Combined administration of an mGlu2/3 receptor agonist and a 5-HT 2A receptor antagonist markedly attenuate the psychomotor-activating and neurochemical effects of psychostimulants.
BACKGROUND
It was recently reported that administration of the metabotropic glutamate 2 and 3 (mGlu2/3) receptor agonist prodrug LY2140023 to schizophrenic patients decreased positive symptoms. However, at the single, potentially suboptimal, dose that was tested, LY2140023 trended towards being inferior to olanzapine on several indices of efficacy within the Positive and Negative Syndrome Scale.


OBJECTIVE
In this study, we examined whether the antipsychotic potential of mGlu2/3 receptor agonism can be enhanced with 5-HT(2A) receptor antagonism.


METHODS
Specifically, we characterized the effects of co-administering submaximally effective doses of the 5-HT(2A) receptor antagonist M100907 (0.2 mg/kg) and the mGlu2/3 receptor agonist LY379268 (1 mg/kg) on amphetamine-induced and MK-801-induced psychomotor activity in rats, an assay sensitive to antipsychotics. We also determined the effects of co-administering these two compounds on MK-801-induced dopamine and norepinephrine efflux in the nucleus accumbens (NAc).


RESULTS
At the submaximally effective doses tested, the effects of M100907 and LY379268 on amphetamine-induced and MK-801-induced psychomotor activity were significantly greater when given together than when given separately. Furthermore, coadministration of these doses of M100907 and LY379268 reduced MK-801-induced dopamine efflux in the NAc. This effect on dopamine release was not observed with the administration of either compound alone, even at higher doses that attenuated MK-801-induced psychomotor activity.


CONCLUSIONS
Our results suggest that a single compound having both mGlu2/3 receptor agonist and 5-HT(2A) receptor antagonist activity, or coadministration of two compounds selective for these receptors, could be superior in terms of efficacy and/or reduced side-effect liability relative to an mGlu2/3 receptor agonist alone.
Uslaner
Jason M
JM
Department of Schizophrenia Research, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA. jason_uslaner@merck.com
Smith
Sean M
SM
Huszar
Sarah L
SL
Pachmerhiwala
Rashida
R
Hinchliffe
Richard M
RM
Vardigan
Joshua D
JD
Hutson
Pete H
PH
D000596:Amino Acids / Q000494:pharmacology*; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005464:Fluorobenzenes / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology*
D000596:Amino Acids; D014150:Antipsychotic Agents; D018690:Excitatory Amino Acid Agonists; D005464:Fluorobenzenes; C534551:LY 2140023; D010880:Piperidines; D018094:Receptors, Metabotropic Glutamate; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D016291:Dizocilpine Maleate; D000661:Amphetamine; C079049:volinanserin; D004298:Dopamine; D009638:Norepinephrine
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