clozapine-n-oxide and Hyperglycemia

Catecholamine (CA) neurons in the ventrolateral medulla (VLM) contribute importantly to glucoregulation during glucose deficit. However, it is not known which CA neurons elicit different glucoregulatory responses or whether selective activation of CA neurons is sufficient to elicit these responses. Therefore, to selectively activate CA subpopulations, we injected male or female Th-Cre+ transgenic rats with the Cre-dependent DREADD construct, AAV2-DIO-hSyn-hM3D(Gq)-mCherry, at one of four rostrocaudal levels of the VLM: rostral C1 (C1r), middle C1 (C1m), the area of A1 and C1 overlap (A1/C1), and A1. Transfection was highly selective for CA neurons at each site. Systemic injection of the Designer Receptor Exclusively Activated by Designer Drugs (DREADD) receptor agonist, clozapine-N-oxide (CNO), stimulated feeding in rats transfected at C1r, C1m, or A1/C1 but not A1. CNO increased corticosterone secretion in rats transfected at C1m or A1/C1 but not A1. In contrast, CNO did not increase blood glucose or induce c-Fos expression in the spinal cord or adrenal medulla after transfection of any single VLM site but required dual transfection of both C1m and C1r, possibly indicating that CA neurons mediating blood glucose responses are more sparsely distributed in C1r and C1m than those mediating feeding and corticosterone secretion. These results show that selective activation of C1 CA neurons is sufficient to increase feeding, blood glucose levels, and corticosterone secretion and suggest that each of these responses is mediated by CA neurons concentrated at different levels of the C1 cell group.

Topics: Activation, Metabolic; Adrenal Medulla; Animals; Antipsychotic Agents; Behavior, Animal; Catecholamines; Clozapine; Feeding Behavior; Female; Humans; Hyperglycemia; Luminescent Proteins; Male; Medulla Oblongata; Nerve Tissue Proteins; Neurons; Organ Specificity; Pharmacogenomic Variants; Rats, Transgenic; Receptors, Drug; Recombinant Fusion Proteins; Red Fluorescent Protein; Spinal Cord Lateral Horn

Hundreds of hormones and ligands stimulate cyclic AMP (cAMP) signaling in different tissues through the activation of G-protein-coupled receptors (GPCRs). Although the functions and individual effectors of cAMP signaling are well characterized in many tissues, pleiotropic effects of GPCR agonists limit investigations of physiological functions of cAMP signaling in individual cell types at different developmental stages

Topics: Animals; Blood Glucose; Cells, Cultured; Clozapine; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Glucose; Green Fluorescent Proteins; Hepatocytes; Hyperglycemia; Integrases; Liver; Mice; Mice, Inbred C57BL; Mice, Transgenic; Receptors, G-Protein-Coupled; RNA, Untranslated; Signal Transduction