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PubMed2006

Corticotropin releasing factor increases in brown adipose tissue thermogenesis and heart rate through dorsomedial hypothalamus and medullary raphe pallidus.

Corticotropin releasing factor, acting at hypothalamic corticotropin releasing factor receptors, contributes to the neural signaling pathways mediating stress-related responses, as well as those involved in maintaining energy balance homeostasis. Sympathetically-regulated lipid metabolism and heat production in brown adipose tissue contributes to the non-shivering thermogenic component of stress-evoked hyperthermia and to energy expenditure aspects of body weight regulation. To identify potential central pathways through which hypothalamic corticotropin releasing factor influences brown adipose tissue thermogenesis, corticotropin releasing factor was microinjected into the lateral ventricle (i.c.v.) or into hypothalamic sites while recording sympathetic outflow to brown adipose tissue, brown adipose tissue temperature, expired CO2, heart rate and arterial pressure in urethane/chloralose-anesthetized, artificially-ventilated rats. I.c.v. corticotropin releasing factor or corticotropin releasing factor microinjection into the preoptic area or the dorsomedial hypothalamus, but not the paraventricular nucleus of the hypothalamus, elicited sustained increases in brown adipose tissue sympathetic nerve activity, brown adipose tissue temperature, expired CO2 and heart rate. These sympathetic responses to i.c.v. corticotropin releasing factor were eliminated by inhibition of neuronal activity in the dorsomedial hypothalamus or in the raphe pallidus, a putative site of sympathetic premotor neurons for brown adipose tissue, and were markedly reduced by microinjection of ionotropic glutamate receptor antagonists into the dorsomedial hypothalamus. The increases in brown adipose tissue sympathetic outflow, brown adipose tissue temperature and heart rate elicited from corticotropin releasing factor into the preoptic area were reversed by inhibition of neuronal discharge in dorsomedial hypothalamus. These data indicate that corticotropin releasing factor release within the preoptic area activates a sympathoexcitatory pathway to brown adipose tissue and to the heart, perhaps similar to that activated by increased prostaglandin production in the preoptic area, that includes neurons in the dorsomedial hypothalamus and in the raphe pallidus.

Action Potentials↗
PubMed1997

Serotonin 5-HT1A and 5-HT2/1C receptors in the midbrain periaqueductal gray differentially modulate defensive rage behavior elicited from the medial hypothalamus of the cat.

Recent studies have established that the expression of defensive rage behavior in the cat is mediated over a descending pathway from the medial hypothalamus to the dorsolateral quadrant of the midbrain periaqueductal gray matter (PAG). The present study was designed to determine the roles played by 5-HT1A and 5-HT2/1C receptors in this region of PAG in modulating defensive rage behavior elicited from the cat's medial hypothalamus. Monopolar stimulating electrodes were implanted into the medial hypothalamus from which defensive rage behavior could be elicited by electrical stimulation. During the course of the study, the 'hissing' component of the defensive rage response was used as a measure of defensive rage behavior. Cannula-electrodes were implanted into sites within the PAG from which defensive rage could also be elicited by electrical stimulation in order that 5-HT compounds could be microinjected into behaviorally identifiable regions of the PAG at a later time. Microinjections of the selective 5-HT1A agonist, (+)-8-hydroxy-dipropylaminotetralin hydrobromide (8-OHDPAT) (50 pmol, 2.0 and 3.0 nmol), into the PAG suppressed the hissing response in a dose-dependent manner. Administration of the selective 5-HT1A antagonist, 4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl] ethyl]-N-2-pyridinyl-benzamide hydrochloride (p-MPPI) (1.5 and 3.0 nmol), blocked the suppressive effects of 8-OHDPAT upon hissing. In contrast, microinjections of the 5-HT2/1C receptor agonist (+)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride ((+)-DOI hydrochloride) (0.01, 1.0 and 1.5 nmol) facilitated the occurrence of hissing elicited from the medial hypothalamus in a dose-dependent manner. Immunohistochemical analysis revealed the presence of 5-HT axons and preterminals throughout the PAG, and in particular, in its dorsolateral aspect which receives major inputs from the medial hypothalamus in association with defensive rage behavior. The overall findings of the study provide evidence that activation of 5-HT1A and 5-HT2/1C receptors within the midbrain PAG differentially modulate the expression of defensive rage behavior elicited from the medial hypothalamus of the cat.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2002

Effects of chronically administered venlafaxine on 5-HT receptor activity in rat hippocampus and hypothalamus.

