Sigma (σ) receptors have generated a great deal of interest on the basis of their possible role in psychosis and on locomotor behaviors. The effects of σ drugs on these various functions are apparently mediated by different a receptor subtypes (σ 1 andσ 2 ). However, little information is currently available on the discrete anatomical distribution of these putative σ receptor subtypes in the rat brain. The aim of the present study was to investigate, by quantitative autoradiography, the respective distribution of purportedσ 1 andσ 2 receptor subtypes in the rat brain using [ 3 H]1,3-di(2-tolyl)guanidine, a universal σ ligand, 86 and [ 3 H](+)pentazocine, a selectiveσ 1 ligand. 7 Putativeσ 2 receptor sites were visualized using [ 3 H]1,3-di(2-tolyl)guanidine in presence of a saturating concentration of (+)pentazocine. Specific [ 3 H]1,3-di(tolyl)guanidine and [ 3 H](+)pentazocine binding sites were found to be widely but discretely distributed in the rat brain. The highest densities of specific labeling were seen in various cranial nerve nuclei, followed by certain hippocampal sub-fields and laminae, the red nucleus, the interpeduncular nucleus and mid-layers of primary and secondary motor cortices. Lower amounts of specific binding were present in various other structures including most thalamic and hypothalamic nuclei, and the cerebellum. Interestingly, [ 3 H]1,3-di(2-tolyl)guanidine binding in the motor cortex was found to be particularly resistant to a saturating concentration of (+)pentazocine suggesting an enrichment in the putativeσ 2 receptor subtype. This also applies for a few other structures such as the nucleus accumbens, substantia nigra pars reticulata, central gray matter, occulomotor nucleus and cerebellum. On the other hand, theσ 1 subtype is more abundant in most other regions with the highest densities seen in the dentate gyrus of the hippocampal formation, facial nucleus, and various thalamic and hypothalamic nuclei.The comparative localization of theσ 1 andσ 2 receptor binding sites probably relates to the differential effects ofσ 1 andσ 2 drugs in the rat brain.