Glucose modulates rat substantia nigra GABA release in vivo via ATP-sensitive potassium channels.

Abstract

Glucose modulates beta cell insulin secretion via effects on ATP-sensitive potassium (KATP) channels. To test the hypothesis that glucose exerts a similar effect on neuronal function, local glucose availability was varied in awake rats using microdialysis in the substantia nigra, the brain region with the highest density of KATP channels. 10 mM glucose perfusion increased GABA release by 111±42%, whereas the sulfonylurea, glipizide, increased GABA release by 84+20%. In contrast, perfusion of the KATP channel activator, lemakalim, or depletion of ATP by perfusion of 2-deoxyglucose with oligomycin inhibited GABA release by 44±8 and 45±11%, respectively. Moreover, the inhibition of GABA release by 2-deoxyglucose and oligomycin was blocked by glipizide.During systemic insulin-induced hypoglycemia (1.8±0.3 mM), nigral dialysate GABA concentrations decreased by 49±4% whereas levels of dopamine in striatal dialysates increased by 119+18%.We conclude that both local and systemic glucose availability influences nigral GABA release via an effect on KATP channels and that inhibition of GABA release may in part mediate the hyperexcitability associated with hypoglycemia.These data support the hypothesis that glucose acts as a signaling molecule, and not simply as an energy-yielding fuel, for neurons. (J. Clin. Invest. 1995. 95:2403-2408

Alterations in blood glucose levels under hyperinsulinemia affect accumbens dopamine

“…One of three concentrations of insulin (2.4 mU, "low"; 4.8 mU, "moderate"; 9.6 mU/kg per min; "high") was infused for each rat (n= 4, 5, and 4, respectively) in Experiment 1, whereas only one concentration (9.6 mU/kg per min; n= 5 for both conditions) was infused for each rat in Experiment 2. The insulin concentrations (2.4-9.6 mU/kg/min) were similar to those previous reported in hyperinsulinemia-glycemic studies that assessed the effects of hyperinsulinemia on neurotransmitter levels in the hypothalamus [15,25] and midbrain [16] in rats. Assessment of blood glucose levels were achieved by arterial samples taken every 10 min and measurements were done with a handheld glucometer (∼10 μl; Ascenia Elite, Bayer Co; sensitivity 1.1 mmol/L to 33.3 mmol/L).…”

“…Relevant to the present application, this method also has been utilized to control for insulin induced hypoglycemia [15,16]. In the following experiments, acute in vivo microdialysis was used to assess DA and its metabolites in the nucleus accumbens concurrent with the hyperinsulinemic-glycemic clamp.…”

The effect of modafinil on counter-regulatory and cognitive responses to hypoglycaemia

“…If we postulate that the brain's response to hypogly- caemia is activation of sympathetic centres, we must also postulate that any neurotransmitter released by glucose-sensing neurones must be inhibitory of the adrenergic responses, since its release by the glucosesensing neurone will be stimulated by hyperglycaemia and inhibited by hypoglycaemia, the equivalent of insulin release from the pancreatic beta cell. Hypoglycaemia and agents that close the beta cell K-ATP channel both stimulate neuronal GABA, at least in some brain regions, providing indirect evidence for the above hypothesis [15]. Modafinil, like the state of hypoglycaemia, has been shown to enhance c-fos immunoreactivity within the hypothalamus [38].…”

“…Streptozotocin-induced diabetic rats have high GABA levels, low noradrenaline and reduced sympathetic nerve activity within the VMH [14]. Infusion of glucose into rat substantia nigral neurones increases GABA concentrations, whilst both the perfusion of the glucoprivic agent 2-deoxyglucose and systemic hypoglycaemia significantly reduced GABA in some [15] but not all studies [16,17]. Perfusion of the neurones with K-ATP channel activators lowered GABA levels, and antagonists increased them, in a manner analogous to the insulin secretory responses to these agents by pancreatic beta cells, demonstrating the close relationship between GABA, intracellular ATP levels, the K-ATP channel complex and glucose sensing.…”

Central lipid detection and the regulation of feeding behavior

“…Other circulating parameters like plasmatic glucose encoding nutritional status can also influence mesolimbic system. In fact systemic glucose administration suppressed the firing of dopaminergic neurons within the SN (Saller and Chiodo, 1980) and local glucose in the SN increased GABA release (During et al, 1995). Authors suggested that glucose acts as a signaling molecule in DA neurons which played an important role in maintaining motivated feeding behaviors especially in response to abrupt decreases in glucose use (Saller and Chiodo, 1980).…”