In vitro neuropharmacological evaluation of penitrem-induced tremorgenic syndromes: Importance of the GABAergic system

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 GABAA-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 GABAA-receptor function in forebrain. Conversely, penitrem A may act as a bicuculline-like convulsant in cerebellum.

► A new ligand with region-specific effects on GABAA receptors is reported.
► The differential effects observed may explain selective neuropathology.
► No actions on pre- and postsynaptic glutamatergic processes indicate selectivity.