The distribution of serotonin-2 (5-HT2) receptors in the rat brain was studied by light microscopic quantitative autoradiography. Receptors were labeled with four ligands: [3H]ketanserin, [3H]mesulergine, [3H]LSD and [3H]spiperone, which are reported to show high affinity for 5-HT2 receptors. Co-incubation with increasing concentrations of several well-known 5-HT2-selective drugs, such as pirenperone, cinanserin and ketanserin, resulted in an inhibition of the binding of the four 3H-labeled ligands to the same areas. However, all of them recognized, in addition to 5-HT2 sites, other populations of binding sites. Receptor densities were quantified by microdensitometry with the aid of a computer-assisted image-analysis system. Our results reveal a heterogeneous distribution of 5-HT2 receptor densities in the rat brain. Very high concentrations were localized in the claustrum, olfactory tubercle and layer IV of the neocortex. The anterior olfactory nucleus, piriform cortex and layer I of neocortex were also rich in 5-HT2 receptors. Intermediate concentrations of receptors were found in caudate putamen, nucleus accumbens, layer V of neocortex, ventral dentate gyrus and mammillary bodies. Areas containing only low concentrations of receptors included the thalamus, hippocampus, brainstem, medulla, cerebellum and spinal cord. The specificity of the different ligands used is discussed in terms of the other populations of sites recognized by them. The distribution of 5-HT2 receptors here reported is discussed in correlation with (a) the known distribution of serotoninergic terminals, (b) the specific anatomical systems and (c) the central effects reported to be mediated by 5-HT2-selective drugs.

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Depression is a major health problem worldwide. Most prescribed antidepressants, the selective serotonin reuptake inhibitors (SSRI) show limited efficacy and delayed onset of action, partly due to the activation of somatodendritic 5-HT 1A -autoreceptors by the excess extracellular serotonin (5-HT) produced by SSRI in the raphe nuclei. Interestingly, intranasal C-1A-siRNA administration produced the same effects, thus opening the way to the therapeutic use of C-1A-siRNA. Hence, C-1A-siRNA represents a new approach to treat mood disorders, as monotherapy or in combination with SSRI.3

The axonal transport blocker colchicine has been extensively used in immunohistochemical studies to induce accumulation of neuroactive compounds, especially neuropeptides, in neuronal somata and thus improve their visualization. To assess whether colchicine might, in addition, influence the synthesis of such compounds, we have now used in situ hybridization to examine the levels of mRNAs encoding for several neuropeptides (galanin [GAL], cholecystokinin [CCK], somatostatin [SOM], neuropeptide Y [NPY]) and neurotransmitter-synthesizing enzymes (choline acetyltransferase [ChAT], tyrosine hydroxylase [TH], amino acid decarboxylase [AADC], and glutamic acid decarboxylase [GAD]) after intraventricular administration of the drug. The results show that colchicine differentially modifies the levels of several mRNA species in different brain areas. Thus GAL mRNA levels increase in virtually all regions examined, including the basal forebrain, hypothalamus, dorsal raphe nucleus, locus coeruleus, and nucleus tractus solitarii. In addition, after colchicine treatment, GAL mRNA appears to be induced in the ipsilateral hemisphere in regions such as the cortex, hippocampus, striatum, lateral septum, and some nuclei of the thalamus as well as within white matter, where it cannot be detected in control animals. Although GAL mRNA in the vast majority of cases is neuronal, some findings indicate a possible glial localization. In parallel, colchicine depletes ChAT mRNA and increases GAD mRNA in the basal forebrain and striatum and decreases AADC mRNA in the dorsal raphe nucleus and locus coeruleus. In the latter nucleus, NPY and TH mRNA levels are increased by colchicine. In contrast, TH mRNA and also CCK mRNA levels decrease in the substantia nigra. In the cortex, hippocampus, and thalamus ipsilateral to colchicine injection CCK mRNA levels are markedly decreased, whereas SOM mRNA is decreased and NPY mRNA increased in the hippocampus but unchanged in the cortex. The results are discussed with reference to the possible artifacts that the use of colchicine might induce in immunohistochemical mapping studies and in relation to possible neurotoxic actions of colchicine, in some cases perhaps related to impaired retrograde transport of growth factor(s).

Serotonin 5‐HT4 receptors are widely distributed in the periphery and in brain, where they modulate the release of various neurotransmitters and have been implicated in learning and memory. Nine C‐terminal splice variants of this receptor have been cloned in mammalian species. In the rat, three such variants have been described: 5‐HT4(a), 5‐HT4(b), and 5‐HT4(e). In the present study, we have examined several aspects of the distribution of these receptors in brain. First, we provide, in rat and guinea pig, a detailed comparison of the distribution of 5‐HT4 receptors labeled by the antagonist [125I]‐SB 207710 with the distribution of their encoding mRNA visualized by in situ hybridization histochemistry (ISHH). The results suggest that, in several projection systems (striato‐nigral and striato‐pallidal pathways, projection from dentate granule cells to field CA3, habenulo‐interpeduncular pathway), 5‐HT4 receptors are located both somatodendritically and axonally. Second, we have analyzed the distribution of mRNA for the three known rat splice variants by reverse transcription‐polymerase chain reaction (RT‐PCR) and by ISHH. RT‐PCR indicates that all three variants are widely distributed, with 5‐HT4(b) mRNA being present in all regions examined (olfactory tubercle, striatum, hippocampus, inferior colliculus, substantia nigra, parietal cortex) and 5‐HT4(a) and 5‐HT4(e) showing a somewhat more restricted distribution. In other regions (periaqueductal gray, reticular formation, medial septum, diagonal band), faint ISHH signals are observed for 5‐HT4(a)+4(e) mRNAs, whereas 5‐HT4(b) mRNA signals are almost undetectable. Finally, neurotoxic lesions of basal ganglia components in guinea pig also indicate a location of these receptors on terminals of striatal projection neurons. J. Comp. Neurol. 484:418–439, 2005. © 2005 Wiley‐Liss, Inc.

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