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PubMed1994

Noradrenaline, dopamine and serotonin levels and metabolism in the human hypothalamus: observations in Parkinson's disease and normal subjects.

In order to determine whether, besides the severe striatal dopamine (DA) loss, other brain neurotransmitter changes may be a constant biochemical feature of idiopathic Parkinson's disease (iPD), we measured the concentration of the three major brain monoamines noradrenaline (NA), DA, and serotonin (5-HT) and their metabolites in five rostro-caudal subdivisions of the hypothalamus of eight control patients and nine patients with morphologically confirmed iPD. In the whole hypothalamus of the iPD patients we found a mild to moderate mean reduction of NA (-52%, P < 0.05), DA (-25%), and 5-HT (-26%). At the subregional level, the most consistently affected area was the intermediate subdivision of the hypothalamus proper where all three monoamines were statistically significantly reduced. Evaluation of individual patient values indicated that, in contrast to the constant and severe DA reduction present in putamen of each of the iPD patients (DA loss ranging from 96% to 99%), several of these patients had whole (and subregional) hypothalamic monoamine values well within the range of controls. We conclude that, although possibly involved in autonomic and/or endocrine disturbances in some patients with iPD, none of the observed monoamine changes in the hypothalamus is an obligatory feature of iPD. Our study demonstrates the need for evaluation of individual patient values rather than mean differences in order to permit valid conclusions to be drawn as to whether an observed neurochemical change can be regarded as specific to a given brain disorder.

Aged↗

PubMed1994

Effect of opioid antagonism on beta-endorphin processing and proopiomelanocortin-peptide release in the hypothalamus.

Previous studies have shown that chronic opioid receptor blockade has significant effects on POMC gene expression and peptide levels in the hypothalamus. We have now examined the effects of the opioid antagonist naltrexone on beta-EP processing in the hypothalamus and on the release of 2 POMC-derived peptides, beta-EP and gamma 3-MSH, from the perifused hypothalamus in vitro. The beta-EP immunoactivity in the medial basal hypothalamus (MBH) of 7 rats infused for 1 week with naltrexone by osmotic minipump, was individually analyzed by HPLC and compared to 7 control rats. The mean ratio of beta-EP1-31 compared to beta-EP1-27 plus beta-EP1-26 was 2.34 +/- 0.41 in the naltrexone treated rats, significantly higher than the ratio of 1.26 +/- 0.09 in the control rats (P < 0.02). Thus in the setting of chronic opioid antagonism although beta-EP content decreases, there is relatively more beta-EP1-31, the biologically active opioid form of the peptide, compared to the C-terminally cleaved forms of beta-EP which have reduced biological activity. To study the effects of naltrexone on beta-EP and gamma 3-MSH release, hypothalami were perifused in vitro with 10(-6) M naltrexone. Basal release of gamma 3-MSH was significantly higher from the naltrexone treated brains compared to the controls (221 +/- 20 pg/60 min vs. 161 +/- 6.7 pg/60 min) (P < 0.01); KCl stimulated gamma 3-MSH was also significantly higher in the naltrexone group (951 +/- 94 vs. 543 +/- 85 pg/60 min) (P < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1979

Yohimbine blocks lateral hypothalamus-mediated behaviors.

There exist behavioral and physiological similarities between rats injected with yohimbine and those with lesions of the lateral hypothalamus. The present study sought to determine if behaviors mediated by the lateral hypothalamus would be significantly altered by yohimbine. Deficits in performance of an active avoidance task have been observed after lateral hypothalamic lesions. Likewise, in the present experiment, yohimbine significantly reduced the ability of trained rats to perform in a similar paradigm. Systemic injections of yohimbine caused decrements in lateral hypothalamic self-stimulation behaviors as well as in locomotor activity produced by lateral hypothalamic stimulation. Similar behaviors mediated by the substantia nigra were relatively unaltered by yohimbine. A final experiment revealed that yohimbine reduces the enhanced glucose utilization normally observed at the lateral hypothalamus during electrical stimulation. These data support the view that the lateral hypothalamus may be an important target of yohimbine's CNS actions.

Animals↗

PubMed1994

Selective reduction in dopamine turnover in the rat frontal cortex and hypothalamus during withdrawal from repeated cocaine exposure.

The effects of 7 days repeated cocaine administration on the dynamics of dopamine release and metabolism in four rat brain regions (frontal cortex, hypothalamus, nucleus accumbens and striatum) were evaluated 1 week (long-term effects) after the final cocaine injection. 3-Methoxytyramine and 3,4-dihydroxyphenylacetic acid (DOPAC) rates of formation were respectively used to assess the dynamics of dopamine release and metabolism. Consistent with a previous report, cocaine withdrawal was associated with marked reductions in DOPAC rate of formation in the frontal cortex and hypothalamus but not in the nucleus accumbens or the striatum. Dopamine release as indicated by 3-methoxytyramine steady-state concentration and its rate of formation was normal in all four brain regions 1 week after repeated cocaine exposure. The ratios of 3-methoxytyramine rate of formation to that of DOPAC were calculated and found to be increased in the frontal cortex and hypothalamus suggesting dopamine reuptake inhibition, at least 1 week after cocaine withdrawal, continued to be depressed in these regions. It is concluded that repeated cocaine has no long-term effect on dopamine release but produces selective long-term reductions in dopamine turnover in frontal cortex and hypothalamus. Cocaine withdrawal is therefore better associated with changes in dopamine turnover than with its release.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1996

Localization of leptin receptor mRNA and the long form splice variant (Ob-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization.

Expression of the leptin receptor gene has been examined in mouse hypothalamus and other brain regions by in situ hybridization. With a probe recognizing all the known splice variants, receptor mRNA was evident in several brain regions (cortex, hippocampus, thalamus), with strong expression in the hypothalamus (arcuate, ventromedial, paraventricular and ventral premammillary nuclei), choroid plexus and leptomeninges. A probe specific to the long splice variant of the leptin receptor (Ob-Rb), containing the putative intracellular signaling domain, again revealed strong expression in the hypothalamus; there was, however, minimal hybridization to choroid plexus and leptomeninges. These results indicate that the hypothalamus is a key site of leptin action, although other brain regions are also targeted.

Alternative Splicing↗

PubMed1988

The stimulatory and inhibitory role of the hypothalamus in the regulation of ovulation in grass frog, Rana temporaria L.

In our previous experiments it was found that lesions placed in the infundibular hypothalamus induced an advanced ovulation in hibernating frogs, Rana temporaria. It was suggested that this premature ovulation was the effect of gonadotropin-releasing hormone (GnRH) due to the injury of some hypothalamic area inhibiting its release or its action on the pituitary gonadotrophs. To investigate this hypothesis, the following experiments were undertaken: (1) an attempt to induce ovulation with exogenous GnRH in hibernating frogs; (2) an attempt to inhibit ovulation with anti-GnRH serum in preovulatory hibernating animals nonlesioned and with lesions of the infundibular hypothalamus; and (3) administration of bromocriptine in hibernating animals to assess whether this substance, as an agonist of dopamine, possesses an inhibitory action on the ovulation. The following results were obtained: (1) lesions of the infundibular hypothalamus in hibernating preovulatory females caused an advanced ovulation during hibernation; (2) the exogenous GnRH administered to preovulatory females induced ovulation during hibernation; (3) the anti-GnRH serum injected into hibernating preovulatory lesioned females inhibited preterm ovulation during, but not after, hibernation; (4) the immunoneutralization of endogenous GnRH in nonlesioned females resulted in an inhibition of the posthibernatory ovulation; (5) bromocriptine inhibited posthibernatory ovulation in nonlesioned hibernating animals. Thus, the results of these experiments support the suggestion that induction of accelerated ovulation in lesioned hibernating animals involved the releasing action of GnRH. This action of GnRH seemed to be facilitated by the ablation of inhibitory dopaminergic function of hypothalamus in lesioned animals.

Animals↗

PubMed1988

Changes in progesterone metabolism in the chicken hypothalamus during induced egg laying stop and molting.

In the present study, we have established and validated a radioenzyme assay which permits us to quantify progesterone metabolism in the chicken brain. Progesterone metabolism was then studied in five brain areas obtained by microdissection from the telencephalon (part of the lobus paraolfactorius immediately rostral to the preoptic area), the preoptic area, and the hypothalamus. Three metabolites of progesterone were produced in large amounts in these brain regions and were quantified in this study: 5 beta-pregnane-3,20-dione (5 beta-DHP) as well as its metabolite 3 alpha-hydroxy-5 beta-pregnane-20-one (5 beta,3 alpha-ol) and 5 alpha-pregnane-3,20-dione (5 alpha-DHP). The unmetabolized progesterone was also recovered and quantified. The 5 beta-reduction of progesterone (production of 5 beta-DHP and 5 beta,3 alpha-ol) was very active but its 5 alpha-reduction (production of 5 alpha-DHP) was almost absent in the lobus paraolfactorius. An opposite pattern of metabolism was found in the preoptic area and the hypothalamus (higher 5 alpha- but lower 5 beta-reductase activity). The changes in progesterone metabolism in these brain areas were then studied in groups of hens submitted to induced egg laying stop and molting. A significant decrease in progesterone 5 alpha-reduction was found in the median hypothalamus of hens during the period of molt. Simultaneously, the experimental procedures induced significant decreases in the production of 5 beta-DHP by the lobus paraolfactorius, anterior, and medial hypothalamus but induced a significant increase in the production of this metabolite in the preoptic area. These changes are likely to be involved in the control of reproductive functions including sexual behavior and secretion of luteinizing hormone-releasing hormone, and a number of possible causal mechanisms are presented. These should now be tested experimentally especially in view of the very limited information which is now available on the biological effects of the metabolites of progesterone.

3-Hydroxysteroid Dehydrogenases↗

PubMed1989

Androgen metabolism in the male hamster--2. Aromatization of androstenedione in the hypothalamus and in the cerebral cortex; kinetic parameters and effect of exposure to different photoperiods.

It has been demonstrated that exposure of the hamster to a short photoperiod (light on less than 12 h/day) induces an increased sensitivity of the hypothalamic-pituitary axis to the feedback effect of testosterone. It was consequently felt of interest to investigate whether the photoperiod might act by increasing the formation of estrogens in the CNS and/or in the anterior pituitary. The aromatase activity was studied utilizing a sensitive in vitro assay that measures the amount of 3H2O formed during the conversion of [1 beta-3H]androstenedione to estrone. First of all it has been investigated whether the aromatizing enzymes, previously found in the hypothalamus, were present also in the cerebral cortex and in the anterior pituitary; secondly, the kinetic parameters of the enzyme were determined; finally, the possible variation of the central aromatase activity in hamsters exposed to a long or to a short photoperiod was investigated. The results obtained indicate that both in the hypothalamus and in the cerebral cortex the aromatization of androstenedione is linear with respect to time of incubation and tissue concentration; moreover, in the two structures, the enzyme demonstrated a similar Michaelis-Menten constant (0.03 and 0.08 microM respectively). From a quantitative point of view, the hypothalamus seems to possess an aromatizing activity higher than that of the cerebral cortex. Exposure of the hamsters to a short photostimulation for 60 days resulted in a significant regression of the reproductive system (decreased testicular weight and serum LH levels) and in a decrease of the aromatase activity of the hypothalamus. There was no effect of the photoperiod on the aromatase of the cerebral cortex. Since androgens are known to stimulate the aromatase, the present data might be tentatively interpreted by suggesting that the variation in the formation of estrogens during the short photoperiod might be the consequence of the decreased serum testosterone levels typical of the hamster in the quiescent gonadal period.

