title: In vitro neuropharmacological evaluation of penitrem-induced tremorgenic syndromes: importance of the GABAergic system.
abstract: The effects of the fungal neurotoxin penitrem A on the GABAergic and glutamatergic systems in rat brain were evaluated. Penitrem A inhibited binding of the GABA(A)-receptor ligand [³H]TBOB to rat forebrain and cerebellar membrane preparations with IC₅₀ (half maximal inhibitory concentration) values of 11 and 9 μM, respectively. Furthermore, penitrem A caused a concentration-dependent increase of [³H]flunitrazepam and [³H]muscimol binding in rat forebrain, but not in cerebellar preparations. The stimulation of [³H]flunitrazepam binding by penitrem A was abolished by the addition of GABA. In cerebellar preparations, a different pharmacological profile was found, with penitrem A allosterically inhibiting [³H]TBOB binding by interacting with a bicuculline-sensitive site. Moreover, penitrem A inhibited the high affinity uptake of GABA and glutamate into cerebellar synaptosomes with IC₅₀ values of 20 and 47 μM, respectively. The toxin showed no effect on NMDA or AMPA glutamate receptor binding. In conclusion, our results suggest that penitrem A exerts region-specific effects in the brain, leading to positive modulation of GABA(A)-receptor function in forebrain. Conversely, penitrem A may act as a bicuculline-like convulsant in cerebellum.
authors.affiliation: Section of Chemistry and Toxicology, Norwegian Veterinary Institute, P.O. Box 750, Sentrum, N-0106 Oslo, Norway. ama@unilab.no
authors.forename: Angel S
authors.initials: AS
authors.lastname: Moldes-Anaya
authors.forename: Frode
authors.initials: F
authors.lastname: Fonnum
authors.forename: Gunnar S
authors.initials: GS
authors.lastname: Eriksen
authors.forename: Thomas
authors.initials: T
authors.lastname: Rundberget
authors.forename: S Ivar
authors.initials: SI
authors.lastname: Walaas
authors.forename: Mattis B
authors.initials: MB
authors.lastname: Wigestrand
mesh_terms: D000818:Animals; D008297:Male; D009183:Mycotoxins / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014202:Tremor / Q000139:chemically induced* / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D009183:Mycotoxins; C003626:tremortin; D005680:gamma-Aminobutyric Acid