Bicyclic phosphates increase the cyclic GMP level in rat cerebellum, presumably due to reduced GABA inhibition

Abstract

Isopropyl bicyclic phosphate (IPTBO) (0.06 mg/kg i.p.) increased the content of cyclic GMP in rat cerebellar cortex 4-fold. Pretreatment with the nicotinamide antagonist 3-acetylpyridine (3-AP) 65 mg/kg i.p. 48 h before), which destroys the climbing fibers, did not antagonize the induced increase. In contrast, GABA (15 mumol intraventricularly) and muscimol (3 mumol and 10 mumol i.p.) abated the IPTBO induced increase of cyclic GMP. The Na+-independent receptor binding of GABA to synaptosomal membranes, as well as uptake and release of GABA in synaptosomes, were unaffected by IPTBO, but the binding of dihydropicrotoxinin to brain membranes was blocked by IPTBO (IC50 = 1 X 10(-6) M). Glutamate (3.75 or 7.5 mumol intraventricularly) increased the level of cyclic GMP in the cerebellum, but the glutamate level in the cerebellum was not affected by IPTBO (0.06 mg/kg). The present results suggest that the elevation of cerebellar cyclic GMP caused by the bicyclic phosphates is not due to activation of the climbing fibers but rather due to a GABA antagonistic effect. The mechanism of action of the bicyclic phosphates is possibly similar to that of picrotoxinin.