INCREASED POTENCY AND BINDING OF MAZINDOL TO PUTATIVE BRAIN ANORECTICRECEPTORS IN OBESITY-PRONE RATS

A class of sodium-sensitive, low affinity binding sites in the brain r ecognizes [H-3]mazindol (MAZ). Competition for [H-3]MAZ binding at the se sites correlates with the anorectic potency of various phenethylami ne drugs suggesting that these might be anorectic binding sites. Here [H-3]MAZ binding, in the absence of sodium, was assessed by quantitati ve receptor autoradiography in rat brain. Binding was saturable, wides pread and heterogenous with K-d = 3-229 mu M and B-max = 0.64-21.9 nmo l/mg protein in various brain areas. By saturation studies, highest bi nding was in the somatosensory cortex, central amygdalar nucleus and b ed nucleus of the stria terminalis. Hypothalamic subnuclei had interme diate and the piriform cortex had low binding. Rats were identified as prone to develop (DIO-prone) or resist (DR-prone) diet-induced obesit y by their low vs. high 24 h urine norepinephrine excretion, respectiv ely. While similar in body weight and basal 30 min intake of 4% sucros e, DIO-prone rats had 28% greater inhibition of sucrose intake by 3 mg /kg MAZ, i.p. (86 +/- 5%) than DR-prone rats (67 +/- 6%; P = 0.05). DI O-prone rats also had 23-55% higher levels of 10 nM [H-3]MAZ binding i n various hypothalamic and amygdalar nuclei, the somatosensory, pirifo rm and gustatory cortices and thalamus. Given their greater sensitivit y the highest dose of MAZ used and their higher binding of MAZ to puta tive brain anorectic receptors, DIO-prone rats might have a deficiency of an endogenous satiety factor which could predispose them to develo p obesity when challenged with high energy, high sucrose diets.