Androstenedione↗

PubMedDate not supplied

Subcellular localization of immunoreactive dynorphin and vasopressin in rat pituitary and hypothalamus.

Dynorphin is found mainly in the particulate fraction of rat pituitary gland and hypothalamus homogenates. Dynorphin-like immunoreactivity (DYN-LI) from neurointermediate lobe (NIL) homogenates migrates at the same rate as vasopressin-like immunoreactivity (AVP-LI), in sucrose density gradients, whereas DYN-LI from the hypothalamus appears to migrate principally in a less dense region of the gradient. This suggests that dynorphin and vasopressin from pituitary are present in organelles of similar size and density, while the bulk of the dynorphin in the hypothalamus appears to be stored in a different subcellular organelle. Anterior lobe (AL) dynorphin appears to migrate in two separate bands on density gradients: the less dense band (slower) migrates at a similar rate to that of dynorphin and vasopressin from NIL. When alpha-neo-endorphin was measured in sucrose gradients of NIL and hypothalamus, it was found to co-migrate with DYN-LI.

Animals↗

PubMed1986

Beta-endorphin concentrations in the hypothalamus, pituitary and plasma of streptozotocin-diabetic rats with and without insulin substitution therapy.

The concentrations of beta-endorphin like immunoreactivity (beta-END) in the hypothalamus, pituitary and plasma were studied in rats of either sex, one month after induction of diabetes by single iv injection of streptozotocin. As controls, both normal and undernourished rats, weight-matched with diabetic rats, were used. Diabetic male and female rats had a marked depletion of beta-END stores in the hypothalamus and neurointermediate lobe (NIL) but not in the anterior pituitary. Depletion of beta-END was reversed to normal by insulin replacement therapy. Severe undernourishment was not as effective as diabetes to reduce beta-END stores in the hypothalamus and NIL. A significant reduction of beta-END was observed only in the NIL of undernourished female rats. Plasma beta-END and beta-lipotropin (beta-LPH) concentrations were not significantly altered in diabetic rats. These results indicate that the lack of insulin may affect beta-END synthesis in the hypothalamus and NIL.

Animals↗

PubMed1987

Concentrations of histamine in the hypothalamus of the rat: effect of extraction volume and interpretation of the effects of acutely-administered morphine.

The effect of varying the ratio of extraction volume to tissue weight (EVR) on the apparent concentration of histamine (HA) in the hypothalamus of the rat was examined. Increasing the weight of tissue (by pooling 1, 2 or 3 hypothalami), in a constant extraction volume, resulted in progressive decreases in apparent concentration of histamine in the hypothalamus. These concentrations were 642, 450 and 282 ng/g, respectively. Morphine (10 mg/kg, i.p.) significantly reduced the concentration of histamine in the hypothalamus. Expressed as percentages of the saline-control values (obtained for the extraction volume to tissue weight of 35.7, 57.2 and 118.4 ml/g), treatment with morphine resulted in 24, 17 and 11% reductions in the concentration of histamine in the hypothalamus, respectively. However, expressed in terms of ng/g, the reductions in histamine induced by morphine were 68, 75 and 69 ng/g, respectively. It is concluded that morphine may consistently affect a single pool of histamine. The possibility that de novo histamine is formed in the homogenate during the extraction process is discussed.

Animals↗

PubMed1976

Quantitative changes in the metabolism of 20alpha-hydroxy-4-pregnen-3-one by rat hypothalamus and pituitary during proestrus.

