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Corticosteroids Regulate Brain Hippocampal SHT,, Receptor Mrna Expression

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Corticosteroids Regulate Brain Hippocampal SHT,, Receptor Mrna Expression The Journal of Neuroscience, March 1993, 13(3): 914-923 Corticosteroids Regulate Brain Hippocampal SHT,, Receptor mRNA Expression D. T. Chalmers, S. P. Kwak, A. Mansour, H. Akil, and S. J. Watson Mental Health Research Institute, University of Michigan, Ann Arbor, Michigan 48109 Using in situ hybridization techniques, the expression of ology of depressive illness and other affective disorders. In ad- 5-HT,, receptor mRNA was measured within the hippocam- dition to neuroendocrine function, serotonergic transmission is pal formation after bilateral adrenalectomy (ADX). After 24 implicated in normal and abnormal mental states (Eison, 1990) hr ADX, 5HT,, receptor mRNA expression was significantly and selective serotonergic compounds are clinically effective increased in all hippocampal subfields in ADX animals rel- antidepressants and anxiolytics (Cohn and Wilcox, 1985; Traber ative to sham-operated controls (SHAM). The magnitude of and Glaser, 1987). Thus, it is likely that the functional inter- the increase was most pronounced within CA2 (127%) and actions between the HPA system and the central serotonergic CA3/4 (94%)subfields of dorsal hippocampus, intermediate system may be significant, providing a biochemical basis for in the dentate gyrus (73%), and least within CA1 (60%). hormonally induced alterations in CNS circuits. Administration of exogenous cotticosterone (CORT) at the Corticosteroids have been shown to alter several elements of time of ADX maintained the level of 5-HT,, receptor mRNA serotonergic neurotransmission. Removal of circulating corti- expression within the range of SHAM animals. In vitro re- costeroids by adrenalectomy (ADX) results in anatomically spe- ceptor autoradiographic analysis of 5HT,, receptors in ad- cific decreases in indices of 5-HT metabolism, while stressful jacent sections from the same animals indicated a simul- procedures, which raise corticosteroid levels, produce corre- taneous increase in 5-HT,, binding throughout the sponding increases in 5-HT turnover (Curzon et al., 1972; Van hippocampus in response to ADX. 5-HT,, binding increased Loon et al., 198 1). Activity of tryptophan hydroxylase, the rate- to a similar extent (-30%) in CA subfields and dentate gyrus limiting 5-HT biosynthetic enzyme, appears to be sensitive to but remained within SHAM levels in CORT-replaced animals. circulating corticosteroid levels (Singh et al., 1990). However, 5-HT,, receptor mRNA levels were also increased in hip- corticosteroids may also act to modulate serotonergic neuro- pocampal subregions of 1 week ADX animals relative to transmission directly by regulating 5-HT receptors. Autoradio- SHAM animals. Within both CA1 and CA2 subfields, the in- graphic studies (Biegon et al., 1985) first identified increased crements were approximately double those observed after 5-HT, receptor binding in the rat hippocampal formation 1 week 1 d ADX. 5-HT,, receptor binding was increased in every after bilateral ADX. Subsequent investigations have confirmed hippocampal subfield to a similar extent as that observed the sensitivity of 5-HT, receptors to circulating corticosteroid after 1 d ADX. Increases in both 5-HT,, receptor mRNA ex- levels (De Kloet et al., 1986; Martire et al., 1989) and indicate pression and 5-HT,, receptor binding were preventable by that specific hippocampal subfields are exquisitely sensitive to administration of exogenous CORT at the time of ADX. Hip- adrenal steroids. More recent electrophysiological studies have pocampal 5-HTlC receptor mRNA and D, receptor mRNA shown a suppression of 5-HT-induced hyperpolarizations with- expression were not significantly altered by either acute or in CA 1 pyramidal cells after brief application of steroids (Joels chronic ADX treatment. These data indicate that adrenal et al., 1991) establishing a functional coupling for steroid-5- steroids may selectively regulate hippocampal 5-HT,, re- HT receptor interactions within the hippocampus. ceptors at the level of 5HT,, receptor mRNA expression. The complex displacement of high-affinity 3H-5-HT binding [Key words: 5-HT,, receptors, mRNA, cortkosteroids, hip- by spiperone (Peroutka and Snyder, 1979) first confirmed the pocampus, receptor regulation, in situ hybridization] heterogeneity of 5-HT, receptors, which have been further phar- macologically classified into at least four receptor subtypes, The ability of peripherally secreted adrenal steroids to enter the 5-HT,,-5-HT,,. Recent molecular cloning of 5-HT receptors CNS and alter mood and behavior is well established (McEwen, is supportive of this original classification (Julius et al., 1988; 1987). Documented abnormalities of hypothalamc+pituitary- Albert