The biarylpropylsulfonamide class of
alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (
AMPA) potentiators represented by N-2-(4-(4-cyanophenol)phenol)propyl-2-propanesulfonamide (
LY404187) and (R)-4'-[1-fluoro-1-methyl-2-(
propane-2-sulfonylamino)-ethyl]-
biphenyl-4-
carboxylic acid methylamide (
LY503430) are positive, allosteric
AMPA receptor activators, which enhance
AMPA receptor-mediated neurotransmission by reducing desensitization of the
ion channel. Although these compounds have efficacy in in vivo rodent models of cognition, depression, and
Parkinson's disease, little is known about biochemical pathways activated by these agents. Given the well established regulation of the
nitric oxide/cGMP pathway by excitatory neurotransmission, the current study characterized
AMPA receptor potentiator-mediated cGMP response in mouse cerebellum. Acute treatment by both
LY404187 and
LY503430 [2.0, 5.0, or 10 mg/kg subcutaneously (s.c.)] elevated basal cerebellar cGMP levels in a dose-dependent manner. Pretreatment with the noncompetitive, allosteric
AMPA receptor-selective antagonist 7H-1,3-dioxolo[4,5-h][2,3]
benzodiazepine-7-carboxamide, 5-(4-aminophenyl)-8,9-dihydro-N,8-dimethyl-monohydrochloride-(9CI) (
GYKI 53655) [3.0 mg/kg intraperitoneally (i.p.)], completely blocked the effect of
LY404187, demonstrating that activation of
AMPA receptors induces cGMP levels. Interestingly, pretreatment with the
N-methyl-d-aspartate (
NMDA) open channel blocker
dizocilpine (0.3 and 1.0 mg/kg i.p.) also abolished the
AMPA receptor potentiator-mediated cGMP accumulation, indicating that activation of
AMPA receptors leads to
NMDA receptor-mediated transmission involved in cGMP regulation. Pharmacological augmentation of the endogenous
glutamate tone via the
alkaloid harmaline (20-60 mg/kg i.p.) synergized with
AMPA potentiator activity and provided further direct evidence of in vivo allosteric activation of
AMPA receptors by
LY404187. The synergism between
harmaline and
LY404187 was specific, since cGMP accumulation induced by foot-
shock stress was not augmented by the
AMPA receptor potentiator. Taken together, these data indicate that the cGMP system may play an important role in pharmacological efficacy of the biarylpropylsulfonamide class of
AMPA receptor potentiators.