The glucostatic theory supports the function of central and peripheral substrate 'sensors' to monitor cellular glucose metabolism and activate compensatory autonomic, endocrine, and behavioral responses to energy imbalance. Hyperphagia and hyperglycemia occur in response to fourth ventricular administration of glucose uptake inhibitors or antimetabolites. These findings suggest that decreased glucose oxidation (and consequent diminished generation of metabolic intermediates and/or glycolytic endproducts) within the periventricular hindbrain is a stimulus for motor output that restores glucostasis. Our preliminary observations that caudal fourth ventricular infusion of the monocarboxylate, lactate, attenuates glucoprivic feeding support this view. In the hindbrain, the nucleus of the solitary tract (NTS) and adjacent area postrema (AP) have been characterized as 'glucoprivic-sensitive' by electrophysiological, neuroanatomical, and pharmacological data. Our studies show that caudal fourth ventricular administration of the monocarboxylate uptake inhibitor, alpha-cyano-4hydroxycinnamic acid (4-CIN), elicits feeding and expression of the genomic regulatory factor, Fos, by catecholaminergic neurons within the NTS and AP. These data suggest that the neural circuitry controlling food intake is activated in response to decreased lactate oxidation within the periventricular CNS, and that the NTS and AP complex is critical for initiation and/or relay of regulatory signals of metabolic imbalance within this part of the brain. Studies described under aim 1 will utilize multiple pharmacologicai strategies to evaluate the significance of lactate utilization within the periventricular hindbrain for regulation of food intake. Experiments outlined under aim 2 will evaluate the role of catecholaminergic neurons in the NTS and AP in lactate deficit-induced feeding by investigating whether selective ablation of these cells by immunotoxin administration blocks ingestive responses to diminished lactate uptake, and if local noradrenergic/adrenergic cells that express the neuronal monocarboxylate transporter variant transcription undergo transcriptional activation during central glucoprivation. In light of evidence that the gaseous neurotransmitter, nitric oxide (NO), is critical for glucoprivic hyperphagia, and that nitrergic neurons within the NTS are genomically responsive to 2DG, aim 3 will determine if neuronal nitric oxide synthase (nNOS) activity in the NTS is enhanced by decreased availability of glucose-derived energy substrates, and if pharmacological suppression of local enzyme activity attenuates feeding responses to this metabolic imbalance.