title: Subchronic administration and combination metabotropic glutamate and GABAB receptor drug therapy in fragile X syndrome.
abstract: The most common cause of inherited mental retardation, fragile X syndrome, results from a triplet repeat expansion in the FMR1 gene and loss of the mRNA binding protein, fragile X mental retardation protein (FMRP). In the absence of FMRP, signaling through group I metabotropic glutamate receptors (mGluRs) is enhanced. We previously proposed a mechanism whereby the audiogenic seizures exhibited by FMR1 null mice result from an imbalance in excitatory mGluR and inhibitory GABA(B) receptor (GABA(B)R) signaling (Mol Pharmacol 76:18-24, 2009). Here, we tested the mGluR5-positive allosteric modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB), the mGluR5 inverse agonist 2-methyl-6-(phenylethynyl)pyridine (MPEP), and GABA(B) receptor agonists, alone and in combination on receptor protein expression and audiogenic seizures in FMR1 mice. Single doses of MPEP (30 mg/kg), the GABA(B)R orthosteric agonist R-baclofen (1 mg/kg), or the GABA(B)R-positive allosteric modulator N,N'-dicyclopentyl-2-(methylthio)-5-nitro-4,6-pyrimidine diamine (GS-39783) (30 mg/kg), reduced the incidence of seizures. However, when administered subchronically (daily injections for 6 days), MPEP retained its anticonvulsant activity, whereas R-baclofen and GS-39783 did not. When administered at lower doses that had no effect when given alone, a single injection of MPEP plus R-baclofen also reduced seizures, but the effect was lost after subchronic administration. We were surprised to find that subchronic treatment with R-baclofen also induced tolerance to a single high dose of MPEP. These data demonstrate that tolerance develops rapidly to the antiseizure properties of R-baclofen alone and R-baclofen coadministered with MPEP, but not with MPEP alone. Our findings suggest that cross-talk between the G-protein signaling pathways of these receptors affects drug efficacy after repeated treatment.
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Laura K K
authors.initials: LK
authors.lastname: Pacey
authors.forename: Sujeenthar
authors.initials: S
authors.lastname: Tharmalingam
authors.forename: David R
authors.initials: DR
authors.lastname: Hampson
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001418:Baclofen / Q000008:administration & dosage / Q000494:pharmacology; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology; D015153:Blotting, Western; D003517:Cyclopentanes / Q000008:administration & dosage / Q000494:pharmacology; D004347:Drug Interactions; D004361:Drug Tolerance; D020195:Epilepsy, Reflex / Q000517:prevention & control; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000188:drug therapy*; D018755:GABA Agonists / Q000008:administration & dosage / Q000494:pharmacology; D018757:GABA Modulators / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D018080:Receptors, GABA-B / Q000187:drug effects*; D018092:Kainic Acid Receptors / Q000187:drug effects; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*
chemical_list: D000927:Anticonvulsants; D001418:Baclofen; D001549:Benzamides; D003517:Cyclopentanes; D018691:Excitatory Amino Acid Antagonists; D051860:Fragile X Messenger Ribonucleoprotein 1; D018755:GABA Agonists; D018757:GABA Modulators; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D018080:Receptors, GABA-B; D018092:Kainic Acid Receptors; D018094:Receptors, Metabotropic Glutamate; C494553:3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide; C497684:Fmr1 protein, mouse; C478058:N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine; C121465:6-methyl-2-(phenylethynyl)pyridine