CYTOTOXIC ACTION OF LINDANE IN CEREBELLAR GRANULE NEURONS IS MEDIATEDBY INTERACTION WITH INDUCIBLE GABA(B) RECEPTORS

The cytotoxic action of the gamma-isomer of hexachlorocyclohexane (gam ma-HCH, lindane) was studied in cultured mouse cerebellar granule neur ons maintained in the presence or absence of the GABA(A) receptor agon ist THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol), The cells w ere exposed for 24 hr to lindane (30-300 mu M) in the culture medium, Changes in mitochondrial function were investigated by using the MTT [ 4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) test. The r esults showed that lindane-induced cytotoxicity was concentration-depe ndent. In cerebellar granule cells not treated with THIP, lindane-indu ced cytotoxicity did not appear to be related to GABA(A) or GABA(B) re ceptors, However, in THIP-treated cultures, lindane-induced cytotoxici ty was found to be mediated by an action of the insecticide on GABA re ceptors, In the latter case, GABA reduced the lindane-induced cytotoxi city, but the protective effect was not potentiated by flunitrazepam. The GABA(A) receptor agonist muscimol (50 mu M) also protected the THI P-treated cultures against lindane-induced cytotoxicity, In addition, the GABA(B) receptor agonist R(+)baclofen protected the cells from lin dane-induced cytotoxicity and the effect of baclofen was blocked by GA BA(B) receptor antagonists. Pertussis toxin was found to reverse the p rotective effect of baclofen only at the highest lindane concentration (300 mu M). The lindane-induced cytotoxicity could be partly explaine d as being secondary to excitotoxicity as a mixture of the excitatory amino acid receptor antagonists APV (D -(-)-2-amino-5-phosphonopentano ate) and CNQX (6-cyano-7-nitro-quinoxaline-2,3-dione) shifted the conc entration-response curve for lindane-induced cytotoxicity to the right , It is suggested that the cytotoxic effects of lindane in THIP-treate d cerebellar granule neurons are primarily related to an action of lin dane on GABA(B) receptors and to a lesser extent on inducible low-affi nity, benzodiazepine insensitive GABA(A) receptors. (C) 1998 Wiley-Lis s, Inc.