Metabolic-endocrine correlates of the lateral hypothalamic syndrome: the first 48 hours

Mature (224 g) male Sprague-Dawley rats received bilateral electrolytic (1 mA for 8 sec) lesions in the lateral hypothalamic area (LHAL) or sham operations (CON). One group of CON was allowed to eat ad lib (CON-ADLIB), a second CON group was pair-fed to the LHAL rats (CON-PF). Tap water was available ad lib. Two days after the operation/sham operation all rats were killed by decapitation. Body weight, body weight change, food intake, carcass fat, liver weight, epididymal fat pad weight, in vitro incorporation of U-C14-glucose into liver total lipid, glycogen and CO2 (oxidation) (DPM, DPM/mg protein) as well as oxidation in fat pad tissue, plasma glucose and insulin were significantly reduced in LHAL and CON-PF rats compared with CON-ADLIB. Glucose carbon incorporation into epididymal fat pad lipid and glycogen were normal in LHAL and CON-PF. Liver protein and plasma free fatty acids (FFA) were both higher in LHAL and CON-PF than in CON-ADLIB groups. Thus, many of the somatic and metabolic changes that appear in the first few days after lesion production are simply due to hypophagia. However, CON-PF rats also exhibited some significant differences from the LHAL group, i.e., their plasma glucose and incorporation of glucose carbon into liver glycogen (DPM) were significantly lower than in LHAL rats; alternatively, plasma FFA levels were higher in CON-PF than in LHAL rats. Also, liver weight/100 g body weight was lower and fat pad weight/100 g body weight was higher in CON-PF than in LHAL rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Normal pancreatic and intestinal enzymes in hypophagic growth-retarded rats that received dorsomedial hypothalamic lesions shortly after weaning

Male weanling Sprague-Dawley rats received bilateral electrolytic lesions in the dorsomedial hypothalamic nuclei (DMNL rats). Sham-operated rats served as controls. After being fed lab chow for two postoperative weeks, the animals were divided into four groups. One group of DMNL rats and controls received a high-caloric diet (high-fat diet, chocolate chip cookies, 32% sucrose solution, potato chips and marshmallows), whereas another group of DMNL rats and controls continued to receive lab chow. The experiment was terminated on the 185th postoperative day. In accordance with previous findings, DMNL rats, irrespective of diet, were lighter and shorter than controls. In addition, DMNL rats fed junk food were lighter than DMNL rats fed lab chow, and junk-fed controls weighed as much as chow-fed controls. Both DMNL rats and controls fed junk food were also shorter and showed higher carcass fat than their chow-fed counterparts. Also, DMNL rats fed junk food had less carcass fat than junk-fed sham-operated controls, whereas in accordance with previous findings, there was no difference between chow-fed DMNL rats and chow-fed sham-operated controls. Irrespective of diet, DMNL rats ate less calories than their respective sham-operated controls. Both absolute and percent pancreas weight and protein/pancreas were unaffected in DMNL rats but were reduced in both junk-fed groups in comparison with their chow-fed counterparts. Both concentrations and contents of pancreatic trypsinogen, amylase and lipase were unaffected in DMNL rats but total activities of all three enzymes were dramatically reduced in the junk-fed compared with the chow-fed DMNL rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Involvement of nucleus accumbens AMPA receptor trafficking in augmentation of D- amphetamine reward in food-restricted rats

Rationale

Chronic food restriction (FR) increases behavioral responsiveness to drugs of abuse and associated environments. Pre- and postsynaptic neuroadaptations have been identified in the mesoaccumbens dopamine pathway of FR subjects but the mechanistic basis of increased drug reward magnitude remains unclear.

Objectives

Effects of FR on basal and d-amphetamine-induced trafficking of AMPA receptor subunits to the nucleus accumbens (NAc) postsynaptic density (PSD) were examined, and AMPA receptor involvement in augmentation of d-amphetamine reward was tested.

Materials and methods

FR and ad libitum fed (AL) rats were injected with d-amphetamine (2.5 mg/kg, i.p.) or vehicle. Brains were harvested and subcellular fractionation and Western analyses were used to assess AMPA receptor abundance in NAc homogenate and PSD fractions. A follow-up experiment used a curve-shift protocol of intracranial self-stimulation to assess the effect of 1-naphthylacetyl spermine (1-NASPM), a blocker of Ca²⁺-permeable AMPA receptors, on rewarding effects of d-amphetamine microinjected in NAc shell.

Results

FR increased GluA1 in the PSD, and d-amphetamine increased p-Ser845-GluA1, GluA1, GluA2, but not GluA3, with a greater effect in FR than AL rats. d-amphetamine lowered reward thresholds, with greater effects in FR than AL rats, and 1-NASPM selectively reversed the enhancing effect of FR.

Conclusions

Results suggest that FR leads to increased synaptic incorporation of GluA1 homomers to potentiate rewarding effects of appetitive stimuli and, as a maladaptive byproduct, d-amphetamine. The d-amphetamine-induced increase in synaptic p-Ser845-GluA1, GluA1, and GluA2 may contribute to the rewarding effect of d-amphetamine, but may also be a mechanism of synaptic strengthening and behavior modification.     

Individual differences in dopamine uptake in the dorsomedial striatum prior to cocaine exposure predict motivation for cocaine in male rats

A major theme of addiction research has focused on the neural substrates of individual differences in the risk for addiction; however, little is known about how vulnerable populations differ from those that are relatively protected. Here, we prospectively measured dopamine (DA) neurotransmission prior to cocaine exposure to predict the onset and course of cocaine use. Using in vivo voltammetry, we first generated baseline profiles of DA release and uptake in the dorsomedial striatum (DMS) and nucleus accumbens of drug-naïve male rats prior to exposing them to cocaine using conditioned place preference (CPP) or operant self-administration. We found that the innate rate of DA uptake in the DMS strongly predicted motivation for cocaine and drug-primed reinstatement, but not CPP, responding when “price” was low, or extinction. We then assessed the impact of baseline variations in DA uptake on cocaine potency in the DMS using ex vivo voltammetry in naïve rats and in rats with DA transporter (DAT) knockdown. DA uptake in the DMS of naïve rats predicted the neurochemical response to cocaine, such that rats with innately faster rates of DA uptake demonstrated higher cocaine potency at the DAT and rats with DAT knockdown displayed reduced potency compared to controls. Together, these data demonstrate that inherent variability in DA uptake in the DMS predicts the behavioral response to cocaine, potentially by altering the apparent potency of cocaine.Subject terms: Motivation, Addiction, Reward     

Vasopressin administration in the first month of life: Effects on growth and water metabolism in hypothalamic diabetes insipidus rats

Rats homozygous for the mutant gene for diabetes insipidus (Brattleboro strain) are stunted in growth compared to rats heterozygous for the mutant gene and normal rats without the mutant gene. The hypothesis was tested that normal growth depends upon the presence of vasopressin. It was expected that replacement therapy of vasopressin to rats homozygous for diabetes insipidus would make possible a normal growth rate similar to that of rats heterozygous for diabetes insipidus. Rats heterozygous and homozygous for diabetes insipidus were treated with 0.25 U (Days 0–9) and 0.5 U (Days 10–29) of vasopressin during the first month of life. During the treatment period, vasopressin significantly increased the urine osmolalities of the homozygous rats demonstrating the renal effectiveness of the vasopressin. The results showed that remedial vasopressin administration could not produce normal growth rates in homozygous rats and may be detrimental. Six weeks following vasopressin treatment, homozygous, diabetis insipidus rats which had received vasopressin had increased 24 hr water intakes and decreased urine osmolalities compared to control, homozygous rats. Heterozygous rats also had decreased urine osmolalities resulting from vasopressin six weeks after the cessation of vasopressin treatment.     