The in vitro conversion of 20alpha-hydroxy-4-pregnen-3-one (20alpha-DHP) by medial basal hypothalamus and anterior pituitary was investigated throughout the day of proestrus in the 4-day cyclic rat. Reverse isotopic dilution analysis was utilized to quantitate the substrate remaining and three metabolic products: 20alpha-hydroxy-5alpha-pregnan-3-one, 5alpha-pregnane-3alpha,20alpha-diol and progesterone. Serum levels of 20alpha-DHP, progesterone, LH and FSH were measured by radioimmunoassay. Conversion of 20alpha-DHP to its 5alpha-reduced metabolites (20alpha-hydroxy-5alpha-pregnan-3-one and 5alpha-pregnane-3alpha,20alpha-diol) by the pituitary was constant throughout proestrus except for a significant decrease at 1600 h, near the end of the critical period. Although 5alpha-reduction of 20alpha-DHP by the hypothalamus fluctuated, it was relatively high at 1600 h and was lowest at 1400 h. Small amounts of progesterone (less than2%) were formed but there was not variation with time. The decrease in pituitary enzymic activity coincided with the time when serum levels of LH, FSH and progesterone were increasing but not with later times when the elevated serum levels were maintained. Thus, there may be endogenous regulation of 5alpha-reductase and 3alpha-hydroxysteroid dehydrogenase activity in rat pituitary and perhaps hypothalamus on the afternoon of proestrus. The regulation and subsequent effects of quantitative changes in 5alpha-reduction of 20alpha-DHP by pituitary and hypothalamus remain to be elucidated.

20-alpha-Dihydroprogesterone↗

PubMed1994

Chronic caloric restriction induces stress proteins in the hypothalamus of rats.

The induction of stress proteins (sps) in the hypothalamus of female Fischer 344 rats in response to caloric restriction (CR) and to heat stress was investigated. Caloric restriction was found to elicit sps 27, 34, 70, and 90 in the hypothalamus of both young and old rats while none was found in the hypothalamus of ad libitum (AL) fed controls. Heat stress initiated heat shock proteins (hsps/sps) 27, 70, and 90 in the hypothalamus of the young (AL) fed animals, the same proteins evoked by feeding stress. The same sps were induced in the old (AL) rats although the expression showed substantial decline with age. This reduction was less marked, however, with the old CR rats. Stress protein 34, an infrequently reported protein, was related to feeding and was not induced by heat shock. Recent reports point to the important role sps play in the cellular reaction to stress, as well as their involvement in the higher functions. The findings reported here suggest that sps are involved in the regulatory mechanisms allowing CR animals to tolerate stress related to metabolic substrate deprivation.

Aging↗

PubMed1987

Heroin self-administration: effects of antagonist treatment in lateral hypothalamus.

The involvement of the lateral hypothalamus and medial prefrontal cortex in mediating heroin self-administration was examined by means of intracranial microinjections of the quaternary opiate antagonist methyl naltrexone over a dose range of 0-3.0 micrograms. In animals trained to respond on a continuous reinforcement schedule for intravenous heroin (0.03 mg/kg/infusion), microinfusions of antagonist into the lateral hypothalamus prior to a self-administration session produced significant dose-related increases in responding on the drug manipulandum, similar to increases in responding observed after treatment with naltrexone systemically. Microinfusions of quaternary antagonist into the medial prefrontal cortex over the same dose range effective in the lateral hypothalamus did not produce response increases. These data suggest that opiate action in the lateral hypothalamus, but not in the medial prefrontal cortex, is salient in maintenance of intravenous self-administration.

Animals↗

PubMed1987

Anatomical mapping of the rat hypothalamus for calcitonin-induced anorexia.

The primary physiological function of calcitonin, a peptide hormone secreted by the thyroid gland, is to modulate plasma calcium concentrations. Calcitonin also has several effects on the central nervous system including an inhibition of feeding behavior. In the present study synthetic salmon calcitonin (15 ng in 0.3 microliter) was found to produce a marked suppression of eating when infused in several hypothalamic areas. The greatest inhibition was produced by infusions into the paraventricular nucleus of the hypothalamus, the perifornical area and several areas on the floor of the hypothalamus. A less marked inhibition of eating was produced by infusions in the nucleus accumbens. Infusions in the olfactory tubercule, the ventrolateral hypothalamus, the medial forebrain bundle and the posterior nucleus of the hypothalamus had no effect. It is concluded that the anorectic effects of calcitonin on the central nervous system are mediated by several hypothalamic and extrahypothalamic sites.

