The cytotoxic action of the ␥-isomer of hexachlorocyclohexane (␥-HCH, lindane) was studied in cultured mouse cerebellar granule neurons maintained in the presence or absence of the GABA A receptor agonist THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3ol). The cells were exposed for 24 hr to lindane (30-300 µM) in the culture medium. Changes in mitochondrial function were investigated by using the MTT (3-[4,5dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) test. The results showed that lindane-induced cytotoxicity was concentration-dependent. In cerebellar granule cells not treated with THIP, lindaneinduced cytotoxicity did not appear to be related to GABA A or GABA B receptors. However, in THIPtreated cultures, lindane-induced cytotoxicity was found to be mediated by an action of the insecticide on GABA receptors. In the latter case, GABA reduced the lindane-induced cytotoxicity, but the protective effect was not potentiated by flunitrazepam. The GABA A receptor agonist muscimol (50 µM) also protected the THIP-treated cultures against lindaneinduced cytotoxicity. In addition, the GABA B receptor agonist R(؉)baclofen protected the cells from lindaneinduced cytotoxicity and the effect of baclofen was blocked by GABA B receptor antagonists. Pertussis toxin was found to reverse the protective effect of baclofen only at the highest lindane concentration (300 µM). The lindane-induced cytotoxicity could be partly explained as being secondary to excitotoxicity as a mixture of the excitatory amino acid receptor antagonists APV (D-(-)-2-amino-5-phosphonopentanoate) and CNQX (6-cyano-7-nitro-quinoxaline-2,3dione) shifted the concentration-response curve for lindane-induced cytotoxicity to the right. It is suggested that the cytotoxic effects of lindane in THIPtreated cerebellar granule neurons are primarily related to an action of lindane on GABA B receptors and to a lesser extent on inducible low-affinity, benzodiazepine insensitive GABA A receptors.