The effects of chronic administration of the mixed serotonin [5-hydroxytryptamine (5-HT)]/norepinephrine re-uptake inhibitor venlafaxine (5 mg/kg daily by osmotic minipump for 28 days) on the sensitivity of somatodendritic 5-HT(1A) autoreceptors on serotonergic neurons innervating the hypothalamus, and on 5-HT(1B) autoreceptors in both hypothalamus and hippocampus, were determined using in vivo microdialysis in freely moving rats. Venlafaxine induced a reduction in sensitivity of 5-HT(1B) autoreceptors in hypothalamus, but did not affect the sensitivity of 5-HT(1A) autoreceptors, or of 5-HT(1B) autoreceptors in hippocampus. The corticosterone and oxytocin responses to the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 0.05 or 0.2 mg/kg), a measure of postsynaptic 5-HT(1A) receptor activity in the hypothalamus, were reduced in animals administered 5 or 10 mg/kg venlafaxine daily by intraperitoneal injection for 21 days. This desensitization of post-synaptic 5- HT(1A) receptors in the hypothalamus may be a consequence of increased 5-HT levels induced by desensitization of the presynaptic 5-HT(1B) receptors. These results taken together with those of previous studies suggest that the hypothalamus might be an important site of drug action, and that venlafaxine has an overall mechanism similar to that of selective serotonin re-uptake inhibitors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1983

Is the 5 alpha-reductase of the hypothalamus and of the anterior pituitary neurally regulated? Effects of hypothalamic deafferentations and of centrally acting drugs.

The following experiments have been performed in order to verify whether the conversion of testosterone into its 5 alpha-reduced metabolites, 5 alpha-androstane-17 beta-ol-3-one (DHT), 5 alpha-androstane-3 alpha,17 beta-diol (3 alpha-diol) and 5 alpha-androstane-3 beta,17 beta-diol (3 beta-diol), in the hypothalamus and in the anterior pituitary is controlled by neural stimuli. Long-term castrated male rats have been submitted to anterior and total deafferentations of the hypothalamus and to the administration of the following centrally acting drugs: reserpine, p-chlorophenylalanine pCPA and atropine sulphate. The possible involvement of the central opioid system has also been investigated utilizing morphine and naloxone. Neither hypothalamic deafferentations, nor the treatment with reserpine, pCPA, atropine, morphine or naloxone produce any significant modification in the metabolism of testosterone in the hypothalamus. Hypothalamic deafferentations and treatments with reserpine, morphine and naloxone are also ineffective in changing the pattern of testosterone metabolism in the anterior pituitary. On the contrary, atropine and pCPA seem to affect the conversion of testosterone in the gland, both drugs producing an increased formation of DHT and 3 alpha-diol but not of 3 beta-diol. It is concluded that the 5 alpha-reductase-3-hydroxysteroid-dehydrogenase system of the hypothalamus does not appear to be controlled either neurally by inputs coming from other brain structures, or by variations of the neurotransmitter content in the hypothalamus itself. Serotonin and acetylcholine seem to participate in the control of testosterone metabolism at pituitary level, even if it is not clear whether their action takes place directly on the gland, or is mediated through some hypothalamic factor(s). Moreover, it does not appear that brain opioids are involved in the control of the enzymatic complex under consideration either in the hypothalamus or in the anterior pituitary.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1992

The human hypothalamus: comparative morphometry and photoperiodic influences.

