Cholecystokinin, dopamine and glutamate in subcortical and peripheral control of food intake

Abstract

This thesis analyzes some of the mechanisms whereby cholecystokinin octapeptide (CCK-8) inhibits food intake in male rats. Depletion of monoamines using reserpine blocked the capacity for ingestive responses. These responses were restored in reserpinized rats by treatment with the non-competitive N-methyl-D-aspartate receptor antagonist MK-801. MK-801 facilitated the intake of an intraorally infused 1M solution of sucrose and reversed the inhibitory effect of CCK-8. Injection of CCK-8 or intake of sucrose increased the concentration of dopamine and glutamate in the nucleus of the solitary tract (NTS), a brainstem relay that transmits feeding-related information from the gastrointestinal tract to the forebrain. Binding-sites for CCK-A and CCK-B, dopamine D2, but not D1, receptor ligands and MK-801 were found in the NTS. These results suggest that release of dopamine and glutamate in the brainstembrain mediates the inhibitory effect of CCK-8 on food intake. A full dopamine D1 receptor agonist caused minor suppression of intraoral intake but a dopamine D2 receptor agonist suppressed intraoral intake when injected into the NTS. Forebrain dopamine may be redundant in the control of intraoral intake, because lesioning the ascending dopamdeformitiesinergic pathways by injection of 6-OHDA into the lateral hypothalamus did not prevent the animals from showing essentially normal intraoral intake and respond to CCK-8 by reducing their intake. Lesioning the noradrenergic projections from the locus coeruleus to the forebrain with the neurotoxin DSP-4 attenuated the intraoral intake of sucrose but did not affect the total amount of food consumed during a day. Intraoral intake was partially. restored in DSP-4-treated rats by intracerebroventricular injection of noradrenaline. Intracerebroventricular injection of neuropeptide Y inhibited intraoral intake in neurologically intact rats and in DSP-4-treated rats whose intake had been restored by injection of noradrenaline. Injection of CCK-8 markedly suppressed intraoral intake, but binding of [125I]CCK-8 to the NTS was unchanged by the DSP-4 treatment. The noradrenergic innervation of the forebrain may thus be a substrate which interacts with CCK-8 in the control of meal size. Infusion of CCK-8 into the hepatic portal vein inhibited intraoral intake. This effect was blocked by pretreatment with a CCK-A-receptor antagonist or by hepatic vagal deafferentation. Infusion of MK-801 into the hepatic portal vein facilitated intraoral intake and this effect was blocked by hepatic vagotomy. CCK-8 may activate receptors located on hepatic vagal afferents by a hormonal mechanism and the activity of these receptors may be modulated by glutamate. It is suggested that CCK and glutamate interacts both peripherally and centrally in the control of food intake