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Species Differences in Regional Patterns of 3H-8-OH-DPAT and 3H-Zolpidem Binding in the Rat and Human Brain

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Abstract

The rat has proven to be a valuable preclinical model for characterizing effects of psychotrophic drugs and for identifying new psychotherapeutic agents in pharmacological screens. However, substantial differences have been described between the rat and human brain in regard to the neuroanatomical distribution of some drug and neurotransmitter receptor binding sites. To assess the utility of the rat as a model for the neuroanatomical topography of 5-HT1A and type 1 benzodiazepine (BDZ) receptors in humans, the distribution of binding sites for 3H-8-OH-DPAT (5-HT1A agonist) and 3H-zolpidem (type 1 BDZ agonist) was compared with autoradiography in select regions of the rat and human brain. Concordance in the binding patterns for the two ligands was observed in several brain regions for the two species. However, substantial differences were also found in the topography of binding sites for the ligands in the rat and human brain. High 3H-8-OH-DPAT binding was seen in the dorsal raphe nucleus and hippocampal formation in both the rat and human brain. However, species differences were observed in the relative distribution of ligand binding among hippocampal subregions. In the cerebral cortex, the laminar distribution of 3H-8-OH-DPAT binding sites was notably different for rats and humans. In humans, outer cortical layers were most densely labeled with 3H-8-OH-DPAT, whereas in the rat cortex, the highest binding was in the inner layers. A striking difference between rats and humans was observed for 3H-8-OH-DPAT binding in the lateral septal nucleus, which was densely labeled in the rat but weakly labeled in humans. Substantial differences between rats and humans were also observed for 3H-zolpidem binding. In the rat brain, high densities of binding sites were found in the medial septum, inferior colliculus, and substantia nigra reticulata. These regions showed very low 3H-zolpidem binding in the human brain. Intermediate binding was seen in the rat cerebral cortex, and low binding was found in the hippocampus. By contrast, in humans, cerebral cortical regions were the most densely labeled of all regions studied, and certain hippocampal subregions exhibited relatively high binding. The striking neuroanatomical differences in 3H-8-OH-DPAT and 3H-zolpidem binding observed between rats and humans suggest that different functional consequences may be produced within specific brain regions after administration of drugs that influence 5-HT1A and type 1 BZD receptors.

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Subjects

Male Sprague–Dawley (Charles River, Raleigh, NC) rats weighing 300–400 g were maintained under a 12 L:12 D cycle with continuous access to Purina rat chow and water. Rats were killed by decapitation and brains were frozen with powdered dry ice and stored at −70°C before sectioning.

Human brain regions were dissected at autopsy as authorized by the Chief Medical Examiner, State of North Carolina. Subjects died suddenly from gun shot wounds, stab wounds, vehicular trauma, or sudden cardiac arrest.

3H-8-OH-DPAT Binding in Rat and Human Brain

Discrete and selective labeling of neuroanatomical regions was observed with 3H-8-OH-DPAT in the rat and human brain. For both species, the topography of binding was identical across individual subjects. Although concordance in the neuroanatomical distribution 3H-8-OH-DPAT binding was found in some regions for rats and humans, substantial species differences were also observed.

3H-8-OH-DPAT Binding in Rat and Human Cerebral Cortex

A distinctly different laminar pattern of 3H-8-OH-DPAT binding was observed in human cerebral cortical regions in

Discussion

Similar binding affinities and pharmacological selectivity between rats and humans have been demonstrated with numerous ligands for neurotransmitter receptors, including 3H-OH-DPAT and 3H-zolpidem [see 12, 18, 23, 36, 37, 38. Thus, at a molecular level, the rat appears to be an excellent model system for neuropharmacological research. At a behavioral level also, the rat has proven to be a valuable heuristic model to characterize actions of drugs and to identify compounds that modulate 5-HT1A

Acknowledgements

This work was supported by MH-39144, AA00214, MH-33127, HD-03110, DA09491, and AA09079.

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