Central neural pathways for angiotensin-induced thirst.

Evidence is reviewed implicating the preoptic region in angiotensin-induced thirst. The most responsive area according to results obtained with behavioral, electrophysiological, and autoradiographic mapping techniques is at the caudal border of the medial preoptic region and rostral border of the anterior hypothalamus. The neural pathway from this preoptic site for angiotensin-induced thirst extends along the medial forebrain bundle through the midlateral hypothalamus to the paramedial midbrain tegmentum and to an area ventrolateral to the central gray. Lesions of this pathway in the midlateral hypothalamus and rostral midbrain significantly attenuated drinking induced by microinjections of angiotensin II into the preoptic area but did not disrupt water intake induced by microinjections of angiotensin II into the subfornical organ or cerebral ventricles. Although the efferent pathways from angiotensin-receptive sites in the subfornical organ and cerebral ventricles are unknown, it appears from these observations that the medial forebrain bundle is not involved. Lesions of the medial forebrain bundle-lateral hypothalamus also do not disrupt drinking induced by microinjections of hypertonic saline into the preoptic region although lesions placed 1 mm further lateral do. Since fat lateral hypothalamic lesions are without effect on drinking induced by centrally administered angiotensin II, this suggests that intracellular and extracellular thirst signals are subserved by separate neural pathways in the hypothalamus.     

Plasma Osmolality Predicts Extracellular Fluid Catechol Concentrations in the Lateral Hypothalamus

The lateral hypothalamus has an important role in regulating food and water intake. We have investigated the endogenous release of monoamines from the lateral hypothalamus during manipulations of plasma osmolality and circulating volume. Adult male Sprague-Dawley rats implanted with carbon paste in vivo electrochemical (EC) electrodes in the lateral hypothalamus were placed on a 72-h water deprivation schedule. Although the carbon paste EC electrode has an intrinsically ambiguous signal in which changes in ascorbic acid may appear as changes in catechol concentrations, pharmacologic studies in lateral hypothalamus indicated that the electrode most likely measured norepinephrine and possibly epinephrine. On the test day, the EC electrodes were scanned with linear sweep voltammetry from -0.2 to +0.4 V at a rate of 5 mV/s. Semiderivative signal processing showed catechol and hydroxyindole peaks at +0.11 and +0.23 V, respectively. Baseline recordings were made prior to rats drinking distilled water, 10% sucrose, 5% dextrose, 0.30% NaCl, 0.90% NaCl, or 10% d-mannitol. To control for the act of drinking, other implanted dehydrated rats were intraperitoneally injected with 5% dextrose, 0.30% NaCl, or 0.90% NaCl. To dissociate the effects of osmolality and circulating volume on the EC response, hydrated rats implanted with EC electrodes were subcutaneously injected with 12% NaCl or intraperitoneally injected with 35% polyethylene glycol. Other rats subjected to water deprivation and osmotic challenges were decapitated and trunk blood was collected for measurements of plasma osmolality and hematocrit. Similar experiments were conducted using homozygous Brattleboro rats which lack arginine vasopressin (AVP) but which preserve normal plasma osmolality with prodigious drinking.(ABSTRACT TRUNCATED AT 250 WORDS)     

Interhemispheric asymmetry of positive emotional reactions in rats

Interhemispheric asymmetry of positive emotional reactions was studied in rats: satisfaction of drinking need and self-stimulation. Successive inactivation of the hemispheres was carried out by potassium spreading depression. Switching off of the right as well as the left hemispheres symmetrically influenced the whole quantity of the water, drunk by the rats to a full thirst satisfaction, i. e. the magnitude of need. However, at different stages of drinking need satisfaction an interhemispheric asymmetry was observed: under a strong drinking motivation the right hemisphere dominated, under a weak motivation--the left one. Switching off of the right hemisphere lowered the frequency of self-stimulation of the lateral hypothalamus and switching off the left one heightened it, testifying to the dominance of the right hemisphere in the reaction of self-stimulation. This reaction was also characterized by asymmetry of the lateral hypothalamus nuclei; reactivity to hemispheres inactivation (decreasing or increasing of self-stimulation frequency) of the right nucleus was more expressed than that of the left one.     