The concept of the hypothalamus as a distinct neurological entity concerned with a variety of regulatory processes dates back to the end of the 19th century. Before 1900 there were only vague intimations of the function of the brain surrounding the third ventricle and these were based primarily on various pathological and assorted clinical observations. Since then a large body of evidence has been derived implicating that the hypothalamus contains the control systems which are critically involved in many physiological, endocrine and behavioral processes. Among these are feeding and drinking, reproduction and the regulation of the sleep-wake cycle and temperature. Although the human hypothalamus accounts for only 4 cm3, or 0.3% of the adult brain volume, it contains the integrative systems critical for all these processes. A comparative morphometric analysis of the hypothalamus among mammals revealed that the volume of this part of the brain is highly correlated with brain size, irrespective of the ecological strategy or evolutionary history of the species considered. It appears that the human hypothalamus has just the size we may expect of such a large-brained mammal, but it is considerably larger than would be predicted from its body size. In mammals the preoptic region of the hypothalamus is implicated in the neural control of endocrine functions and in the temporal organization of a wide spectrum of biological rhythms. In recent years, the pivotal role of two hypothalamic cell groups have been considered in this context: the sexually dimorphic nucleus (SDN-POA) as part of the neural circuitry underlying masculine sexual behavior and reproductive functions and the suprachiasmatic nucleus (SCN) as the principal component of the central clock mechanism. Consistent with its role in the temporal organization of circadian processes, investigations in rodents and non-human primates suggest that the SCN is also involved in the seasonal control of reproductive and metabolic phenomena. Since the environmental light-dark cycle is the main Zeitgeber for circadian and seasonal rhythms in most species, including man, photic information could have substantial effects, not only on the neural activity of the biological clock, but also on its underlying structure. Our observations on the human SCN in relation to photoperiod indeed revealed a marked seasonal variation in the morphology of the human SCN. The volume of the SCN was, on average, twice as large in the autumn as in the summer and contained more than twice as many vasopressin immunoreactive neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

Circadian Rhythm↗
PubMed2000

Control of food intake via leptin receptors in the hypothalamus.

Food intake is regulated via neural circuits located in the hypothalamus. During the past decade our knowledge on the specific mediators and neuronal networks that regulate food intake and body weight has increased dramatically. An important contribution to the understanding of hypothalamic control of food intake has been the characterization of the ob gene product (leptin) via positional cloning. Absence of circulating, functionally active, leptin hormone results in massive obesity as seen in ob/ob mice. Leptin inhibits food intake and increases energy expenditure via an interaction with specific leptin receptors located in the hypothalamus. Leptin receptors, of which there are several splice variants (Ob-Ra through Ob-Re), belong to the superfamily of cytokine receptors, which use the JAK-STAT pathway of signal transduction. Obese db/db mice, which have a mutation in the db locus, are unable to perform JAK-STAT signal transduction due to absence of functionally active (long form; Ob-Rb) leptin receptors. Ob-Rb is primarily expressed in the hypothalamus, with particularly high levels in the arcuate, paraventricular, and dorsomedial nuclei and in the lateral hypothalamic area. The abundance of leptin receptors in the ventromedial and lateral hypothalamus supports early observations that these two regions are intimately associated with the regulation of food intake. Leptin receptors have been identified in neuropeptide Y (NPY)/lagouti-related peptide (AgRP)- and proopiomelanocortin (POMC)/cocaine- and amphetamine-regulated transcript (CART)-containing neurons of the ventromedial and ventrolateral arcuate nucleus, respectively, and in melanin-concentrating hormone (MCH)- and hypocretin/orexin-containing neurons of the lateral hypothalamus, suggesting that the above-mentioned messengers are mediators of leptin's action in the hypothalamus. Indeed, functional studies show that NPY, AgRP, POMC-derived peptides, CART, MCH, and hypocretins/orexins all are important regulators of food intake. Leptin is essential for normal body weight balance, but the exact mechanisms by which leptin activates hypothalamic neuronal circuitries is known to a limited extent. In order to find pharmaceutical approaches to treat obesity, further studies will be needed to reveal the exact mechanisms by which leptin lowers body weight and which role leptin and leptin receptors have in the pathogenesis of human obesity.

Animals↗
PubMed1998

Differential regulation of AP-1 DNA binding activity in rat hypothalamus and pituitary by estrogen.