Glutamate microinjection into the hypothalamic paraventricular nucleus attenuates ulcerative colitis in rats

Aim： To investigate the effects of glutamate microinjection into hypothalamic paraventricular nucleus （PVN） on ulcerative colitis （UC） in rats and to explore the relevant mechanisms. Methods： 2,4,6-Trinitrobenzenesulfonic acid （100 mg/kg in 50% ethanol） was instilled into the colon of adult male SD rats to induce UC. A colonic damage score （CDS） was used to indicate the severity of the colonic mucosal damage. The pathological changes in the colonic mucosa were evaluated using immunohistochemistry, Western blotting, biochemical analyses or ELISA. Ten minutes before UC induction, drugs were microinjected into the relevant nuclei in rat brain to produce chemical stimulation or chemical lesion. Results： Microinjection of glutamate （3, 6 and 12 pg） into the PVN dose-dependently decreased the CDS in UC rats. This protective effect was eliminated after kainic acid （0.3 IJg） was microinjected into PVN or into the nucleus tractus solitarius （NTS） that caused chemical lesion of these nuclei. This protective effect was also prevented when the AVP-V1 receptor antagonist DPVDAV （200 ng） was microinjected into the NTS. The discharge frequency of the vagus was markedly decreased following microinjection of glutamate into the PVN. Microinjection of glutamate into the PVN in UC rats significantly increased the cell proliferation and anti-oxidant levels, and decreased the apoptosis and Bax and caspase 3 expression levels and reduced the pro-inflammatory factors in the colonic mucosa. Conclusion： The activation of hypothalamic PVN exerts protective effects against UC, which is mediated by the NTS and vagus. The effects may be achieved via anti-oxidative, anti-apoptotic, and anti-inflammatory factors.     

Role of norepinephrine in the dorsomedial hypothalamic panic response: an in vivo microdialysis study

Blockade of gamma-aminobutyric acid-A (GABA(A)) receptors in the dorsomedial hypothalamus (DMH) elicits a panic-like response that includes increases in heart rate (HR), blood pressure (BP), respiration rate (RR), and anxiety. Norepinephrine (NE) has been postulated to be critical in regulating panic and anxiety responses. Therefore, the first study sought to determine changes in extracellular NE levels within the DMH following acute blockade of GABA(A) receptors in the DMH using in vivo microdialysis. Rats were implanted with femoral arterial catheters and microdialysis probes into the DMH. Following recovery, the DMH of conscious rats were perfused with 100, 150, or 200 microM solutions of the GABA(A) receptor antagonist bicuculline methiodide (BMI) via the microdialysis probe. HR and BP responses were recorded and the changes in extracellular levels of NE in the dialysate samples from the DMH were determined by HPLC. Rats receiving BMI injections showed dose-dependent increases in both the extracellular NE levels in the DMH as well as HR and BP. The second study was conducted to test the functional importance of NE in the DMH to the BMI-induced physiological responses. The effects of BMI microinjection into the DMH were measured at baseline and 10 days after local injection of either vehicle or two doses of 6-hydroxydopamine (6-OHDA), a neurotoxin known to lesion NE terminals. There was a significant loss of tissue NE levels as well as BMI-induced HR, BP and RR responses in the 6-OHDA-treated but not vehicle-treated rats. Thus, blockade of GABA(A) receptors in the DMH results in NE release and the presence of NE appears to be necessary for eliciting the physiological components of the panic-like responses in this region.     

Cholecystokinin octapeptide and caerulein injection into the dorsomedial nucleus accumbens potentiate apomorphine-induced jaw movements in rats.

The effects of bilateral intra-accumbal and intrastriatal injections of CCK-8 sulphate and its analogue, caerulein, on apomorphine-induced jaw movements were studied in ketamine-anaesthetized rats after C1 spinal transection. Jaw movements were detected by a photo-transducer attached to the mandible. CCK-8 (5, 10 and 20 ng) and its analogue, caerulein (1 and 5 ng), injected into the dorsomedial nucleus accumbens increased the frequency of apomorphine (0.2 mg/kg i.v.)-induced jaw movements. The potentiation was prevented by administration of a CCK-A receptor antagonist, lorglumide (5 ng), together with CCK-8 (20 ng) or caerulein (5 ng). Injection of lorglumide alone into the dorsomedial nucleus accumbens did not alter apomorphine (0.5 mg/kg i.v.)-induced jaw movements. Injections of CCK-8 (20 ng) and caerulein (5 ng) into adjacent sites (the ventrolateral nucleus accumbens, dorsal striatum and ventral striatum) did not affect the responses elicited by apomorphine (0.2 mg/kg i.v.). These results demonstrate that CCK-8 modulates responses elicited by a dopamine receptor agonist, apomorphine, in a region of the brain where CCK-8 is known to co-exist with dopamine.     