Hypothalamic orexin--a neurons are involved in the response of the brain stress system to morphine withdrawal

Both the hypothalamus-pituitary-adrenal (HPA) axis and the extrahypothalamic brain stress system are key elements of the neural circuitry that regulates the negative states during abstinence from chronic drug exposure. Orexins have recently been hypothesized to modulate the extended amygdala and to contribute to the negative emotional state associated with dependence. This study examined the impact of chronic morphine and withdrawal on the lateral hypothalamic (LH) orexin A (OXA) gene expression and activity as well as OXA involvement in the brain stress response to morphine abstinence. Male Wistar rats received chronic morphine followed by naloxone to precipitate withdrawal. The selective OX1R antagonist SB334867 was used to examine whether orexins' activity is related to somatic symptoms of opiate withdrawal and alterations in HPA axis and extended amygdala in rats dependent on morphine. OXA mRNA was induced in the hypothalamus during morphine withdrawal, which was accompanied by activation of OXA neurons in the LH. Importantly, SB334867 attenuated the somatic symptoms of withdrawal, and reduced morphine withdrawal-induced c-Fos expression in the nucleus accumbens (NAc) shell, bed nucleus of stria terminalis, central amygdala and hypothalamic paraventricular nucleus, but did not modify the HPA axis activity. These results highlight a critical role of OXA signalling, via OX1R, in activation of brain stress system to morphine withdrawal and suggest that all orexinergic subpopulations in the lateral hypothalamic area contribute in this response.     

Conditioned-reflex activation of electrical self-stimulation of the brain: a model of a situational craving for narcotics]

Rats with electrodes implanted into lateral hypothalamus were trained to press a lever to obtain electrical stimulation of the brain. After elaboration of self-stimulation (SS) conditioning of morphine-induced activation of SS-response was carried out. Five pairings were performed of morphine (3 mg/kg, i.p.) administration and SS in the box with distinct environmental cues (brightness, color, floor texture, background noise). After morphine withdrawal activation of SS was reproduced after simple placing of the animal in "conditioned" chamber. This effect was naloxone-sensitive. The observed effect is considered to be the adequate model of addictive substances craving.     

Eating or Drinking Elicited by Direct Adrenergic or Cholinergic Stimulation of Hypothalamus

A double cannula system, allowing repeated stimulation of central structures with crystalline chemicals, was developed. This technique was employed to study the effects of adrenergic and cholinergic stimulation of the lateral hypothalamus of rats. Drug-specific effects on the feeding and drinking mechanisms, respectively, were observed.     

吗啡和纳洛酮对损毁下丘脑诱致的大鼠胃粘膜损伤之影响

本实验观察了静注吗啡和纳洛酮对电解损毁后部下丘脑诱致的大鼠胃粘膜损伤的影响并观察了在静注吗啡、纳洛酮后和侧脑室注射纳洛酮后其胃酸分泌和血清胃泌素水平之变化。实验揭示,吗啡仅略为降低该神经源性胃粘膜损伤程度,而纳洛酮则明显地减少其胃粘膜损伤;静注吗啡能抑制后部下丘脑损毁后大鼠的胃酸分泌,增加其血清胃泌素水平,而静注纳络酮后,这种大鼠的胃酸分泌增加,但血清胃泌素水平无明显变化;侧脑室注射纳洛酮对后部下丘脑损毁后大鼠胃酸分泌和血清胃泌素水平无明显影响。本结果表明,胃酸可能是导致这种消化道损伤的条件之一,而不是最重要因素;静注纳洛酮对后部下丘脑损毀后大鼠胃粘膜变化有保护作用。后者提示,内源性阿片样肽可能参与这种神经源性胃粘膜损伤的形成。     

Effect of morphine on the concentration of monoamines in the emotiogenic zones of the hypothalamus in adult and old rats

The content of monoamines in the emotiogenic hypothalamic zones has been shown to noticeably change with aging of rats. The level of noradrenaline and serotonin increased in the ventromedial nucleus of the hypothalamus, while the concentration of noradrenaline increased in the lateral hypothalamic zone. Single i.p. injections of 10 mg/kg morphine evoked qualitatively different shifts in the monoamine concentrations in the hypothalamic emotiogenic zones of the rats of different ages: the level of dopamine increased in adult animals, while the levels of noradrenaline and serotonin dropped in old rats. It is supposed that in old age the effect of morphine on dopaminergic structures in the emotiogenic hypothalamic zones becomes more moderate, whereas that on the noradrenergic and serotonergic structures is facilitated. The age-related specificities of the morphine effect on the monoaminergic regulation of the emotiogenic hypothalamic zones can determine considerable modifications of a psychotropic effect of the drug in old age.     

Naloxone-induced hypodipsia: a CNS mapping study

Opiate antagonists have been shown to reliably attenuate drinking behavior. Recent research points to a central site of action for this antidipsogenic effect. To pursue this issue of site specificity, naloxone, a specific opiate antagonist, was delivered into a number of discrete subcortical areas in 23 hour water-deprived rats. Water intake was measured at 5, 15, 30 and 60 minutes post drug injection. Compared to saline control injections, naloxone reliably depressed water intake, in a dose-related manner, in lateral hypothalamus, preoptic area and zona incerta. Previous research has repeatedly implicated these areas in drinking behavior. Placements which were not generally effective included lateral ventricle, nucleus accumbens, substantia nigra and cortex/corpus callosum. Latency to drink was never affected by any dose of naloxone injected into any site, suggesting an opioid influence on mechanisms involved in termination and/or maintenance rather than on initiation of drinking.     

Effect of morphine on hypothalamic corticotropin-releasing factor (CRF) and pituitary-adrenocortical activity

The effects of intraperitoneal and intra-third ventricular administration of morphine on the hypothalamic corticotropin-releasing factor (CRF) and the pituitary-adrenocortical activity were examined in unanesthetized, freely moving rats. Hypothalamic CRF was measured by rat CRF radioimmunoassay. Intraperitoneal or intra-third ventricular administration of morphine increased blood concentrations of ACTH and corticosterone while intraperitoneal administration tended to increase CRF concentration in the whole hypothalamus including the median eminence and intra-third ventricular administration increased CRF concentration in the hypothalamus excluding the median eminence. However, morphine seemed to inhibit the increase in CRF concentration in the hypothalamus induced by the ether-laparotomy stress. The main site of morphine action on the hypothalamo-pituitary-adrenocortical system seemed to be in the hypothalamic area.     

Role of enkephalin-reactive system of the caudate nucleus in acquisition of alimentary conditioned reflex in dogs

Bilateral injections of 15 and 45 mcg of synthetic analogue of TYR-D-ALA-LEY-Enkefaline-ARG into the body of the caudate nuclei in dogs produced a manifested increase in parameters of Pavlovian alimentary conditioned reflexes. Moreover, the dose of 15 mcg of LEY-enkefaline enhanced the background salivation and prolonged food consumption. Excited dogs became calm. During analogous injections into the right lateral hypothalamus the effect diminished while injections of 15 mcg of morphine hydrochloride were ineffective. The data point to role of the enkefaline-containing system in alimentary behaviour.     

