Activation of lateral hypothalamic mGlu1 and mGlu5 receptors elicits feeding in rats

Abstract

Metabotropic glutamate receptors (mGluRs) have been popular drug targets for a variety of central nervous system (CNS) disease models, ranging from seizures to schizophrenia. The current study aimed to determine whether mGluRs participate in lateral hypothalamic (LH) stimulation of feeding. To this end, we used satiated adult male Sprague-Dawley rats stereotaxically implanted with indwelling bilateral LH guide cannulas to determine if injection of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), a broad mGluR group I and II agonist, would elicit feeding. Administration of 100 nmol ACPD induced feeding with a short latency. Similarly, unilateral LH injection of the selective mGluR group I agonist (S)-3,5-dihydroxyphenylglycine (DHPG) elicited significant feeding beginning 60 min postinjection and continuing until 4 h postinjection. Administration of the mGluR5 agonist, (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) produced a smaller delayed feeding response. These delayed but prolonged eating responses suggest that activation of LH mGluR1 and/or mGluR5 might be sufficient to elicit feeding. To determine which subtypes were involved, LH DHPG injections were preceded by LH injection of either the group I antagonist n-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC), the mGluR1 antagonist 6-amino-n-cyclohexyl-n,3-dimethylthiazolo[3,2-a]benzimi dazole-2-carboxamide hydrochloride (YM-298198) or the mGluR5 antagonist 3-((2-methyl-4-thiazolyl)ethynyl)pyridine (MTEP), and food intake was measured. PHCCC blocked DHPG-elicited feeding, and each of the other antagonists produced significant feeding suppression. These findings suggest roles for mGluR1 and/or mGluR5 in lateral hypothalamic circuits capable of stimulating feeding behavior.