Ap-1 proteins such as Fos and Jun are nuclear transcription factors that have been postulated to function as third messengers in signal transduction pathways to regulate target gene expression. Using electrophoretic mobility shift assays (EMSA), we have studied estrogen (E) effects on regulation of AP-1 DNA binding activity in the rat hypothalamus and pituitary. AP-1 binding is defined herein as the specific association with a consensus AP-1 site during EMSA. Specific AP-1 binding activity was observed in nuclear extracts from the hypothalamus and pituitary of ovariectomized (OVX) female and castrated (CAS) male rats. Treatment with E increased the levels of AP-1 binding activity in the pituitary and uterus, whereas E decreased the levels of AP-1 binding in the hypothalamus, of OVX females. These effects were observed within 60 min and maintained for at least 72 h after a single dose of estrogen. Estrogen-induced changes in AP-1 binding were much more prominent in OVX females than in CAS males. Treatment with progesterone in OVX females had no significant effects on AP-1 binding activity in either pituitary or hypothalamus. Analysis of AP-1 binding activity in both hypothalamus and pituitary by supershift, immunodepletion and shift-Western blot indicated that part of the AP-1 binding was due to the presence of Fos and Jun proteins. However, Western blot analysis shows that the levels of Fos and Jun proteins in the hypothalamic nuclear extracts were not altered by E treatment. We conclude that E produced tissue and sex-differentiated alterations in AP-1 DNA binding activity in the hypothalamus and pituitary of female rats, which may be related to differential estrogenic actions on gene regulation.

Animals↗
PubMed1999

Osmotic activation of the hypothalamo-neurohypophysial system reversibly downregulates the NMDA receptor subunit, NR2B, in the supraoptic nucleus of the hypothalamus.

NMDA receptor activation produces a characteristic pattern of neuronal firing in magnocellular neuroendocrine cells (MNCs) of the supraoptic nucleus of the hypothalamus (SON) which has been associated with greater hormone release in vivo and in vitro. In addition, i.c.v. administered NMDA receptor blockers suppress the dehydration-induced rise in plasma vasopressin and drinking. To investigate the role of NMDA receptor subunits in the neuroendocrine functions of the magnocellular neuroendocrine cells of the hypothalamus, we examined the effects of osmotic stimulation on the protein expression of the NMDA receptor subunits, NR1 and NR2B, important in binding glycine and glutamate, respectively. Homogenates of SON, paraventricular nucleus of the hypothalamus (PVN), cortex and lateral hypothalamus from control rats and rats given 2% saline water to drink for 4-10 days were subjected to SDS-PAGE and Western blot analysis. This saline water drinking regimen produced a significant rise in plasma osmolality levels. NR1 and NR2B immunoreactivity was detected in SON, PVN, lateral hypothalamus and cortex but not in liver homogenates using subunit-specific polyclonal antibodies and quantified using computer-assisted densitometry. Mean NR2B immunoreactivity was significantly lower in SON (29%) and PVN homogenates (23%) from saline-treated rats than in those from control rats. In addition, the effect of dehydration on NR2B was regionally specific since no significant changes in NR2B expression were observed in homogenates of cortex and lateral hypothalamus. Rehydration allowed recovery of plasma osmolality as well as NR2B protein levels in the SON. These results suggest that changes in NMDA receptor subunit expression contribute to the plasticity manifested by in magnocellular neuroendocrine cells in response to osmotic activation of the hypothalamo-neurohypophysial system. In addition, our results indicate that NMDA receptors on SON and PVN MNCs may contribute to neuroendocrinological functions associated with body fluid homeostasis.

Animals↗
PubMed1999

D-Fenfluramine induces serotonin-mediated Fos expression in corticotropin-releasing factor and oxytocin neurons of the hypothalamus, and serotonin-independent Fos expression in enkephalin and neurotensin neurons of the amygdala.

