Effect of chronic dexfenfluramine on Fos in rat brain

The acute appetite suppressant effect of dexfenfluramine (DF) in rats, which may depend upon its action to release serotonin (5-HT) in the brain, often declines with repeated dosing (tolerance). The mechanisms of this tolerance remain unclear. Previously, we used Fos-like immunoreactivity (Fos-IR) to map potential brain sites activated by single injections of DF in rats. A dose of 5 mg DF/kg activated the central amygdala (CeA), bed nucleus of the stria terminalis (BST), caudate-putamen (CPu), lateral parabrachial nucleus (LPB), nucleus tractus solitarius (NST), frontal cerebral cortex and the parvocellular paraventricular hypothalamic nucleus (PVN). We now report studies using Fos-IR in an attempt to understand which regions might underlie tolerance to the action of DF. Pretreatment of rats with an escalating dosage regimen of DF (0.5-4 mg/kg, i.p.) was associated with complete loss of Fos-IR to a probe dose (5 mg DF/kg) in the cortex, CPu, PVN and NTS, and partial loss of Fos-IR in the BST, CeA and LPB. Second, repeated treatment with DF (2 mg/kg), which has been shown to produce tolerance the anorexia caused by DF but not cholecystokinin (CCK), likewise reduced Fos-IR induced in the above brain regions, but had no effect on Fos-IR induced by either CCK or the 5-HT agonist, 5-carboxamidotryptamine. Third, repeated treatment with 5-HT (2 mg/kg, s.c.) had no effect on Fos-LR induced by a probe dose of DF. These data show that regionally heterogeneous hyporesponsiveness to the induction of Fos by DF develops after repeated low doses of DF; however, the Fos response to other putative anorectics or weight reducing agents is not affected. This may be related to behavioral tolerance.