Animals↗

PubMed1995

Regulation of adenylate cyclase by galanin, neuropeptide Y, secretin and vasoactive intestinal polypeptide in rat frontal cortex, hippocampus and hypothalamus.

This study characterizes regional regulation of adenylate cyclase by galanin, neuropeptide Y (NPY), secretin and vasoactive intestinal peptide (VIP) in rat brain frontal cortex, hypothalamus and hippocampus. In our experimental system, galanin caused small detectable activation (10-20%) of basal adenylate cyclase activity in frontal cortex and hippocampus but had no effect on basal adenylate cyclase activity in hypothalamus. Galanin inhibited forskolin-stimulated adenylate cyclase in all three brain regions-hypothalamus, hippocampus and frontal cortex by 54.5%, 44.3% and 25.7%, respectively. NPY reduced basal and forskolin-stimulated enzyme activities by 35% only in frontal cortex, but not in the other two brain areas. Secretin had no effect in frontal cortex but caused similar adenylate cyclase activation in hypothalamus and hippocampus. VIP had a stimulatory effect of 32.8% and 32.4% in frontal cortex and hippocampus, respectively. The results indicate regional differences in adenylate cyclase modulation by the four peptides and reveal interesting relations in comparison with peptide and receptor densities in the three investigated brain regions.

Adenylyl Cyclases↗

PubMed1992

Defense reaction elicited by microinjection of kainic acid into the medial hypothalamus of the rat: antagonism by a GABAA receptor agonist.

Electrical stimulation of either the midbrain central gray or the medial hypothalamus induces a defense reaction in the rat, characterized mainly by increased locomotion, rearing, and leaping. However, microinjection of the excitatory amino acid glutamate was effective only in the former region. Because excitatory amino acids do not depolarize axons of passage, it was suggested that the hypothalamus is devoid of soma/dendrites of neurons commanding the defense reaction. In the present study, we show that a subtoxic dose (60 pmol) of another excitatory amino acid, kainic acid, injected into the medial hypothalamus significantly enhanced locomotion and rearing of Wistar rats systematically observed in an open field. Similar behavioral changes have been reported following microinjection of drugs impairing GABAergic neurotransmission. Local pretreatment with the GABAA receptor agonist THIP (2 nmol) blocked the effect of kainic acid. Therefore, the medial hypothalamus of the rat seems to contain a population of neuronal cell bodies commanding the defense reaction, which is activated by excitatory amino acids and tonically inhibited by GABAergic fibers.

Agonistic Behavior↗

PubMed1984

Descending pathways from hypothalamus to dorsal motor vagus and ambiguus nuclei in the rat.

The anatomical pathways between the hypothalamus and cell groups of the lower medulla that are involved in the neural control of endocrine pancreas activity were investigated. As part of this control system the descending pathways originating from lateral, dorsomedial and ventromedial hypothalamic nuclei towards the dorsal motor vagus and ambiguus nuclei, were studied by retrograde transport of horseradish peroxidase. Very small injections of the tracer, by means of the iontophoretic delivery method, were placed in the dorsal motor vagus, ambiguus and solitary tract nucleus as well as in the various nuclei of the medullary reticular formation. Subsequent retrograde labeling was studied in the hypothalamus and the brainstem. The appearance of considerable retrograde labeling in mesencephalic periventricular grey and rostral mesencephalic reticular formation indicated a possible role for these structures as intermediates in an indirect hypothalamo-medullary control circuitry. This led us to extend the peroxidase injections to these mesencephalic areas after which the hypothalamus was investigated for retrograde labeling. All data combined indicated the existence of three descending pathways, direct and indirect, between hypothalamus and the parasympathetic motor nuclei of the lower medulla.

Animals↗