Effects of 9 -tetrahydrocannabinol and ethyl alcohol on adjunctive behavior and the lateral hypothalamus

The fact that electrical stimulation of the lateral hypothalamus (LH) can be substituted for the delivery of a food pellet in typical schedule induced polydipsia was established and demonstrated the role of this part of the brain in the mediation of adjunctive behavior. The assumption that Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and ethyl alcohol affect behavior because of a differential effect on the same LH mechanism was supported by the following evidence. Relatively small doses of Δ⁹-THC, 0.25, 0.375, and 0.50 mg/kg, enhanced adjunctive drinking; whereas, larger quantities of 0.625 and 0.75 mg/kg had no appreciable effects. The effect is somewhat specific, as it did not occur with strychnine sulfate, and rate dependent within limits as it was most pronounced in animals with low rates of responding or in animals when responding at a low rate. The effect of rate dependency was also apparent with fixed interval schedules of 2 and 4 min and a multiple schedule of a fixed interval and a signalled timed out period of nonreinforcement. Low rates of responding were enhanced by all doses of Δ⁹-THC, 1.0, 1.5, 2.0, 2,5, and 3.0 mg/kg, and there was an obvious dose related decrease in high rates. A similar effect was observed with low and high rates of electrical self-stimulation through implanted LH electrodes. The hypothesis that some drugs such as Δ⁹-THC and ethyl alcohol can enhance the positive feedback in an LH mediated motor control system by the facilitation of the same mechanism which initially generated the behavior was confirmed. Oral self administration of ethyl alcohol in a saccharin sweetened fluid enhanced recovered adjunctive drinking of the solution in quantities which should be sufficient to produce physical dependence if continued for relatively long periods. Recovered adjunctive drinking occurs in animals without food or water deprivation and it is an intense and persistent phenomenon.     

Ventromedial hypothalamus vs. lateral hypothalamic D2 satiety receptors in the body weight increase induced by systemic sulpiride

Two experiments were conducted in order to see if dopamine satiety receptors in the lateral hypothalamus or satiety mechanisms in the ventromedial hypothalamus were involved in the hyperphagia and body weight increase induced by systemic sulpiride. In the first experiment, it was shown that systemic sulpiride (20 mg/kg) does not block the anorexia caused by intraperifornical injections of amphetamine. In the second experiment, sulpiride (20 mg/kg during 18 days) did not produce an additional increase in body weight in previously VMH-lesioned female rats. This last fact cannot be explained by a ceiling effect since insulin (5 U/day during 7 days) increased body weight in the same VMH rats in which sulpiride was not effective. These results do not support the hypothesis that systemic sulpiride reaches the perifornical dopamine D2 receptors to disinhibit feeding, but suggest instead an involvement of the ventromedial hypothalamus. This last suggestion is more in agreement with the hypothesis that sulpiride alters feeding and body weight gain through the induction of a functional gonadectomy.     

Impaired diet-induced thermogenesis in brown adipose tissue from rats made obese with parasagittal hypothalamic knife-cuts

Two experiments were performed to determine if bilateral parasagittal hypothalamic knife-cuts (KCs), which produce long-term overeating and obesity, after biochemical indices of brown adipose tissue (BAT) reactivity to thermogenic stimuli. In the first study, responses to environmental cold were tested. Four weeks after surgery, KC rats had gained 4-5 times more weight than controls and were obese (increased Lee Obesity Index and weight of gonadal white fat). Before being sacrificed, groups of KC and control rats were exposed to 4 degrees C for 21 hr or remained at 28 degrees C. Interscapular BAT weighed 300% more in KC rats, due largely to increased white fat content. Functional indices of BAT thermogenic capacity (protein content, DNA content, cytochrome oxidase activity and mitochondrial guanosine diphosphate (GDP) binding) were normal at 28 degrees C. Exposure to 4 degrees C produced greatly enhanced responses but these were equivalent for both groups. This suggested an intact capacity for non-shivering thermogenesis in obese KC rats. In the second study, the same BAT responses were examined in other rats fed a palatable "cafeteria" diet (CAFE). One week after surgery, KC and control rats were subdivided into groups that received chow alone or chow plus four different palatable foods daily. Before sacrificing 4-5 weeks later, KC rats had gained 3-4 times more weight than controls and were obese. Interscapular BAT weighed 200-300% more in KC rats. CAFE feeding produced larger increments in all variables for KC vs. control rats. Most importantly, GDP binding was reduced in both KC groups, and significantly more so after CAFE feeding.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of acute continuous exposure of the rat to cigarette smoke on amine levels and utilization in discrete hypothalamic catecholamine nerve terminal systems and on neuroendocrine function

Summary The effects of acute continuous exposure to the smoke from 1–4 cigarettes have been studied in the male rat in terms of hypothalamic catecholamine levels and utilization as well as the secretion of anterior pituitary hormones. Catecholamine levels in discrete hypothalamic catecholamine nerve terminal systems were studied by quantitative histofluorimetry. Catecholamine utilization was studied by means of the tyrosine hydroxylase inhibition method using -methyl-(±)-p-tyrosine methyl ester. The serum hormone levels of adenohypophyseal hormones and of corticosterone were measured by the use of radioimmunoassay procedures. The results show that acute continuous exposure to unfiltered but not to filtered (Cambridge glass fibre filters) cigarette smoke leads to small but dose-dependent reductions of amine levels in most of the hypothalamic noradrenaline and dopamine nerve terminal system. These effects were associated with an enhancement of regional hypothalamic noradrenaline utilization but not of dopamine utilization in the median eminence. Furthermore, a reduction of TSH and prolactin serum levels was noted as well as increases in ACTH secretion. These results are partly different from those previously obtained with rats acutely exposed to intermittent unfiltered cigarrete smoke. This difference is suggested to be due to a temporary blockade of catecholamine release following acute continuous exposure to cigarette smoke.This work has been supported by a grant (1223) from the Council for Tobacco Research, New York, USA and by a grant from the Svenska Tobaks monopolet Send offprint requests to K. Andersson at the above address     

Long-term effects of lateral hypothalamic lesions on brown adipose tissue in rats

A classic feature of animals with lateral hypothalamic (LH) lesions is their regulation of body weight at sub-normal levels. The present studies were done to determine whether this is associated with enhanced thermogenic activity of their brown adipose tissue (BAT). Three groups of young chow-fed male Holtzman rats were formed: (1) animals receiving bilateral radiofrequency heat lesions of the dorsal LH and then permitted free access to chow (LH rats); (2) non-lesioned animals that were pair-fed (PF) to the lesioned rats during a 2 week post-operative recovery period (Phase 1); (3) non-lesioned, ad lib fed (NORM) controls. After Phase 1, each group was divided and permitted free access to chow alone or an additional selection of palatable, novel food items (a "cafeteria" diet) for 2-3 weeks (Phase 2) to stimulate diet-induced thermogenesis in BAT. Finally, half of each sub-group was exposed to 4 degrees C for 15 hr to stimulate nonshivering thermogenesis in BAT. During Phase 1 LHs and PFs ate 50% less than NORMs. This resulted in a weight deficit of 16% for LHs and 12% for PFs. After the additional period of feeding palatable foods (Phase 2) LHs collectively weighed 14% less than NORMs whereas previously PFs had a weight deficit of only 4%. They gained less weight than NORMs or PFs despite a similar energy intake. LHs had small deposits of gonadal white adipose tissue [both total amount and expressed per metabolic body mass (kg 0.75)]. The weight of interscapular BAT was less in the LHs but its concentration of protein (mg/g) was higher.(ABSTRACT TRUNCATED AT 250 WORDS)     

大鼠脾虚证与血清甲状腺激素及下丘脑、胸腺细胞核T3受体关系

目的：探讨脾虚证与血清甲状腺激素及下丘脑、胸腺细胞核T3受体的关系。方法：成年SD大鼠32只了随机分为4组（每组8只）：A组（正常组）、B组（脾虚组）、C组（治疗组）、D组（自复组）。采用放射配基分析法,测定各组大鼠血清T3、T4、FT3、FT4、 γ－T3 及下丘脑、胸腺细胞核T3受体的含量。结果：B、D组大鼠血清T3、T4、FT3、FT4含量均较A、C组低,有显差异（P＜0.05或P＜0.01）;各且间血清γ－T3 含量无显性差异;B、D组下丘脑、胸腺细胞T3受体含量较A、C组低,有显差异（P＜0.01）。结论：血清甲状腺激素及下丘脑、胸腺细胞核T3受体的水平降低,可导致甲状腺激素生物效应低下,经由神经内分泌免疫调节环路,削弱免疫功能,这可能是脾虚证的一种重要病机。     

Hypothalamic GABAA receptor blockade modulates cerebral cortical systems sensitive to acute stressors

Pharmacologic blockade of GABA binding sites in the hypothalamus elicits a pattern of physiological and behavioral arousal. The latter outcome implicates a perturbation in the neural functioning of higher brain centers. The effect that hypothalamic GABA_A receptor modulation has on the function of cerebral cortical neural substrates linked with responses to stressors was assessed using microinfusion of bicuculline methiodide (BMI) into the medial hypothalamus of freely moving, handling habituated rats. BMI led to rapid increases in frontal cortical dopamine (DA) utilization (calculated from the sum of the levels of the DA metabolites, homovanilic and dihydroxyphenylacetic acids, divided by DA levels) resembling that identified following restraint-induced stress. Also, cortical GABA_A receptor function [using chloride (Cl^–) enhancement of³H-flunitrazepam (Flu) binding as an index] was disrupted; i.e. there was a loss of typical Cl^– enhancement of³H-Flu binding in animals after BMI infusions. However, placing animals in restraint after BMI infusion reversed the effects of BMI, with both DA utilization and Cl^– facilitated³H-Flu binding similar to control basal values. Muscimol infusions in separately prepared animals did not alter either frontal cortical DA utilization or GABA_A receptor function. The present results implicate GABA in the hypothalamus as gating activity of cortical systems involved in sensation of and/or responses to stressors. These findings may have important implications for effects of autonomic arousal on neural substrates involved in mediating stress responses.     

Increased NPY activity in the PVN contributes to food-restriction induced reductions in blood pressure in aortic coarctation hypertensive rats

We hypothesized that hypothalamic NPYergic mechanisms mediate the blood pressure lowering effect of caloric restriction in hypertensive rats. Aortic coarctation-induced (AC) hypertensive rats (n=25) were assigned to either an ad libitum fed control group (AL) or food restricted group (FR; 60% of AL consumption) for 3 weeks. Rats were instrumented chronically with vascular catheters and bilateral guide cannulae directed at the paraventricular hypothalamic nuclei (PVN). Blood pressure (BP) and heart rate (HR) responses to bilateral PVN microinjection of saline (200 nl) or the putative NPY receptor antagonists [D-Trp32]NPY(1-36) (3.3 micrograms/200 nl) and [D-Tyr27,36 Thr32]NPY(27-36) (D-NPY(27-36); 3.3 micrograms/200 nl) were determined. The FR rats were then refed and cardiovascular responses to PVN injections of NPY receptor antagonists were again determined. FR rats had significantly reduced resting BP (159+/-4 vs. 129+/-4 mmHg) and HR (360+/-11 vs. 326+/-9 bpm) compared to AL controls. Refeeding restored BP and HR of FR rats to levels similar to AL (BP=153+/-4 mmHg, HR=359+/-11 bpm). PVN administration of [D-Trp32]NPY produced foraging behavior and concurrent increases in BP and HR in FR, AL and Re-fed rats. The behavioral activation suggests that [D-Trp32]NPY(1-36) produced activation of NPY receptors. In contrast, D-NPY (27-36) did not produce any behavioral response or affect BP or HR in AL or Re-fed rats. In FR rats, D-NPY (27-36) produced significant increases in BP (peak=15+/-3 mmHg) which partially reversed the effect of FR on BP. Thus, in FR rats with reduced BP, PVN administration of an NPY receptor antagonist increases BP. NPY blockade in the PVN accounted for about 50% of the BP effect of food restriction, thus other mechanisms are likely to be involved. These findings are consistent with the hypothesis that NPYergic mechanisms may contribute to the reduction of BP produced by food restriction.     

