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Sigma receptors are associated with cortical limbic areas in the primate brain

Putative sigma receptors are a current target for antipsychotic drug development. Novel antipsychotic agents which possess selective and high affinity for sigma binding sites may serve as an alternative to the principal neuroleptic drugs currently in clinical use which mediate extrapyramidal side effects and dyskinesias through their blockade of dopamine receptors. We have used in vitro autoradiography to localize putative sigma receptors labelled with (+)‐[3H]‐3‐(3‐hydroxyphenyl)‐N‐(1‐propyl) piperidine [(+)‐[3H]‐3‐PPP] in the brain of the rhesus macaque. The binding characteristics of (+)‐[3H]‐3‐PPP in the primate brain were comparable to those previously described in the rodent. Saturation analysis demonstrated a single class of sites in cerebellar and hippocampal membranes with a Kd value of 28 nM. Sigma receptors labeled with (+)‐[3H]‐3‐PPP in the primate brain displayed the appropriate rank order of potency and stereoselectivity in competition binding assays. Haloperidol displaced (+)‐[3H]‐3‐PPP binding in the low nanomolar range, and the (+) isomer of pentazocine was 50‐fold more potent than (‐) pentazocine. Computerized densitometric analysis of the autoradiograms demonstrated a striking enrichment of sigma binding sites over the paralimbic belt cortices, including the orbitofrontal, cingulate, insular, parahippocampal, and temporopolar gyri. Peak densities of sigma receptors were seen over the medial and central nuclei of the amygdala and were widely distributed within the hippocampal formation. Sigma binding sites densities were elevated over the suprachiasmatic and supraoptic nuclei of the hypothalamus. Moderate sigma receptor densities were observed over the ventromedial sectors of the caudate and the putamen. Sigma receptors were also elevated over autonomic relay nuclei of the brainstem, including the nucleus of the solitary tract and the dorsal motor nucleus of the vagus. The distribution of sigma receptors in the primate brain suggests that the paralimbic belt cortices, amygdala, hippocampus, hypothalamus, and autonomic relay nuclei of the brainstem may be interrelated by a topographic chemical linkage. The autoradiographic visualization of sigma receptor distributions in the primate brain provides further support for a role of sigma receptor mechanisms in the functions of the limbic system. © 1992 Wiley‐Liss, Inc.