Abstract
The novel serotonin receptor subtypes, 5-HT6 and 5-HT7, are located in limbic regions and have nanomolar affinities for atypical antipsychotics. These factors have led some to speculate about the involvement of 5-HT6 and 5-HT7 receptors in schizophrenia. However, relatively little is known about these receptor subtypes, including the regulation of their expression in limbic regions. In particular, the regulation of extracellular serotonin levels in the striatum and hippocampal formation by glutamate receptors led us to examine the effects of systemic ionotropic glutamate receptor modulator treatment on 5-HT6 and 5-HT7 receptor expression in these regions. MK-801 treatment induced a dose-dependent decrease in striatal 5-HT6 receptor mRNA levels; similarly, both aniracetam and NBQX treatments also led to decreases in striatal 5-HT6 receptor mRNA levels. Hippocampal 5-HT6 and 5-HT7 receptor expression were not dramatically affected by any of the treatments. To our knowledge, this is the first demonstration of the regulation of striatal 5-HT6 receptor mRNA expression, and provides neurochemical anatomical evidence for the interaction of serotonergic and glutamatergic systems. Furthermore, although these two neurotransmitter systems are separately implicated in schizophrenia, the glutamatergic regulation of the expression of a receptor subtype associated with schizophrenia suggests that alterations in serotonin receptor expression in schizophrenia may result, in part, from altered glutamatergic activity.
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References
Bartolini L, Risaliti R, Pepeu G . (1992): Effect of scopolamine and nootropic drugs on rewarded alternation in a T-maze. Pharmacol, Biochem, Behav 43: 1161–1164
Bourson A, Borroni E, Austin RH, Monsma FJ, Sleight AJ . (1995): Determination of the role of the 5-ht6 receptor in the rat brain: A study using antisense oligonucleotides. J Pharmacol Exp Ther 274: 173–180
Bourson A, Boess FG, Bos M, Sleight AJ . (1998): Involvement of 5-HT6 receptors in nigro-striatal function in rodents. Br J Pharmacol 125: 1562–1566
Burnet PWJ, Eastwood SL, Harrison PJ . (1996): 5-HT1A and 5-HT2A receptor mRNAs and binding site densities are differentially altered in schizophrenia. Neuropsychopharmacology 15: 442–455
Clarke PBS, Reuben M . (1995): Inhibition by dizocilpine (MK-801) of striatal dopamine release induced by MPTP and MPP+: Possible action at the dopamine transporter. Br J Pharmacol 114: 315–322
Eberle-Wang K, Mikeladze Z, Uryu K, Chesselet M-F . (1997): Pattern of expression of the serotonin2C receptor messenger RNA in the basal ganglia of adult rats. J Comp Neurol 384: 233–247
Fredrick JA, Meador-Woodruff JH . (in press): Effects of clozapine and haloperidol on 5-HT6 receptor mRNA levels in rat brain. Schizophrenia Res
Gerard C, El Mestikawy S, Lebrand C, Adrien J, Ruat M, Traiffort E, Hamon M, Martres M-P . (1996): Quantitative RT-PCR distribution of serotonin 5-HT6 receptor mRNA in the central nervous system of control or 5,7-dihydroxytryptamine-treated rats. Synapse 23: 164–173
Gustafson EL, Durkin MM, Bard JA, Zgombick J, Branchek TA . (1996): A receptor autoradiographic and in situ hybridization analysis of the distribution of the 5-ht7 receptor in rat brain. Br J Pharmacol 117: 657–666
Heidmann DEA, Metcalf MA, Kohen R, Hamblin MW . (1997): Four 5-hydroxytryptamine7 (5-HT7) receptor isoforms in human and rat produced by alternative splicing: Species differences due to altered intron-exon organization. J Neurochem 68: 1372–1381
Hollmann M, Heinemann S . (1994): Cloned glutamate receptors. Ann Rev Neurosci 17: 31–108
Joyce JN, Shane A, Lexow N, Winokur A, Casanove MF, Kleinman JE . (1993): Serotonin uptake sites and serotonin receptors are altered in the limbic system of schizophrenics. Neuropsychopharmacology 8: 315–336
Laruelle M, Abi-Dargham A, Casanova MF, Toti R, Weinberger DR, Kleinman JE . (1993): Selective abnormalities of prefrontal serotonergic receptors in schizophrenia. Arch Gen Psychiat 50: 810–818
LeCorre S, Sharp T, Young AH, Harrison PJ . (1997): Increase of 5-HT7 (serotonin 7) and 5-HT1A (serotonin 1A) receptor mRNA expression in rat hippocampus after adrenalectomy. Psychopharmacology 130: 368–374
Lindefors N, Barati S, O'Connor WT . (1997): Differential effects of single and repeated ketamine administration on dopamine, serotonin, and GABA transmission in rat medial prefrontal cortex. Brain Res 759: 205–212
Maione S, Rossi F, Biggs CS, Fowler LJ, Whitton PS . (1997): AMPA receptors modulate extracellular 5-hydroxytryptamine concentration and metabolism in rat striatum in vivo.. Neurochem Int 30: 299–304
McQuade R, Sharp T . (1997): Functional mapping of dorsal and medial raphe 5-hydroxytryptamine pathways in forebrain of the rat using microdialysis. J Neurochem 69: 791–796
Meltzer HY . (1992): The importance of serotonin–dopamine interactions in the action of clozapine. Br J Psychiat 17: 46–53
Monsma FJ, Shen Y, Ward RP, Hamblin MW, Sibley DR . (1993): Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs. Mol Pharmacol 43: 320–327
Nishimura M, Sato K, Okada T, Yoshiya I, Schloss P, Shimada S, Tohyama M . (1998): Ketamine inhibits monoamine transporters expressed in human embryonic kidney 293 cells. Anesthesiology 88: 768–774
Paxinos G, Watson C . (1982): The Rat Brain in Stereotactic Coordinates. New York, Academic Press
Pepeu G, Spignoli G . (1989): Nootropic drugs and brain cholinergic mechanisms. Prog Neuro-Psychopharmacol & Biol Psychiatry 13: S77–S88
Roth BL, Craigo SC, Choudhary MS, Uluer A, Monsma FJ, Shen Y, Meltzer HY, Sibley DR . (1994): Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors. J Pharmacol Exp Ther 268: 1403–1409
Shen Y, Monsma FJ, Metcalf MA, Jose PA, Hamblin MW, Dibley DR . (1993): Molecular cloning and expression of a 5-hydroxytryptamine7 serotonin receptor subtype. J Biol Chem 268: 18200–18204
Tao R, Auerbach SB . (1996): Differential effect of NMDA on extracellular serotonin in rat midbrain raphe and forebrain sites. J Neurochem 66: 1067–1075
Tao R, Ma Z, Auerbach SB . (1997): Influence of AMPA/kainate receptors on extracellular 5-hydroxytryptamine in rat midbrain raphe and forebrain. Br J Pharmacol 121: 1707–1715
Ward RP, Hamblin MW, Lachowicz JE, Hoffman BJ, Sibley DR, Dorsa DM . (1995): Localization of serotonin subtype 6 receptor messenger RNA in the rat brain by in situ hybridization histochemistry. Neuroscience 64: 1105–1111
Whitton PS, Biggs CS, Pearce BR, Fowler LJ . (1992): MK-801 increases extracellular 5-hydroxytryptamine in rat hippocampus and striatum in vivo. J Neurochem 58: 1573–1575
Whitton PS, Biggs CS, Richards DA, Fowler LJ . (1994a): N-Methyl-D-aspartate receptors modulate extracellular 5-hydroxytryptamine concentration in rat hippocampus and striatum in vivo. Neurosci Lett 169: 215–218
Whitton PS, Maione S, Biggs CS, Fowler LJ . (1994b): Tonic desensitization of hippocampal α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptors regulates 5-hydroxytryptamine release in vivo.. Neuroscience 63: 945–948
Yan Q-S, Reith MEA, Jobe PC, Dailey JW . (1997): Dizocilpine (MK-801) increases not only dopamine but also serotonin and norepinephrine transmissions in the nucleus accumbens as measured by microdialysis in freely moving rats. Brain Res 765: 149–158
Yau JLW, Noble J, Widdowson J, Seckl JR . (1997): Impact of adrenalectomy on 5-HT6 and 5-HT7 receptor gene expression in the rat hippocampus. Mol Brain Res 45: 182–186
Acknowledgements
This work was supported, in part, by a grant from the Theodore and Vada Stanley Foundation to JHM-W. Dr. Healy was supported by an institutional NRSA (MH15794) and an APA/Lilly Psychiatric Fellowship.
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Healy, D., Meador-Woodruff, J. Ionotropic Glutamate Receptor Modulation of 5-HT6 and 5-HT7 mRNA Expression in Rat Brain. Neuropsychopharmacol 21, 341–351 (1999). https://doi.org/10.1016/S0893-133X(99)00043-3
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DOI: https://doi.org/10.1016/S0893-133X(99)00043-3
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