Contribution of caudal brainstem to d -fenfluramine anorexia

Abstract

Of the central 5-HT substrates that may mediate the anorexic actions of systemically administered d-fenfluramine (d-FEN), those in the forebrain have received the most attention. As a counterpoint to this forebrain focus, we evaluated the contribution of caudal brainstem substrates to the anorexic action of d-FEN. Two experimental protocols were employed. In one we compared the feeding response (intra-oral intake of 12.5% glucose) of intact and chronic supracollicular decerebrate (CD) rats to systemic administration of d-FEN. In the other, d-FEN was administered via fourth intracerebroventricular (ICV) injection to determine whether a dose-related suppression of intra-oral intake could be obtained. A dose-dependent suppression of intra-oral intake was obtained in the CD rat treated with d-FEN (0-8 mg/kg, delivered IP 20 min before testing). The threshold dose was two to three times higher in CD rats than in their intact controls, but the dynamic range of the dose-response curves of the two groups were overlapping with similar slopes of decline and with comparable maximal intake suppression. Fourth ICV administration of d-FEN in the intact rat yielded a dose-related suppression of intra-oral intake. Intake was also suppressed by fourth ICV d-FEN (30 mg) when rats drank 12.5% glucose solution from a spout. The reduced intra-oral intake following fourth ICV d-FEN treatment was partially attenuated by the systemic administration of the serotonin antagonist metergoline (0.4 mg/kg; IP). The CD results demonstrate the sufficiency of caudal brainstem receptors in mediating intake suppressive responses to systemic d-FEN. The fourth ICV results suggest further that 5-HT receptors in the caudal brainstem play a significant role in normal meal size control in the neurologically intact rat.

Serotonin receptors in the caudal brainstem are necessary and sufficient for the anorectic effect of peripherally administered mCPP

“…Results of the present study with the 5-HT 2C/1B agonist, mCPP, extend judgments derived from our previous study (Grill et al 1997a) with the indirect 5-HT agonist, d-fenfluramine (see also results of Grill et al 1997b). In both cases: (1) peripheral (IP) agonist administration yielded a dose-related suppression of intake in both intact and CD rats, and (2) potent intake suppression was obtained with the agonist delivered to the fourth ventricle of neurologically intact rats at doses well below threshold for peripheral action.…”

Leptin and the Control of Food Intake: Neurons in the Nucleus of the Solitary Tract Are Activated by Both Gastric Distension and Leptin

“…Although we cannot entirely rule out a forebrain action, available information is inconsistent with the notion that icv injections also provide leptin to the hypothalamic parenchyma. First, ink or dye injected into the fourth ventricle (in volumes similar to those used here) was observed at and caudal to the injection site, but not rostral to it (48,49). Second, the behavioral effects of a number of peptide ligands (e.g.…”

The Neuroanatomical Axis for Control of Energy Balance

“…A necessary role of specifically brainstem receptors in the intact rat's response is demonstrated in a study in which the effect of systemic mCPP delivery was reversed by 4th-icv delivery of a low dose of the 5HT 2C antagonist, mesulergine (99). Finally, peripheral delivery of mCPP and D-fenfluramine yielded dose-related suppression of intraoral intake in decerebrate and in pair-fed control rats (68,99). A similar profile applies to the actions of dopamine agonists.…”