Alterations in extracellular GABA in the ventral hypothalamus of rats in response to acute glucoprivation

Beverly, J. Lee; Beverly, M. F.; Meguid, M.M.

doi:10.1152/ajpregu.1995.269.5.r1174

Cited by 17 publications

(24 citation statements)

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“…This interpretation may at first glance appear to differ from that reported by Beverly and colleagues (42,46,47). In those studies, it was shown that during an acute episode of hypoglycemia, VMH GABA levels increased in a biphasic manner, and the rise may be mediated by increases in norepinephrine levels.…”

Section: Discussionmentioning

confidence: 79%

ATP-Sensitive K+ Channels Regulate the Release of GABA in the Ventromedial Hypothalamus During Hypoglycemia

Chan

Lawson²,

Zhu³

et al. 2007

Diabetes

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OBJECTIVE-To determine whether alterations in counterregulatory responses to hypoglycemia through the modulation of ATP-sensitive K ϩ channels (K ATP channels) in the ventromedial hypothalamus (VMH) are mediated by changes in GABAergic inhibitory tone in the VMH, we examined whether opening and closing K ATP channels in the VMH alter local GABA levels and whether the effects of modulating K ATP channel activity within the VMH can be reversed by local modulation of GABA receptors.RESEARCH DESIGN AND METHODS-Rats were cannulated and bilateral guide cannulas inserted to the level of the VMH. Eight days later, the rats received a VMH microinjection of either 1) vehicle, 2) the K ATP channel opener diazoxide, 3) the K ATP channel closer glybenclamide, 4) diazoxide plus the GABA A receptor agonist muscimol, or 5) glybenclamide plus the GABA A receptor antagonist bicuculline methiodide (BIC) before performance of a hypoglycemic clamp. Throughout, VMH GABA levels were measured using microdialysis.RESULTS-As expected, diazoxide suppressed glucose infusion rates and increased glucagon and epinephrine responses, whereas glybenclamide raised glucose infusion rates in conjunction with reduced glucagon and epinephrine responses. These effects of K ATP modulators were reversed by GABA A receptor agonism and antagonism, respectively. Microdialysis revealed that VMH GABA levels decreased 22% with the onset of hypoglycemia in controls. Diazoxide caused a twofold greater decrease in GABA levels, and glybenclamide increased VMH GABA levels by 57%. T he established benefits of maintaining nearnormal blood glucose levels in patients with diabetes are limited by the risk of severe hypoglycemia (1,2). The problem is compounded by the fact that with each reoccurring episode of hypoglycemia, the body's ability to restore blood glucose levels to normal is compromised (3). Therefore, it is essential that we achieve a better understanding of how the body senses and activates defense mechanisms against hypoglycemia so that we can develop therapeutic strategies to more effectively prevent or minimize hypoglycemia in diabetic patients. CONCLUSIONS-OurSpecific regions within the brain (4 -12) and periphery (13-15) have been shown to respond to changes in glucose concentrations. One brain region in particular, the ventromedial hypothalamus (VMH), contains glucose-responsive neurons that detect changes in ambient glucose levels and then alter their firing rate accordingly (5,6,16 -19). Two predominant subtypes of glucose-sensitive neurons exist within the brain: the glucose-excited neurons that increase and the glucose-inhibited neurons that decrease their firing rate as glucose levels rise (19,20). Kang et al. (18) have demonstrated that these neurons contain much of the same glucose-sensing machinery (e.g., glucokinase, ATPsensitive K ϩ channels [K ATP channels], etc.) as pancreatic ␤-cells.The K ATP channels provide a close link between neuronal metabolism and the regulation of membrane potential in many tissues (21). K ATP channels are comp...

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Section: Discussionmentioning

confidence: 79%

ATP-Sensitive K+ Channels Regulate the Release of GABA in the Ventromedial Hypothalamus During Hypoglycemia

Chan

Lawson²,

Zhu³

et al. 2007

Diabetes

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“…Given its exquisite sensitivity to low-energy states, it is likely that this enzyme, which is downstream of GK, may take on a very important role in altering neuronal activity during hypoglycemia (29). Second, a number of neurons that are not necessarily glucosensing in type may be influenced by changes in local neurotransmitters such as ␥-aminobutyric acid (GABA) (30,31), glutamate (32), and norepinephrine (33) or neuropeptides such as corticotrophin-releasing hormone and urocortin (34), which are altered during insulin-induced hypoglycemia. Finally, although glucose-excited neurons clearly use the ATP-sensitive K ϩ channel to mediate their glucosensing (7,10,35,36), these channels are present on nonglucosensing neurons (10).…”