Amphetamine reversal of sexual impairment following anterior hypothalamic lesions in female rats

Ovariectomized female rats were sexually receptive after systematic administration of estrogen and progesterone. Anterior hypothalamic lesions abolished their receptivity. Systemic administration of low doses of d-amphetamine restored their receptivity. The reversal may be related to an effect of amphetamine on brain catecholamines involved in female sexual behavior.     

Feeding behavior induced by central norepinephrine injection is attenuated by discrete lesions in the hypothalamic paraventricular nucleus

Extensive brain-cannula mapping studies in the rat have demonstrated that th hypothalamic paraventricular nucleus (PVN) is the most sensitive brain site for elicitingeating behavior with central norepinephrine (NE) injection. The present experiments examined the impact of lesions aimed at the PVN on this NE-elicited eating responses. In rats with NE injection cannulas aimed at the lateral ventricle, bilateral lesions of the PVN significantly attenuated, by 60 to 70%, the eating effect induced by NE, at doses ranging from 20 to 160 nmoles. PVN lesions which extended ventrally to damage tissue lying within the periventricular region were more effective in abolishing the NE response than were lesions that remained confined to the dorsal aspects of the PVN. Large lesions located just dorsal to the PVN had no impact on the NE response. This evidence supports the primary role of the PVN in mediating the eating behavior elicited by central noradrenergic activation.     

Antidiuretic effects of dibutyryl-cyclic AMP microinjected into the hypothalamic supraoptic nucleus in water-loaded and ethanol-anesthetized rats

Effects of dibutyryl-cyclic AMP (db-cAMP) and cyclic AMP (cAMP) microinjected into the hypothalamic supraoptic nucleus (SON) which contains the neurons synthesizing and releasing antidiuretic hormone upon the outflow and the osmotic pressure of urine and the other visceral functions were investigated in water-loaded rats anesthetized with ethanol. When microinjected into the SON the dibutyryl analog of cAMP induced dose-dependent antidiuretic effects without significant effects on any other visceral functions. Dibutyryl-cAMP was much more effective than cAMP; The ED50 value for db-cAMP was approx. 200 nmol versus more than 500 nmol for cAMP. The time course of the antidiuretic effects was relatively slow with minimal urine outflow appearing only after more than 1/2 hour post-injection. The effects induced by db-cAMP demonstrated tachyphylaxis and were partially inhibited by pretreatment with atropine or theophylline, which suggests that the antidiuretic effects were mediated through muscarinic and adenosine receptors present in the nucleus.     

Serotonin influences the behavioral recovery of rats following nucleus basalis lesions.

The present study investigated the effects of serotonergic depletion upon the performance of rats with lesions of the nucleus basalis magnocellularis (NBM) in a nonspatial memory task. NBM lesions were made by injections of ibotenic acid. Serotonin was depleted by systemic injections of p-chloroamphetamine (PCA). After four weeks of testing, the choice accuracy of PCA rats was not different from that of control rats (CON), while the choice accuracy of NBM rats and rats with combined treatment (NBM + PCA) was significantly lower than CON rats, but not different from each other. After prolonged testing, performance improved in NBM rats, but not in NBM + PCA rats indicating that simultaneous loss of both cholinergic and serotonergic neurotransmission produced a significantly longer lasting behavioral deficit than the loss of cholinergic neurotransmission alone.     

