The influence of chronic dietary lithium administration was evaluated on dopamine receptor supersensitivity in the rat corpus striatum. Supersensitivity was induced with either unilateral destruction of dopamine-containing fibers in the nigrostriatal pathway or with 3 weeks of treatment with haloperidol (HAL). Both treatments elevated [3H]spiroperidol binding sites, but in neither case was this increase in ligand binding affected by chronic dietary Li (brain levels 0.8 to 1.2 mEq/1 tissue). Our rats receiving 21 daily injections of HAL did show a behavioral supersensitivity to the dopamine agonist, apomorphine, and this effect was attenuated by concurrent treatment with dietary Li (accompanying paper). However, in contrast to previous data, this behavioral attenuation could not be linked to the prevention of increased [3H]spiroperidol binding in the corpus striatum. Furthermore, co-administration of dietary Li to subjects injected with HAL for 3 weeks did not reverse the increased density of [3H]spiroperidol binding sites which developed in the corpus striatum. Neither HAL nor Li treatment altered the affinity of the radioligand for its binding site. In the same animals, neostriatal dopamine-sensitive adenylate cyclase was not affected by either long-term dietary Li or chronic neuroleptic treatment, supporting the view that membrane antagonist and agonist sites differentially adapt to chronic alterations of synaptic input. Taken together, the results are incompatible with the hypothesis that the anti-manic action of Li is related to its ability to prevent dopamine receptor supersensitivity.