Resistance to diet-induced obesity is associated with increased proopiomelanocortin mRNA and decreased neuropeptide Y mRNA in the hypothalamus

Mechanisms mediating genetic susceptibility to diet-induced obesity have not been completely elucidated. Elevated hypothalamic neuropeptide Y (NPY) and decreased hypothalamic proopiomelanocortin (POMC) are thought to promote the development and maintenance of obesity. To assess the potential role of hypothalamic neuropeptide gene expression in diet-induced obesity, the present study examined effects of a high-fat diet on hypothalamic NPY and POMC mRNA in three strains of mice that differ in susceptibility to develop diet-induced obesity. C57BL/6J, CBA, and A/J mice were fed either normal rodent chow or a high-fat diet for 14 weeks after which hypothalamic gene expression was measured. On the high-fat diet, C57BL/6J mice gained the most weight, whereas A/J mice gained the least weight. On the high-fat diet, NPY mRNA significantly decreased as body weight increased in CBA and A/J mice, but not in C57BL/6J mice. In addition, POMC mRNA significantly increased as body weight increased in A/J mice, but not in CBA and C57BL/6J mice. Since decreased NPY mRNA and increased POMC mRNA would presumably attenuate weight gain, these results suggest that a high-fat diet produces compensatory changes in hypothalamic gene expression in mice resistant to diet-induced obesity but not in mice susceptible to diet-induced obesity.     

Effect of novel environmental stimuli on rat behaviour and central noradrenaline function measured by in vivo microdialysis

Rationale: Although physically aversive stimuli induce functional changes in central noradrenergic neurones, little is known about the noradrenergic response to environmentally aversive stimuli. Objectives: The first aim was to characterise environmental features that are perceived as stressful by rats. The second was to investigate whether changes in the concentration of extracellular noradrenaline are induced by these environmental features. Methods: A light/dark shuttle-box was used to test rats’ behavioural response to a range of stimuli (novelty, bright light, and the presence of an unfamiliar rat), either before or after microdialysis probe implantation. Changes in the concentration of extracellular noradrenaline in the frontal cortex and hypothalamus in vivo were then evaluated on exposure to these same test conditions. Results: Naive rats spent less time in a brightly-lit test arena than a dark one. However, the behavioural response to the light arena was attenuated by the presence of an unfamiliar rat. Probe implantation intensified the response to the light arena but did not affect behaviour in the dark arena. In the microdialysis studies, there was no change in the concentration of extracellular noradrenaline on transfer of rats to the dark arena but there was an increase in both the frontal cortex (+45%) and hypothalamus (+75%) on exposure to the light arena. A similar increase was induced in both brain regions when the light arena contained an unfamiliar rat. Conclusions: Implantation of a microdialysis probe modifies the behavioural responses to certain environmental stimuli. Regardless of this, the extent to which rats perceive a novel environment as aversive is not the only determinant of the noradrenergic response to such stimuli. However, differences in stimulus controllability in the microdialysis and the behavioural experiments could influence the apparent intensity of the stress. Received: 29 October 1998 / Final version: 19 March 1999