Changes in rat serum corticosterone after treatment with metabotropic glutamate receptor agonists or antagonists

From previous work, it appears that glutamate can activate the hypothalamic -pituitary-adrenocortical (HPA) axis by an interaction at either ionotopic or metabotropic (G-protein coupled) receptors. For example, (1S,3R)-1-amino cyclopentane-1,3-dicarboxylate (ACPD), a metabotropic glutamate (mGlu) rece ptor agonist, has been shown to increase the levels of serum corticosterone in rats. The present study was undertaken to further characterize which of the mGlu receptors are substantially involved in control of the HPA axis. The group I mGlu receptor agonists, 3,5-dihydroxyphenylglycine (DHPG), 1S,3 R-ACPD, and 2-chloro-5-hydroxyphenylglycine (CHPG) but not the inactive iso mer 1R,3S-ACPD were found to dose-dependently increase serum corticosterone 1 h after intracerebroventricular (i.c.v.) injection in male rats. The rel ative potency, DHPG (EC50 = 520 nmol) > 1S,3R-ACPD (1.4 mu mol) = CHPG (2.7 mu mol) >> 1R,3S-ACPD (>>3 mu mol) is consistent with activation of group I (mGlu1/5) receptors. The effects of DHPG were long lasting with substanti al elevations in corticosterone remaining for at least 3 h. In a similar ma nner, the group III mGlu receptor agonists, L-AP4 (4-phosphono-2-aminobutyr ic acid) and L-SOP (serine-O-phosphate), were found to increase serum corti costerone levels at 1 h. In contrast, the mGlu group II selective agonists LY354740 (10 mg/kg, i.p.) and subtype-selective doses of the group II antag onist LY341495 (1 mg/kg, i.p.) did not significantly elevate serum corticos terone. Given the group I agonists results, it was surprising to find that group I selective and mGlu1 selective antagonists given alone also increase d serum corticosterone. As with the agonists, the rise in serum corticoster one with LY393675 (an mGlu1/5 antagonist, EC50=20 nmol, i.c.v.) and LY36738 5 (an mGlu1 antagonist, 325 nmol, i.c.v.) were dose-dependent and consisten t with their relative affinity for the group I mGlu receptors. The selectiv e mGlu5 antagonist MPEP [2-methyl-6-(phenylethylnyl)pyridine] increased ser um cortocosterone but only at high doses (>30 mg/kg, i.p.). A model involvi ng the high glutamatergic tone on GABAergic interneurons in the paraventric ular nucleus of the hypothalamus is discussed as a possible explanation for these results.