Neuroendocrine and sympathetic responses to an orexin receptor antagonist, SB-649868, and alprazolam following insulin-induced hypoglycemia in humans.
BACKGROUND
The orexin-hypocretin system is important for translating peripheral metabolic signals and central neuronal inputs to a diverse range of behaviors, from feeding, motivation and arousal, to sleep and wakefulness. Orexin signaling is thus an exciting potential therapeutic target for disorders of sleep, feeding, addiction, and stress.


OBJECTIVE
Here, we investigated the low dose pharmacology of orexin receptor antagonist, SB-649868, on neuroendocrine, sympathetic nervous system, and behavioral responses to insulin-induced hypoglycemic stress, in 24 healthy male subjects (aged 18-45 years; BMI 19.0-25.9 kg/m(2)), using a randomized, double-blind, placebo-controlled, within-subject crossover design. Alprazolam, a licensed benzodiazepine anxiolytic, was used as a positive comparator, as it has previously been validated using the insulin tolerance test (ITT) model in humans.


RESULTS
Of the primary endpoints, ITT induced defined increases in pulse rate, plasma cortisol, and adrenocorticotropic hormone in the placebo condition, but these responses were not significantly impacted by alprazolam or SB-649868 pre-treatment. Of the secondary endpoints, ITT induced a defined increase in plasma concentrations of adrenaline, noradrenaline, growth hormone (GH), and prolactin in the placebo condition. Alprazolam pre-treatment significantly reduced the GH response to ITT (p < 0.003), the peak electromyography (p < 0.0001) and galvanic skin response (GSR, p = 0.04) to acoustic startle, the resting GSR (p = 0.01), and increased appetite following ITT (p < 0.0005). SB-649868 pre-treatment produced no significant results.


CONCLUSIONS
We concluded that the ITT model may be informative for assessing the effects of drugs directly acting on the neuroendocrine or sympathetic nervous systems, but could not be validated for studying low dose orexin antagonist activity.
Brain Mapping Unit, Behavioral and Clinical Neuroscience Institute, University of Cambridge, Cambridge, CB2 3EB, UK, ap531@cam.ac.uk.
Ameera X
AX
Patel
Sam R
SR
Miller
Pradeep J
PJ
Nathan
Ponmani
P
Kanakaraj
Antonella
A
Napolitano
Philip
P
Lawrence
Annelize
A
Koch
Edward T
ET
Bullmore
D000293:Adolescent; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D000525:Alprazolam / Q000494:pharmacology*; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D013006:Growth Hormone / Q000097:blood; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007003:Hypoglycemia / Q000097:blood* / Q000139:chemically induced; D007328:Insulin / Q000633:toxicity*; D047908:Intracellular Signaling Peptides and Proteins / Q000097:blood; D008297:Male; D008875:Middle Aged; D009479:Neuropeptides / Q000097:blood; D009490:Neurosecretory Systems / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000097:blood; D000068796:Orexin Receptor Antagonists; D000068797:Orexins; D011388:Prolactin / Q000097:blood; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*; D055815:Young Adult
D014151:Anti-Anxiety Agents; D001572:Benzofurans; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; C557781:N-((1-((5-(4-fluorophenyl)-2-methyl-4-thiazolyl)carbonyl)-2-piperidinyl)methyl)-4-benzofurancarboxamide; D009479:Neuropeptides; D000068796:Orexin Receptor Antagonists; D000068797:Orexins; D013844:Thiazoles; D000324:Adrenocorticotropic Hormone; D011388:Prolactin; D013006:Growth Hormone; D009638:Norepinephrine; D000525:Alprazolam