et al., 1990). Although original ADX studies did not adrenal axis (HPA) function in depressed subjects (Sachar et. differentiate between 5-HT, receptor subtypes, autoradiograph- al., 1973; Rubin et. al., 1987; Young et. al., 1991) forms the ic data using subtype-specific ligands (Pazos and Palacios, 1985; basis for the putative involvement of corticosteroids in the eti- Palacios et al., 1987) and in situ hybridization histochemistry (Chalmers and Watson, 199 1; Miquel et al., 199 1; Pompeiano Received July 13, 1992; revised Sept. 3, 1992; accepted Sept. 9, 1992. et al., 1992) indicate that the predominant postsynaptic hip- We thank Dr. J. Lopez and Dr. E. Young for their expert advice, Dr. J. Herman for MR and CR riboprobes, and S. Burke for outstanding technical support. This pocampal 5-HT, receptor is of the 5-HT,, type, suggesting that work was supported by grants from NIMH (1 PO1 MH42251) and The Lucille 5-HT,, receptors may be regulated by adrenal steroids. The P. Markey Charitable Trust (88-46) to H.A. and S.J.W. and a Fogerty Fellowship II FO5 TW04452-011 to D.T.C. reported alteration in hippocampal 5-HT,, receptor binding in ‘- Correspondence &&Id be addressed to Dr. D. Chalmers, Mental Health Re- response to restraint-induced stress (Mendelson and McEwen. search Institute, University of Michigan, 205 Zina Pitcher Place, Ann Arbor, MI 48105. 199 l), and the observed sensitivity of 5-HT,, receptors to ADX Copyright 0 1993 Society for Neuroscience 0270-6474/93/130914-10%05.00/0 (Mendelson and McEwen, 1990) are certainly supportive ofsuch The Journal of Neuroscience, March 1993, 13(3) 915 a conclusion. The possibility that the S-HT,, receptor may be transferred to tubes containing 0.5 ml of HCl and assayed for cortico- under corticosteroid control is, in itself, of great interest, as this sterone using competitive protein binding assay. ADX animals from site apparently fails to adapt to long-term changes in seroto- both 1 d and 1 week studies possessed undetectable corticosterone levels; nergic transmission induced by neurotoxic lesion (Verge et al., corticosterone-replaced animals from 1 d and 1 week survival times exhibited plasma corticosterone values of 4 ? 1 &dl and 1 f 1 &dl, 1986) or serotonergic drugs (Hensler et al., 199 1). respectively, which were not statistically different from sham-operated The signal transduction mechanism for corticosteroids in- groups at each time point. The higher mean corticosterone levels in 1 volves the translocation of hormonally bound cytosolic recep- d replaced animals results from the intraperitoneal injection of corti- tors to the cell nucleus, where association with specific genomic costerone as opposed to pellet implantation in 1 week replaced animals. Riboprobe design. 5-HT,, cRNA riboprobe was produced from a BalI- sites induces alterations in transcriptional efficiencies for par- PvuII fragment of the rat 5-HT,, receptor gene (Albert et al., 1990) ticular genes (Yamamoto, 1985). Pharmacological studies have ligated into HincII-cut pGEM blue (Promega). This fragment is com- defined at least two subtypes of corticosteroid receptors, which posed of a 910 base pair (bp) insert covering the sequence from the differ in their affinity for corticosterone (CORT, Reul and De beginning of the second putative transmembrane domain to the middle Kloet, 1985): the mineralocorticoid receptor (MR), which re- of the extracytoplasmic domain found between transmembrane do- mains VI and VII, encompassing the entire sequence of the third cy- sembles the peripheral kidney MR, binds CORT with high af- toplasmic loop. This represents the region of least homology for G-pro- finity, while the glucocorticoid receptor (GR) exhibits a three- tein-coupled receptors. 5-HT,, probe specificity was confirmed by to fivefold lower affinity for the endogenous ligand. Both au- absence of signal in both sections labeled with sense 5-HT,, probe and toradiographic and immunohistochemical studies (Sarrieau et sections pretreated with RNase prior to hybridization with antisense (cRNA) 5-HT,, probe (Chalmers and Watson, 1991). 5-HT,, cRNA al., 1984; Fuxe et al., 1985) indicate that the hippocampus con- probe was synthesized from a 500 bp HincII fragment of the 5-HT,, tains particularly high concentrations of both MRs and GRs cDNA pSR-lc (Julius et al. 1988) ligated into pGEM 32. This insert compared to other brain regions. In situ hybridization studies corresponds to the third putative cytoplasmic loop of the 5-HT,, re- confirm the intrahippocampal synthesis ofthese sites, and reveal ceptor and exhibited low sequence homology with both 5-HT,, and 5-HT, receptor cDNA. Probe specificity was confirmed by absence of a heterogeneous distribution of both MR and GR mRNAs across signal in brain sections labeled with sense 5-HT,, probe and pretreated hippocampal subfields (Herman et al., 1989a). It therefore
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