The neurotransmitters expressed by neurons activated by D-fenfluramine (5 mg/kg, i.p.) were identified in the hypothalamus, amygdala and bed nucleus of the stria terminalis. Induction of Fos immunoreactivity following D-fenfluramine injection was used as an index of neuronal activation. To test whether D-fenfluramine activated neurons by releasing serotonin from the serotonergic nerve terminals, rats were pretreated with fluoxetine (10 mg/kg, i.p.), a serotonin reuptake inhibitor that prevents the release of serotonin stimulated by D-fenfluramine, 12 h before D-fenfluramine injection. The approximate percentages of peptidergic neurons that contained Fos immunoreactivity after D-fenfluramine administration were 94% of corticotropin-releasing factor and 22% of oxytocin cells in the paraventricular nucleus of the hypothalamus, 6% of oxytocin cells in the supraoptic nucleus of the hypothalamus, 36% of enkephalin and 15% of neurotensin cells in the central amygdaloid nucleus, and 19% of enkephalin and 9% of neurotensin cells in the bed nucleus of the stria terminalis. Fluoxetine pretreatment blocked Fos expression in corticotropin-releasing factor- and oxytocin-expressing cells in the hypothalamus, but not in enkephalin-and neurotensin-expressing cells located in the bed nucleus of the stria terminalis and central amygdaloid nucleus. D-Fenfluramine did not induce Fos immunoreactivity in vasopressin-, thyrotropin-releasing hormone-, somatostatin- and tyrosine hydroxylase-containing cells in the hypothalamus, and corticotropin-releasing factor-expressing cells in the central amygdaloid nucleus and bed nucleus of the stria terminalis. These results show that D-fenfluramine stimulates corticotropin-releasing factor- and oxytocin-expressing cells in the hypothalamus via serotonin release. The enkephalin- and neurotensin-expressing cells in the amygdala are activated by D-fenfluramine via non-serotonergic mechanisms. Induction of Fos expression by D-fenfluramine in restricted populations of cells suggests a selective activation of neuronal circuitry that is likely to be involved in the appetite suppressant effects of D-fenfluramine.

Amygdala↗
PubMedDate not supplied

Identification of proopiomelanocortin neurones in rat hypothalamus by in situ cDNA-mRNA hybridization.

Ardrenocorticotropic hormone (ACTH), beta-endorphin and the melanotropins (MSHs) are all derived from a single large precursor molecule, proopiomelanocortin (POMC) by individual processing through a series of co- and post-translational modifications. Although the primary site of synthesis is in the pituitary, POMC-derived peptides have been identified in various tissues, notably the brain (see refs 6, 7 for review). A major question concerning brain POMC is whether it is synthesized within the central nervous system (CNS) itself or whether it is taken up from plasma flowing in a retrograde fashion from the pituitary. POMC peptides have been detected immunohistochemically and biochemically in the medial basal hypothalamus, the amygdala and throughout the brain stem. POMC peptide-containing cell bodies have been identified only in two cell groups, however, principally in the periarcuate region of the hypothalamus and to a lesser extent in the nucleus of the tractus solitarius. These and other observations have suggested that POMC peptides are synthesized locally in the medial basal hypothalamus and reach other regions of the CNS by axonal transport. Civelli et al. identified POMC mRNAs in nucleic acid extracts of rat and bovine hypothalami by solution hybridization as well as Northern gel blot analysis, but because of the close proximity of the hypothalamus to the pituitary and the extremely low amounts of POMC mRNA being measured in the hypothalamus, the possibility of tissue contamination during dissection could not be ruled out. We report here the anatomical co-localization of POMC-related peptides and POMC-specific mRNAs to a single major cell group in the medial basal hypothalamus. The presence of POMC-specific mRNA in a POMC peptide-containing cell in the brain is strong support for POMC biosynthesis within brain tissue.

Adrenocorticotropic Hormone↗
PubMed1999

Modulation of sibutramine-induced increases in extracellular noradrenaline concentration in rat frontal cortex and hypothalamus by alpha2-adrenoceptors.

