Ultrastructural localization of the serotonin transporter in superficial and deep layers of the rat prelimbic prefrontal cortex and its spatial relationship to dopamine terminals.

Dopamine levels within the prefrontal cortex (PFC) can be manipulated by selective inhibitors of the serotonin transporter (SERT). However, the cellular mechanisms underlying these effects are not clear. The present study sought to examine the distribution of immunogold-silver labeling for SERT (SERT-ir) in the rat prelimbic PFC and to describe its ultrastructural spatial relationship to dopamine axons labeled by immunoperoxidase staining for tyrosine hydroxylase (TH-ir). SERT was localized to axonal profiles that ranged in size from fine caliber fibers containing dense SERT-ir, primarily along the membrane, and rarely forming synapses to large, spherical varicosities exhibiting less dense staining, mainly within the cytoplasm, and more commonly forming synapses. Synaptic contacts of SERT profiles were typically asymmetric, axospinous, and more frequent in superficial (38%) than deep (19%) layers. For TH-ir profiles, only 24% were within the same 13.8 microm(2) microenvironment as SERT-ir profiles. Furthermore, TH-ir and SERT-ir profiles were rarely directly apposed to each other or convergent onto common dendritic structures. Instead, these two profiles were typically separated by an average distance of 1.30 microm in the coronal plane, a value that did not vary with the size of SERT-ir axons, the amount of SERT labeling, or the cortical layer examined. These results are consistent with two populations of SERT profiles within the rat prelimbic PFC that may arise from different raphe nuclei or that represent varicose and intervaricose portions of the same axons. Moreover, the functional interactions between cortical serotonin and dopamine systems that may contribute to the therapeutic efficacy of antidepressant drugs are likely to occur over distances greater than 1 microm.