Section: Discussionmentioning

confidence: 99%

Ventromedial Hypothalamic Glucokinase Is an Important Mediator of the Counterregulatory Response to Insulin-Induced Hypoglycemia

et al. 2008

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OBJECTIVE-The counterregulatory response to insulin-induced hypoglycemia is mediated by the ventromedial hypothalamus (VMH), which contains specialized glucosensing neurons, many of which use glucokinase (GK) as the rate-limiting step in glucose's regulation of neuronal activity. Since conditions associated with increased VMH GK expression are associated with a blunted counterregulatory response, we tested the hypothesis that increasing VMH GK activity would similarly attenuate, while decreasing GK activity would enhance the counterregulatory response to insulin-induced hypoglycemia. RESEARCH DESIGN AND METHODS-The counterregulatory response to insulin-induced hypoglycemia was evaluated in Sprague-Dawley rats after bilateral VMH injections of 1) a GK activator drug (compound A) to increase VMH GK activity, 2) low-dose alloxan (4 g) to acutely inhibit GK activity, 3) highdose alloxan (24 g), or 4) an adenovirus expressing GK short hairpin RNA (shRNA) to chronically reduce GK expression and activity. RESULTS-CompoundA increased VMH GK activity sixfold in vitro and reduced the epinephrine, norepinephrine, and glucagon responses to insulin-induced hypoglycemia by 40 -62% when injected into the VMH in vivo. On the other hand, acute and chronic reductions of VMH GK mRNA or activity had a lesser and more selective effect on increasing primarily the epinephrine response to insulin-induced hypoglycemia by 23-50%.CONCLUSIONS-These studies suggest that VMH GK activity is an important regulator of the counterregulatory response to insulin-induced hypoglycemia and that a drug that specifically inhibited the rise in hypothalamic GK activity after insulininduced hypoglycemia might improve the dampened counterregulatory response seen in tightly controlled diabetic subjects. Diabetes 57:1371-1379, 2008 H ypoglycemia is a major complication of insulin therapy for diabetes, and the incidence of hypoglycemia has increased as clinicians have attempted to maintain tighter control of blood glucose levels in diabetic subjects (1). During hypoglycemia, declining glucose levels are detected by peripheral glucosensors and by specialized glucosensing neurons within select areas of the brain (2). A subset of these glucosensing neurons reside in the ventromedial hypothalamus (VMH), a brain area that includes the arcuate hypothalamic nucleus (ARC) and ventromedial hypothalamic nucleus (VMN). Many previous studies have confirmed the importance of the VMH in mediating the counterregulatory response to hypoglycemia (3,4) and suggest that the glucosensing neurons in this area might be critical regulators of these responses.Glucokinase (GK) (hexokinase IV) is a likely candidate as a regulator of glucosensing in VMH neurons (5-10). In vitro, inhibiting GK activity with either RNA interference (RNAi) or with a variety of drugs reduces the sensitivity of VMN glucosensing neurons. On the other hand, pharmacological activation with Compound A increases their sensitivity to glucose (5-8,10). Also, pharmacological inhibition of GK activity with alloxan i...

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“…Both the DMH and the VMH are areas which are involved in control of reproductive behaviour [45], and decreased GABA activity during lactation would favour a reduction in reproductive behaviour [46]. Possibly more importantly, the VMH is also associated with the control of ingestive behaviour, and there are a number of studies linking GABA to this function, with both anorectic [47, 48, 49]and orexigenic [50, 51, 52, 53]effects of GABA in the VMH reported. Hence, lactation- or suckling-induced changes in GABAergic neuronal activity in the VMH may be involved in regulating the hyperphagia characteristic of lactation.…”

Section: Discussionmentioning

confidence: 99%

Lactation Alters γ-Aminobutyric Acid Neuronal Activity in the Hypothalamus and Cerebral Cortex in the Rat

Kornblatt¹,

Grattan²

2001

Neuroendocrinology

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γ-Aminobutyric acid (GABA) neurons terminating in the hypothalamus have been implicated in the neuroendocrine regulation of reproductive hormones, particularly luteinizing hormone (LH) and prolactin. The aim of this study was to examine whether GABAergic neuronal activity in the hypothalamus was modified during lactation, and whether any observed changes correlated with changes in secretion of these hormones. Animals were divided into three experimental groups: diestrous controls, lactating with pups present (with pups), and lactating with pups removed for 4 h (without pups). Animals were decapitated either without treatment, or 60 min after inhibition of GABA degradation by aminooxyacetic acid (AOAA) (100 mg/kg, i.p.). The rate of GABA accumulation in the tissue after AOAA is a measure of GABA turnover. GABA turnover was estimated in 13 microdissected brain regions, and serum prolactin and LH measured by radioimmunoassay. Suckling was associated with significantly increased prolactin and significantly decreased LH compared with diestrous rats. In lactating rats with pups, GABA turnover was significantly increased in the cingulate cortex compared with diestrous rats. GABA turnover was significantly increased in the ventrolateral preoptic nucleus of lactating rats with pups compared with diestrous rats or lactating rats without pups. There was significantly lower GABA turnover in the anterior hypothalamic area, ventromedial and dorsomedial hypothalamic nuclei in lactating rats without pups compared with diestrous rats. There were no significant changes in other brain regions examined. The results demonstrate that activity of GABAergic neurons in specific parts of the hypothalamus and cerebral cortex is altered during lactation.

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Alterations in extracellular GABA in the ventral hypothalamus of rats in response to acute glucoprivation

Cited by 17 publications

References 0 publications

ATP-Sensitive K+ Channels Regulate the Release of GABA in the Ventromedial Hypothalamus During Hypoglycemia

ATP-Sensitive K+ Channels Regulate the Release of GABA in the Ventromedial Hypothalamus During Hypoglycemia

Ventromedial Hypothalamic Glucokinase Is an Important Mediator of the Counterregulatory Response to Insulin-Induced Hypoglycemia

Lactation Alters γ-Aminobutyric Acid Neuronal Activity in the Hypothalamus and Cerebral Cortex in the Rat

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