1. The effects of sibutramine (0.25 - 10 mg kg-1 i.p.) on extracellular noradrenaline concentration in the frontal cortex and hypothalamus of freely-moving rats were investigated using microdialysis. The role of presynaptic alpha2-adrenoceptors in modulating the effects of sibutramine in these brain areas was also determined. 2. Sibutramine induced an increase in extracellular noradrenaline concentration, the magnitude of which paralleled dose, in both brain areas. In the cortex, this increase was gradual and sustained, whereas in the hypothalamus it was more rapid and of shorter duration. 3. In both the cortex and hypothalamus, pretreatment of rats with the alpha2-adrenoceptor antagonist RX821002 (3 mg kg-1 i.p.) potentiated increases in the accumulation of extracellular noradrenaline induced by sibutramine (10 mg kg-1 i. p.), by 7 and 10 fold respectively. RX821002 also reduced the latency of sibutramine to reach its maximum effect in the cortex, but not in the hypothalamus. 4. Infusion of RX821002 (1 microM) via the probe increased the accumulation of extracellular noradrenaline induced by sibutramine (10 mg kg-1 i.p.) in both brain areas. In the hypothalamus, the effects of RX821002 on the accumulation of noradrenaline induced by sibutramine were 2 fold greater than those in the cortex. 5. These findings support evidence that sibutramine inhibits the reuptake of noradrenaline in vivo, but that the accumulation of extracellular noradrenaline is limited by noradrenergic activation of presynaptic alpha2-adrenoceptors. Furthermore, the data suggest that terminal alpha2-adrenoceptors in the hypothalamus exert a greater inhibitory effect over the control of extracellular noradrenaline accumulation than do those in the cortex.

Adrenergic alpha-Antagonists↗
PubMed2003

Differences in the mechanisms that increase noradrenaline efflux after administration of d-amphetamine: a dual-probe microdialysis study in rat frontal cortex and hypothalamus.

1. The extent to which impulse-independent release of noradrenaline and/or inhibition of its reuptake contribute to the response to d-amphetamine in vivo is unclear. Here, dual-probe microdialysis was used to investigate this question in the rat frontal cortex and hypothalamus. 2. After systemic administration of d-amphetamine (10 mg kg(-1)), or its local infusion (10 micro M), the increase in noradrenaline efflux in the hypothalamus was greater than in the frontal cortex. 3. In contrast, during local infusion of the noradrenaline reuptake inhibitor, BTS 54 354 (50 micro M), the noradrenaline response was similar in the frontal cortex and hypothalamus, even after systemic administration of the alpha(2)-antagonist, atipamezole, to block presynaptic inhibition of transmitter release and neuronal firing. 4. In the frontal cortex, but not the hypothalamus, the noradrenaline response to 10 micro M d-amphetamine was constrained by activation of alpha(2)-adrenoceptors. This suggests that, at this concentration, inhibition of reuptake of noradrenaline, following its impulse-dependent release, is evident in the frontal cortex, but that the noradrenaline response in the hypothalamus derives mostly from impulse-independent release (retrotransport). 5. Atipamezole did not affect the noradrenaline response to 100 micro M d-amphetamine in either brain region possibly because, at this higher concentration, retrotransport of noradrenaline masks any compensatory reduction in impulse-evoked release. 6. It is concluded that inhibition of reuptake and retrotransport make different contributions to the noradrenaline response to d-amphetamine in the frontal cortex and hypothalamus and that retrotransport increases with the concentration of d-amphetamine.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed2000

Cortical cell death induced by IL-1 is mediated via actions in the hypothalamus of the rat.