Reduced hypotensive effect of clonidine after lesions of the nucleus tractus solitarii in rats

Bilateral electrolytic lesion of the area of the nucleus tractus solitarii (NTS) in rats produced a sustained increase in blood pressure and reduced the hypotensive response to a single dose of clonidine (30 μg/kg, i.v.). The same dose of clonidine evoked a much larger drop in blood pressure in another group of rats in which an equivalent increase in blood pressure was produced by bilateral section of the vagosympathetic trunks and occlusion of both carotid arteries. It is concluded that the dorsal part of the medulla oblongata in the area of NTS is an important link in the hypotensive action of clonidine.     

Central action of anorexic agents: effects of amphetamine and fenfluramine in rats with lateral hypothalamic lesions

The effects upon food intake of three dose levels of fenfluramine and amphetamine were compared in rats with bilateral or unilateral lesions of the lateral hypothalamus. Unilateral lesions produced little modulation of drug action but bilateral lesions brought about opposite effects on amphetamine and fenfluramine anorexia. At 8 weeks after operation amphetamine anorexia was significantly diminished in bilaterally lesioned animals whereas fenfluramine anorexia was significantly enhanced. Further tests carried out at 14 and 20 weeks after operation showed that amphetamine regained its anorexic potency in lesioned animals, while the enhanced potency of fenfluramine remained. The results are consistent with the belief that these two anorexic agents operate through quite separate sites and mechanisms of action.     

Effect of peptides introduced into the central nucleus of amygdala on the hypothalamic self-stimulation in chronically alcoholized rats

The reinforcing properties of neuropeptides (substance P, corticoliberin, leu-enkephalin, alaptide) and 70 kDa heat shock protein (HSP) administered into the extended amygdala were studied on the hypothalamic self-stimulation model in rats reared in community or social isolation since the 17th day after birth. Since that time (17th day) half of rats were given 5 - 15 % ethanol solution instead of water (semiforced alcoholization). In the age of 90 - 100 days, all rats were implanted electrodes into lateral hypothalamus and cannulas into the central nucleus of amygdala. In the group of alcohol-dependent rats, the alcohol administration was continued. In rats reared in community, corticoliberin, leu-enkephalin and substance P increased the reinforcing properties of self-stimulation in dose-dependent manner, but alaptide and HSP decreased self-stimulation moderately. In rats reared in social isolation, the vector of neuropeptide effects was retained, although the magnitude of the effects was lower. Therefore, the neuropeptides differently participate in the reinforcing mechanisms of hypothalamus. It is suggested that the extended amygdala modulates the reinforcing properties of lateral hypothalamus, probably by means of extrahypothalamic corticoliberin-containing neurons.     

谷氨酸单钠损毁弓状核对雌性大鼠骨组织形态计量学的实验研究

目的 观测EPO治疗大鼠面神经损伤后对面神经核神经元凋亡的的影响,探讨EPO促进神经再生与修复的机理.方法 96只SD大鼠随机分成4组.利用神经卡压法损伤面神经,每组在术后第7d,14d,21d和28d四个时间点取材,尼氏染色和免疫组织化学方法对面神经核神经元进行染色并定量分析.结果 经EPO治疗后,大鼠面神经核内凋亡抑制基因Bcl-2明显增多,细胞凋亡明显减少,EPO组明显优于对照组(P<0.01).结论 EPO有效提高周围神经损伤后的神经核内凋亡抑制基因的含量的表达,减少神经元凋亡,促进神经的再生与神经功能的恢复.     

Changes in morphine self-administration and morphine dependence after lesions of the caudate nucleus in rats

Rats were trained to bar press for intravenous infusions of morphine sulfate during 1-hr daily test sessions. Small, centrally placed bilateral lesions of the caudate nucleus reduced rates of morphine self-administration to approximately one seventh of preoperative levels; postoperative rates were similar to preoperative rates when the postoperative unit infusion dose of morphine was one tenth of the preoperative dose. Caudate lesions also lowered the threshold dose at which morphine's rewarding property could be detected. Physical dependence was studied in other rats receiving a 3-day continuous infusion of morphine sulfate via implanted subcutaneous silicone reservoirs. Caudate lesions ameliorated withdrawal-induced weight loss and naloxone-induced wet dog shakes. Both the self-administration and dependence data are consistent with the idea that morphine blocks dopaminergic transmission in the striatum.