Hypothalamo — Hyppocampal interrelationships

Changes in hippocampal electrical activity in response to electrical and chemical stimulation of different parts of the hypothalamus were studied in cats with permanently implanted metallic electrodes and a chemical electrode. The results showed that: 1) in response to electrical stimulation of the middle part of the lateral hypothalamus, evoking activation of feeding behavior, the hippocampal theta-rhythm is increased and the delta- and alpha-rhythms are simultaneously depressed; 2) the same picture is observed in response to electrical stimulation of other parts of the lateral hypothalamus, evoking a response of alertness, anxiety, and aggression; 3) after injection of 0.007 ml noradrenalin into the lateral hypothalamus of cats the animals develop a food response, and injection of 0.014 ml acetylcholine causes activation of drinking behavior; these responses take place in association with intensification of the hippocampal theta-rhythm; electrical stimulation of the dorsomedial nucleus evokes desynchronization of hyppocampal electrical activity; 5) in response to threshold stimulation of the ventromedial nucleus, feeding behavior is inhibited and this is accompanied by desynchronization of hyppocampal electrical activity, whereas in response to stronger stimulation, a response of aggression develops and the theta-rhythm is intensified.Institute of Physiology, Academy of Sciences of the Georgian SSR, Tbilisi. Translated from Neirofiziologiya, Vol. 2, No. 5, pp. 497–506, September–October, 1970.     

Regional alterations in cyclic nucleotide levels with acute and chronic morphine treatment.

Systemic morphine briefly elevated the caudate cyclic AMP level and subsequently depressed those levels in the substantia nigra and hypothalamus. Thalamic cAMP was unaffected within sixty minutes of the injection. Cyclic GMP was reduced in all four structures by thirty minutes. Tolerant animals evidenced increased cAMP levels in all but the hypothalamus and reduced cGMP in all four structures. A challenge injection of morphine elevated the two nucleotides briefly in the substantia nigra, depressed only cAMP in the hypothalamus and did not alter levels in the other structures.     

Dual action of morphine on cold-stimulated thyrotropin secretion in male rats

The effect of morphine infused into 4 hypothalamic locations and the periaqueductal gray (PAG) on cold-stimulated thyrotropin (TSH) secretion was studied in male rats. Morphine decreased TSH cold-response when infused into the 3rd ventricle (1-20 micrograms/rat) or the median eminence (5 and 10 micrograms/rat). Infusions bilaterally into the anterior hypothalamus (1-10 micrograms/side) or PAG (1 and 10 micrograms/rat) were ineffective, while those given into the posterior hypothalamus (1 and 5 micrograms/side, but not 10 micrograms/side) significantly enhanced TSH cold-response. Naloxone pretreatment (2 or 5 mg/kg, s.c.) reversed the decreasing effect of morphine in the 3rd ventricle (1 microgram/rat) and the increasing effect of morphine in the posterior hypothalamus (1 microgram/side). We conclude that morphine has a dual hypothalamic action on cold-stimulated TSH secretion: an inhibition periventricularly, and a stimulation in the posterior hypothalamus.     

Neuroprotective effect of N-acylethanolamines in chronic morphine dependence. III. Influence on the content of neurotransmitters in the rat brain

The effect of the mixture of saturated and unsaturated N-acylethanolamines (NAEs) on the functional activity of catecholamine- and serotoninergic systems of the rat brain with experimental morphine dependence was investigated. A significant decrease of dopamine levels was found in the hypothalamus, midbrain and cortex of rats with morphine dependence. The administration of NAEs to rats with morphine dependence in time course dose of 35 mg/kg markedly increased the levels of dopamine in the hypothalamus, middle brain and cortex. Simultaneously the significant decrease of serotonine content was observed in the midbrain and cortex. The results obtained suggest that one of the important aspects of neuroprotective action of NAEs under morphine dependence is the restoration of dopamine content in the brain.     

Wild ginseng attenuates anxiety- and depression-like behaviors during morphine withdrawal

The purpose of this study was to evaluate whether wild ginseng (WG) administration could attenuate anxiety- and depression-like behaviors and expression of corticotrophin-releasing factor (CRF) and neuropeptide Y (NPY) following withdrawal from repeated morphine administration in rats. Male rats were administered daily doses of WG (50, 100, or 200 mg/kg, i.p.) for 5 days, 30 min before morphine injection (40 mg/kg, s.c). The anxiety- and depression-like behavioral responses were measured 72 h after the last morphine injection using an elevated plus maze (EPM) and forced swimming test (FST), respectively. Changes in hypothalamic CRF and NPY expressions were also examined by analyzing their immunoreactivities in the hypothalamus. Daily administration of WG significantly reduced anxiety-and depression-like behavior, and elicited the suppression of CRF expression and the stimulation of NPY expression in the hypothalamus. Our results demonstrated that WG extract might be effective at inhibiting the anxiety and depression responses due to morphine withdrawal by possibly modulating the hypothalamus CRF and NPY systems. Furthermore, these findings imply that WG extract can be used for developing new medication to cure or alleviate morphine withdrawal symptoms and to prevent relapses of morphine use.     