The cytokine IL-1 mediates diverse forms of neurodegeneration, but its mechanism of action is unknown. We have demonstrated previously that exogenous and endogenous IL-1 acts specifically in the rat striatum to dramatically enhance ischemic and excitotoxic brain damage and cause extensive cortical injury. Here we tested the hypothesis that this distant effect of IL-1 is mediated through polysynaptic striatal outputs to the cortex via the hypothalamus. We show that IL-1beta injected into the rat striatum with the excitotoxin alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (S-AMPA) caused increased expression of IL-1beta (mRNA and protein) mainly in the cortex where maximum injury occurs. Marked increases in IL-1beta mRNA and protein were also observed in the hypothalamus. S-AMPA, injected alone into the striatum, caused only localized damage, but administration of IL-1beta into either the striatum or the lateral hypothalamus immediately after striatal S-AMPA resulted in widespread cell loss throughout the ipsilateral cortex. Finally we showed that the cortical cell death produced by striatal coinjection of S-AMPA and IL-1beta was significantly reduced by administration of the IL-1 receptor antagonist into the lateral hypothalamus. These data suggest that IL-1beta can act in the hypothalamus to modify cell viability in the cortex. We conclude that IL-1-dependent pathways project from the striatum to the cortex via the hypothalamus and lead to cortical injury, and that these may contribute to a number of human neurological conditions including stroke and head trauma.

Animals↗
PubMed1977

Age-dependent changes in the oxygen consumption of the cerebral cortex, hypothalamus, hippocampus, and amygdaloid in rats.

The oxygen consumption of the cerebral cortex, hypothalamus, hippocampus, and amygdala, of both sexes, ranging in age from 21-805 days for male rats and from 21-780 days for the estrus and diestrus female rats, was measured. The oxidative activity of the hypothalamus, hippocampus, and amygdala decreased rapidly from Day 21 until the 4th mo. and stabilized till the 27th mo. in the hippocampus and amygdala and gradually decreased from the 12th mo. to the 27th mo. in the hypothalamus. The cerebral cortex showed a different pattern which kept a constant level from day 21 to 12 mo. of age. There was no statistically significant change in any of the regions at the time of vaginal opening. Low oxidative activity of the hypothalamus and amygdala in old age was still observed in castrated/hypophysectomized male rats compared with young ones. Therefore, the decreased oxygen consumption in old age seems to be due primarily to changes in the brain tissue itself and not due secondarily to changes in the gonadotropin and sex hormone levels. Female rats had higher oxygen consumption values than males in the cerebral cortex, the hypothalamus, and the hippocampus. In the amygdala the males had a higher consumption. Estrus female rats showed significantly higher oxygen consumption than diestrus females only in the hypothalamus.

Aging↗
PubMed1995

Increase of noradrenaline release in the hypothalamus of freely moving rat by postsynaptic 5-hydroxytryptamine1A receptor activation.

1. 5-Hydroxytryptamine (5-HT) plays a role in the regulation of noradrenergic neurones in the brain, but the precise mechanism of regulation of noradrenaline (NA) release by 5-HT1A receptors has not been defined. The present study describes the effect of a highly potent and selective 5-HT1A receptor agonist, 5-(3-[[(2S)-1,4-benzodioxan-2-ylmethyl)]amino]propoxy)-1,3-b enzodioxole HC1 (MKC-242), on NA release in the hypothalamus using microdialysis in the freely moving rat. 2. Subcutaneous injection of MKC-242 (0.5 mg kg-1) increased extracellular levels of NA and its metabolite, 3-methoxy-4-hydroxyphenylglycol, in the hypothalamus and hippocampus. 3. The 5-HT1A receptor agonists, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (0.2 mg kg-1) and buspirone (3 mg kg-1) mimicked the effect of MKC-242 in increasing NA release in the hypothalamus. 4. The effects of MKC-242 and 8-OH-DPAT in the hypothalamus were antagonized by pretreatment with WAY100135 (10 mg kg-1), a silent 5-HT1A receptor antagonist. 5. Local administration of 8-OH-DPAT (10-100 microM), citalopram (1 microM), a 5-HT reuptake inhibitor, and MDL72222 (10 microM), a 5-HT3 receptor antagonist, into the hypothalamus, had no effect on NA release. 6. Intracerebroventricular injection with 5,7-dihydroxytryptamine caused a marked reduction in brain 5-HT content, but the treatment affected neither basal NA levels nor the MKC-242-induced increase in NA release. 7. The effect of MKC-242 in increasing NA release was not attenuated by repeated treatment with the drug (0.5 mg kg-1, once a day for 2 weeks). 8. The present results suggest that activation of postsynaptic 5-HT1A receptors increases NA release in the hypothalamus.

