Central monoamine neurotransmitters affect blood glucose homeostasis. Activation of central cholinergic, noradrenergic histaminergic, and serotonergic neurons rapidly increase hepatic glucose output via the sympathetic nervous system. Acute hyperglycemia is mediated by three distinct pathways: the action of epinephrine on the liver, the action of glucagon on the liver, and the direct innervation of the liver. The relative contribution of these factors to hyperglycemia can be altered by diet and the kinds of neurotransmitters evoked in the central nervous system, but the magnitude of epinephrine secretion is closely related to the magnitude of hyperglycemia. On the other hand, neuropharmacological stimulation of central cholinergic muscarinic receptors, histaminergic H1 receptors, and serotonergic 5-HT2 receptors increases hypothalamic noradrenergic neuronal activity, which is associated with hyperglycemia. In contrast, central GABA(A) receptors play an inhibitory role in the regulation of hepatic glucose metabolism. Thus, central monoaminergic neurons could be linked together, and play a homeostatic role in the regulation of hepatic glucose metabolism.