The present study was conducted to investigate the sensitivity of the cholinergic elements of ventral and dorsal striatal regions of the rat brain to the neurotoxin kainic acid (KA). Cholinergic activity was assessed by determining choline-acetyltransferase activity (CAT) and by measurements of acetylcholine (Ach) release from slices prelabeled with [3H]-choline. Direct stereotaxic injections of high-dose KA (4 micrograms/2 microliters) into specific brain regions, reduced CAT in caudate putamen (CP) by 91 +/- 1%, in nucleus accumbens (Nac) by 71 +/- 6%, but CAT in the olfactory tubercle (OT) was not affected by KA. The effects of KA on CP CAT were dose- and volume-dependent. In the OT, KA failed to affect CAT at low, moderate or high doses. Slices obtained from CP injected with KA (3 days prior) showed a 90% reduction in the electrically evoked release of [3H]-transmitter release; however, KA had no effect on transmitter release from OT. These results indicate that KA spares the cholinergic elements of the OT, and reveal the existence of marked differences in excitotoxic action of KA between ventral and dorsal striatal regions and among regions of the ventral striatum. Kainic acid preferentially damages neuronal cell bodies, dendrites and terminals intrinsic within the structures injected, with little or no effect on afferent axons and terminal boutons. Therefore, we propose that most of the Ach present in the OT may be within afferent axons and axon terminals. In the CP and NAc, KA lesions reflect loss of intrinsic cholinergic neurons. In addition, variable levels of excitatory inputs and of excitatory receptors, of the mechanisms available to reduce elevated intracellular calcium concentrations and of the levels of free-radical scavenging resources, also could account for the differences in KA neurotoxicity between OT and CP.