5,7-Dihydroxytryptamine↗
PubMed2003

Molecular and functional resistance to insulin in hypothalamus of rats exposed to cold.

Insulin and leptin act in the hypothalamus, providing robust anorexigenic signals. The exposure of homeothermic animals to a cold environment leads to increased feeding, accompanied by sustained low levels of insulin and leptin. In the present study, the initial and intermediate steps of the insulin-signaling cascade were evaluated in the hypothalamus of cold-exposed Wistar rats. By immunohistochemistry, most insulin receptor (IR) and insulin receptor substrate-2 (IRS-2) immunoreactivity localized to the arcuate nucleus. Basal levels of tyrosine phosphorylation of IR and IRS-2 were increased in cold-exposed rats compared with rats maintained at room temperature. However, after an acute, peripheral infusion of exogenous insulin, significantly lower increases of IR and IRS-2 tyrosine phosphorylation were detected in the hypothalamus of cold-exposed rats. Insulin-induced association of p85/phosphatidylinositol 3-kinase with IRS-2, Ser473 phosphorylation of Akt, and tyrosine phosphorylation of ERK was significantly reduced in the hypothalamus of cold-exposed rats. To test the hypothesis of functional impairment of insulin signaling in the hypothalamus, intracerebroventricularly cannulated rats were acutely treated with insulin, and food ingestion was measured over a period of 12 h. Cold-exposed animals presented a significantly lower insulin-induced reduction in food consumption compared with animals maintained at room temperature. Hence, the present studies reveal that animals exposed to cold are resistant, both at the molecular and the functional level, to the actions of insulin in the hypothalamus.

Animals↗
PubMed1992

Soluble and particulate phenylethanolamine N-methyltransferase in hypothalamus of diabetic rats.

Experimental diabetes increases total phenylethanolamine N-methyltransferase (PNMT) activity in the medulla-pons but not in the hypothalamus. In this study diabetes was induced with streptozotocin (65 mg/kg) in male Sprague-Dawley rats. Twenty-eight days after treatment there were no differences in soluble PNMT activity in the hypothalamus of diabetics and controls, but PNMT activity in a membrane-associated (particulate) fraction of hypothalamus was evaluated approximately twofold in tissues of diabetic animals compared with controls. A specific PNMT inhibitor, incubated with tissue extracts of control rats, abolished greater than 90% of particulate PNMT activity in the hypothalamus but reduced soluble PNMT activity in the hypothalamus by only 47%. These findings indicate that membrane-associated PNMT activity in rat hypothalamus differs from soluble hypothalamic PNMT in the in vitro response to an inhibitor and the in vivo response to diabetes and suggest the importance of separating subcellular hypothalamic fractions prior to assay of PNMT.

Animals↗
PubMed1998

Changes in extracellular serotonin in rat hypothalamus affect thermoregulatory function.

Experiments were carried out to determine the effects of altering the serotonin (5-HT) levels in the hypothalamus on thermoregulatory function in unanesthetized restrained rats. Local perfusion of the hypothalamus with dialysis solution containing 5-hydroxytryptophan (a 5-HT precursor), fluoxetine (a 5-HT reuptake inhibitor), or high potassium significantly increased both colonic temperature (Tco) and the extracellular concentrations of 5-HT in the hypothalamus. Reciprocally, both extracellular concentration of 5-HT in the hypothalamus and Tco were decreased with a dialysis solution containing tetrodotoxin (which blocks the voltage-dependent sodium channel), zero calcium concentration, or systemic administration of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT,5-HT1A agonist). Intrahypothalamic administration of 8-OH-DPAT and (2,5-dimethoxy-4-iodophenyl)-2-aminopropane (a 5-HT2 agonist) produced hypothermic and hyperthermic effects, respectively. The results indicate that elevating the 5-HT levels in the hypothalamus activates postsynaptic 5-HT2 receptors and results in hyperthermic effects, whereas stimulation of presynaptic 5-HT1A receptors in the hypothalamus reduces the endogenous 5-HT release and results in hypothermic effects.

Animals↗