Chronic lithium administration prevents both haloperidol-induced dopaminergic behavioral supersensitivity and increased tritiated neuroleptic binding to dopamine (DA) receptors in rat corpus striatum. Since chronic haloperidol treatment also induces tolerance to the activating effects to the drug on striatal DA synthesis, the ability of lithium to block neurochemical tolerance development was investigated. Whereas lithium treatment significantly (P less than 0.01) attenuated haloperidol-induced behavioral supersensitivity to apomorphine (0.33 and 0.66 mg/kg s.c.), it did not prevent tolerance to the elevation of striatal 3, 4-dihydroxyphenylacetic acid (DOPAC) levels 1 h after last treatment or in response to challenge with a low dose (0.1 mg/kg) of haloperidol during withdrawal. These results demonstrate a dissociation between the development of behavioral supersensitivity and the reduction in DOPAC increase. An assessment of lithium's demonstrated effects on supersensitivity development at various DA receptor sites suggests that tolerance may be mediated by presynaptic DA receptors on terminals of nigrostriatal neurons.