Modulation of stress-induced and stimulated hyperprolactinemia with the group II metabotropic glutamate receptor selective agonist, LY379268.
It is well recognized that glutamate is an integral excitatory neurotransmitter in the neuroendocrine control of several hormonal factors. While the ability of pharmacological agents acting at ionotropic glutamate receptors to modulate the levels of serum prolactin levels has been investigated, there have been few reports of the effects mediated by the G-protein coupled, metabotropic glutamate (mGlu) receptors. The present work was undertaken to investigate the role of the Group II mGlu receptors, mGlu2 and mGlu3 in the regulation of serum polactin levels. LY379268, a Group II selective agonist, did not alter basal levels of circulating prolactin in young (36-40 day old) male rats. However, when an immobilization stress-induced hyperprolactinemia was examined, 10 mg/kg s.c. of LY379268 significantly lowered serum prolactin levels. Similarly, pretreatment with LY379268 was able to reverse the hyperprolactinemia induced with the catecholamine synthesis inhibitor, alpha-methyl-p-tyrosine (aMPT). This inhibition of hyperprolactinemia could be prevented by pretreatment with LY341495, a Group II mGlu receptor antagonist. The Group II antagonist alone had no effect on either basal nor stimulated prolactin levels. The agonist LY379268 was able to prevent the transient hyperprolactinemia associated with stimulation of serotonin 5-HT2A receptors by 2,5-dimethoxy-4-iodoamphetamine (DOI), but did not alter the high levels of circulating prolactin induced with the D2 antagonist, haloperidol. When treatment with LY379268 was delayed until 1 h after aMPT, a time demonstrated to show a full effect of aMPT on serum prolactin levels, the Group II agonist was similarly able to reverse hyperprolactinemia, suggesting LY379268 did not act by preventing the partial catecholamine depletion by aMPT. Similarly, high doses of amphetamine, a dopamine (DA) releaser, were able to reverse the aMPT-induced hyperprolactinemia, consistent with sufficient levels of dopamine remaining after aMPT treatment to modulate prolactin levels. LY379268 did not alter the hyperprolactinemia seen in estrogen-primed, ovariectomized female rats. Taken together the results indicate that stimulation of mGlu2/3 has an indirect inhibitory action on pituitary prolactin release. It is speculated that disinhibition of tubero-infundibular DA release by presynaptic Group II mGlu receptors located on inhibitory inputs to the arcuate hypothalamic nucleus is a possible explanation for the findings.
Johnson
M P
MP
Neuroscience Department, Eli Lilly and Company, Indianapolis, IN 46285, USA. johnson_michael_p@lilly.com
Chamberlain
M
M
D000596:Amino Acids / Q000494:pharmacology*; D000661:Amphetamine / Q000494:pharmacology; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D006966:Hyperprolactinemia / Q000139:chemically induced / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D011388:Prolactin / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D012149:Restraint, Physical; D013315:Stress, Psychological / Q000188:drug therapy* / Q000503:physiopathology; D019805:alpha-Methyltyrosine / Q000494:pharmacology
D000596:Amino Acids; D000662:Amphetamines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; C118218:LY 379268; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D019805:alpha-Methyltyrosine; D011388:Prolactin; D000661:Amphetamine; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine