The effects of hexachlorocyclohexane (HCH) isomers and some GABAergic compounds on [3H]noradrenaline (NA) release from rat hippocampal slices prelabelled with 80 nM [3H]NA were determined. The convulsant gamma-HCH isomer facilitated (EC50 = 21 microM) and the depressant delta-HCH isomer reduced (EC50 = 48 microM) the Ca(2+)-dependent K(+)-evoked release of [3H]NA, whereas alpha- and beta-HCH isomers did not show any effect. Moreover, alpha- and delta-HCH isomers antagonized the facilitation of evoked [3H]NA release induced by the gamma-HCH isomer. The GABAergic convulsant drugs, bicuculline, picrotoxin and pentylenetetrazol, did not cause any modification of the evoked [3H]NA release even at high concentrations. Neither bicuculline nor picrotoxin blocked the effects of HCH isomers on K(+)-evoked release of [3H]NA. Exposure of slices to diazepam reduced the K(+)-evoked release of [3H]NA (EC50 = 33 microM) in a manner similar to that of the delta-HCH isomer. In addition, diazepam (50 microM) blocked the gamma-HCH effect and caused an additive inhibitory response with the delta-HCH isomer. On the other hand, diazepam and delta-HCH induced a time-dependent Ca(2+)-independent enhancement of basal [3H]NA release. The results suggest that modulation of [3H]NA release in the hippocampus by HCH isomers may be involved in the central actions of these compounds, and that sites other than the classic GABAA receptor may underlie their presynaptic mechanisms of action.