LOCATION AND EFFECT OF OBESITY ON PUTATIVE ANORECTIC BINDING-SITES INTHE RAT-BRAIN

Anorectic drugs such as mazindol bind to a class of low affinity, sodi um-sensitive sites in the brain which are affected by ambient glucose concentrations and a predisposition to develop diet-induced obesity (D IG). This study used quantitative autoradiography of 10 nM H-3-mazindo l binding to identify the cellular location of these putative anorecti c binding sites in the brain and to assess the way in which the develo pment of DIG affected their binding. We previously showed that chow-fe d, obesity-prone rats have widespread increases in brain H-3-mazindol binding to these low-affinity sites as compared with diet-resistant (D R) rats. Here, low-affinity H-3-mazindol binding was assessed in the b rains of eight rats which developed DIG vs. eight which were DR after three months on a high-energy diet. DIG rats gained 89% more weight an d had 117% higher plasma insulin levels but no difference in plasma gl ucose levels compared with DR rats. Along with these differences, low affinity H-3-mazindol binding in DIG rats was identical to that in DR rats in all of the 23 brain areas assessed. This suggested that this b inding was downregulated by the development of obesity in DIG rats. In other chow-fed rats, stereotaxic injections of 5,7-dihydroxytryptamin e and 6-hydroxydopamine (60HDA) to ablate serotonin and catecholamine nerve terminals in the ventromedial nucleus of the hypothalamus (VMN) had no effect on H-3-mazindol binding. However, ibotenic acid injected into the VMN, substantia nigra, pars reticulata, and pars compacta de stroyed intrinsic neurons and/or their local processes and decreased l ow-affinity H-3-mazindol binding by 13%-22%. Destruction of dopamine n eurons in the substantia nigra, pars compacta, and noradrenergic neuro ns in the locus ceruleus with 60HDA also reduced H-3-mazindol binding in those areas by 9% and 12%, respectively. This suggested that up to 22% of putative anorectic binding,sites may be located on the cell bod ies of dopamine, norepinephrine, and other neurons, but not on seroton in or catecholamine nerve terminals in the brain. Binding to these sit es may be downregulated by the development of DIG, possibly as a resul t of the concomitant hyperinsulinemia.