Orexin signaling is necessary for hypoglycemia-induced prevention of conditioned place preference.
While the neural control of glucoregulatory responses to insulin-induced hypoglycemia is beginning to be elucidated, brain sites responsible for behavioral responses to hypoglycemia are relatively poorly understood. To help elucidate central control mechanisms associated with hypoglycemia unawareness, we first evaluated the effect of recurrent hypoglycemia on a simple behavioral measure, the robust feeding response to hypoglycemia, in rats. First, food intake was significantly, and similarly, increased above baseline saline-induced intake (1.1 ± 0.2 g; n = 8) in rats experiencing a first (4.4 ± 0.3; n = 8) or third daily episode of recurrent insulin-induced hypoglycemia (IIH, 3.7 ± 0.3 g; n = 9; P < 0.05). Because food intake was not impaired as a result of prior IIH, we next developed an alternative animal model of hypoglycemia-induced behavioral arousal using a conditioned place preference (CPP) model. We found that hypoglycemia severely blunted previously acquired CPP in rats and that recurrent hypoglycemia prevented this blunting. Pretreatment with a brain penetrant, selective orexin receptor-1 antagonist, SB-334867A, blocked hypoglycemia-induced blunting of CPP. Recurrently hypoglycemic rats also showed decreased preproorexin expression in the perifornical hypothalamus (50%) but not in the adjacent lateral hypothalamus. Pretreatment with sertraline, previously shown to prevent hypoglycemia-associated glucoregulatory failure, did not prevent blunting of hypoglycemia-induced CPP prevention by recurrent hypoglycemia. This work describes the first behavioral model of hypoglycemia unawareness and suggests a role for orexin neurons in mediating behavioral responses to hypoglycemia.
Graduate School of Biomedical Sciences, Rutgers University, Newark, New Jersey; Department of Neurology, New Jersey Medical School, Rutgers University, Newark, New Jersey;
Oleg
O
Otlivanchik
Seattle Veterinary Specialists, Kirkland, Washington.
Nicole M
NM
Sanders
Graduate School of Biomedical Sciences, Rutgers University, Newark, New Jersey; Department of Neurology, New Jersey Medical School, Rutgers University, Newark, New Jersey; Neurology Service, Veterans Affairs Medical Center, East Orange, New Jersey; and.
Ambrose
A
Dunn-Meynell
Department of Neurology, New Jersey Medical School, Rutgers University, Newark, New Jersey; Neurology Service, Veterans Affairs Medical Center, East Orange, New Jersey; and levin@njms.rutgers.edu.
Barry E
BE
Levin
D000818:Animals; D001143:Arousal; D001522:Behavior, Animal / Q000187:drug effects; D001583:Benzoxazoles / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D003213:Conditioning, Psychological / Q000187:drug effects; D004195:Disease Models, Animal; D005247:Feeding Behavior / Q000187:drug effects; D007003:Hypoglycemia / Q000378:metabolism* / Q000503:physiopathology / Q000523:psychology; D008297:Male; D009287:Naphthyridines; D000068796:Orexin Receptor Antagonists / Q000494:pharmacology; D064446:Orexin Receptors / Q000187:drug effects / Q000378:metabolism; D000068797:Orexins / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D012201:Reward; D020280:Sertraline / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; D001786:Blood Glucose; D009287:Naphthyridines; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D000068797:Orexins; D014508:Urea; D020280:Sertraline
awareness; diabetes; perifornical hypothalamus; serotonin