Exaggerated feedback control decreases brain serotonin concentration and elicits hyperactivity in a rat model of diet-restriction-induced anorexia nervosa.
5-Hydroxytryptamine (5-HT; serotonin) system is the major neurotransmitter system of interest in research on anorexia nervosa (AN). The AN patients show extreme dieting weight loss, hyperactivity and low basal levels of 5-hydroxyindoleacetic acid (5-HIAA), a major metabolite of 5-HT in the cerebrospinal fluid (CSF). Studies on animal models show that diet restriction (DR) decreases 5-HT metabolism in the brain and hypothalamus which is not necessarily associated with a decrease in the availability of essential amino acid tryptophan (TRP) the precursor of serotonin. To further investigate the mechanism involved in DR-induced decreases of 5-HT the present study uses 8-hydroxy-(2-di-n-propylamino) tetralin (8-OH-DPAT), a selective 5-HT-1A agonist, as a probe to monitor the responsiveness of negative feedback control over 5-HT metabolism. Effects of DR and of 8-OHDPAT on TRP, 5-HT and 5-HIAA concentrations are determined in the hypothalamus, a region of the brain known to role in the regulation of appetite. Animals of DR group given access to food 2h daily for 6 days exhibited 21.6% decrease in the body weight compared to freely feeding (FF) controls. The levels of TRP in the plasma and of 5-HT in the hypothalamus decreased. No effect was found on the levels of TRP in the hypothalamus. 8-OH-DPAT-induced decreases of 5-HT and 5-HIAA were greater in DR than FF group. 8-OH-DPAT-induced hyperactivity was also greater in DR than FF group. The results show that DR-induced decreases of 5-HT are due to an increase in the responsiveness of negative feedback control over 5-HT and not due to smaller availability of TRP. DR-induced increase in activity and 8-OH-DPAT-induced greater hyperactivity in DR than FF group may also be due to exaggerated negative feedback control over 5-HT. It is suggested that drugs decreasing the responsiveness of negative feedback control over 5-HT may be of use for the treatment and prevention of AN in under weight patients on restricted diet.
Haleem
Darakhshan Jabeen
DJ
Department of Biochemistry, Neurochemistry and Biochemical Neuropharmacology Research Unit, University of Karachi, Karachi 75270, Pakistan. darakhshan_haleem@yahoo.com
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000008:administration & dosage; D000818:Animals; D000856:Anorexia Nervosa / Q000209:etiology / Q000503:physiopathology*; D001923:Brain Chemistry / Q000502:physiology*; D025461:Feedback, Physiological / Q000502:physiology*; D005260:Female; D005508:Food Deprivation; D006897:Hydroxyindoleacetic Acid / Q000032:analysis; D007031:Hypothalamus / Q000737:chemistry / Q000187:drug effects; D011595:Psychomotor Agitation / Q000209:etiology*; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000032:analysis*; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage
D017366:Serotonin Receptor Agonists; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin