not alter acid output. Injection of NPY into adjacent non-PVN hypothalamic areas resulted in either an elevated acid output or had no effect depending on the site of injection. Mean arterial blood pressure and heart rate were not consistently affected by NPY. These results show that injection of NPY into the PVN of anesthetized rats inhibits interdigestive gastric acid output in a dose-dependent manner.

Prevention of arginine-vasopressin-induced motor disturbances by a potent vasopressor antagonist.

The antivasopressor analog d(CH2)5Tyr(Me) arginine-vasopressin completely blocked the convulsive-like behavior and other severe motor disturbances which are normally observed following a second central arginine-vasopressin injection. This vasopressor antagonist appears to be selective for arginine-vasopressin-induced motor disturbances, in that the convulsive and motor effects of pentylenetetrazol and somatostatin were not altered significantly by pretreatment with the central antagonist. Results suggest that arginine-vasopressin-induced motor disturbances are mediated via central receptors. The classic antidiuretic (V2) type of arginine-vasopressin receptor does not appear to be involved, since the agonist 1-desamino-8-D-arginine-vasopressin did not elicit convulsive-like behavior or other severe motor disturbances 2 days following a first ('priming') injection of arginine-vasopressin.

Perfusion of vasopressin within the rat brain suppresses prostaglandin E-hyperthermia.

These experiments were undertaken to determine whether arginine vasopressin (AVP) could suppress a prostaglandin hyperthermia and to localize sites of these actions in the rat. Prostaglandin E2 (PGE2) sensitive sites were localized in the ventral-septal area by microinjecting 200 ng/0.5 microliter of prostaglandin E2. During perfusion with an artificial CSF, PGE2 injected into the lateral cerebral ventricle evoked a hyperthermia of more than 1 degree C. Perfusion of 6.5 micrograms/ml of AVP markedly attenuated the PGE2-induced hyperthermia. These results suggest that AVP suppresses PGE2-induced hyperthermia in sites in which PGE2 evokes an increase in core temperature.

Electrophysiological analysis of potential arginine vasopressin projections to the ventral septal area of the rat.

Extracellular electrophysiological studies of neurons in the ventral septal region of the rat have examined afferent input from the paraventricular nucleus, bed nucleus of the stria terminalis and suprachiasmatic nucleus. Short latency excitatory or inhibitory orthodromic potentials were obtained following electrical stimulation of each nucleus, thereby providing evidence for these areas as a possible source of arginine vasopressin (AVP) fibers to the ventral septal region. These projections may mediate the reported antipyretic action of arginine vasopressin in the ventral septal region.