Effects of neuropeptide Y on behavior and noradrenaline level in the brain

The administration of neuropeptide Y in lower doses (1 and 100 ng/rat) into the lateral ventricle of the brain gave rise to the inhibition of locomotor activity, weakening of the orienting-exploratory behaviour, increase in the period of rest in animals. Feeding and drinking behaviour after the administration of neuropeptide was not observed. Alterations of behaviour in rats were followed by a dose-depended increase in noradrenaline in hypothalamus. No changes were observed in the content of noradrenaline in the frontal cortex and septum. Some variations in the level of noradrenaline were found in amygdala and hippocamp. It may be assumed that behavioural effects, aroused by the central administration of neuropeptide Y, is connected with the activation of catecholaminergic systems of hypothalamus.     

Significance of the hypothalamus opioid system in the mechanism of morphine analgesia

It has been demonstrated in experiments on conscious rabbits that microinjections of nalorphine to the paraventricular area of the hypothalamus blocked morphine analgesia assessed from the tail-flick test and evoked potential variation in the sensorimotor area of the brain cortex in response to nociceptive electrocutaneous stimulation. An analogous but less powerful effect was produced by nalorphine injected into the large raphe nucleus. It is assumed that morphine analgesia is primarily mediated by opioid structures of the hypothalamus.     

Immunocytochemical identification of vasopressinergic and oxytocinergic neurons in the hypothalamus of the cat

Our immunocytochemical investigation of the magnocellular neuroendocrine cells in the cat hypothalamus reveals a mixture of vasopressin (VP)- and oxytocin (OT)-containing neurons in the supraoptic (NSO), the paraventricular (NPV) and in five accessory nuclei (NAC). We describe the lateral hypothalamic nucleus (NLH), a new accessory nucleus, lying at the junction of the internal capsule and pallidum, and possibly involved in drinking behavior. Previously characterized incompletely in mammals, the four other accessory nuclei consist of the circularis (NC), anterior fornical (NAF), posterior fornical (NPF) and retrochiasmatic (NRC). The two peptidergic cell types, VP and OT, are equally mixed in the NPV and the NAC, but in the NSO VP neurons predominate. The perikarya of these VP and OT neurons do not show distinct morphological differences at the level of light microscopy. The organization of magnocellular neuroscretory neurons in the cat hypothalamus closely resembles that described in other mammals with the exception of the unique presence of the lateral hypothalamic accessory nucleus.     

Hypothalamic injection of morphine: Feeding and temperature responses

Morphine (2.7, 5.6 and 10.3 nmoles) and norepinephrine (10, 20 and 40 nmoles) were applied to the ventromedial hypothalamus of male rats through cannulae which were implanted stereotaxically. Food intake was enhanced by both drugs as compared with saline. Although intake peaked during the first hour following norepinephrine, it was more gradual following morphine. Both drugs also caused a rise in core temperature, but only with morphine did this persist throughout the 3-hour measurement period. Naloxone (10.6 nmoles) injected into the ventromedial hypothalamus 5 minutes before morphine (5.6 nmoles) caused a short-lived decrease in feeding and temperature when compared with a saline control. The same dose of naloxone given into this site 1 hour after morphine had no apparent effect on either parameter. Naloxone (2 and 10 mg/kg) given subcutaneously suppressed feeding and temperature changes produced by intrahypothalamic morphine. These results indicate that morphine can increase feeding and temperature at a site which is also responsive to norepinephrine, and that naloxone, given intracranially or subcutaneously, can suppress the effects induced by morphine to different degrees.