Chronic fluoxetine induces opposite changes in G protein coupling at pre and postsynaptic 5-HT1A receptors in rat brain

Chronic treatment with the antidepressant fluoxetine may lead to changes in the properties of pre- and postsynaptic 5-HT(1A) receptors due to modifications in the receptor-G protein coupling process. We have evaluated, in rats, the effect of chronic fluoxetine (10 mg/kg/day) at brain 5-HT(1A) receptors using different techniques. The density of 5-HT(1A) receptors was unchanged in fluoxetine-treated rats vs. vehicle group. Stimulation of [(35)S]GTPgammaS binding induced by (+/-)8-OH-DPAT was significantly attenuated in dorsal raphe nucleus after fluoxetine (+3.7 vs. +31.2% in vehicle). The inhibition of dorsal raphe firing by (+/-)8-OH-DPAT (ED(50) in vehicle = 2.1 microg/kg, i.v.) was also attenuated in rats treated with fluoxetine (ED(50)=4.7 microg/kg). In contrast, a significant increase on (+/-)8-OH-DPAT-induced stimulation of [(35)S]GTPgammaS binding was observed in CA(1) (+53.4 vs.+20.2% in vehicle) and dentate gyrus (+105.7 vs. +52.6% in vehicle) but not in entorhinal cortex. Our data demonstrate that fluoxetine-induced desensitization of 5-HT(1A) autoreceptors occurs at G protein level. Moreover, a relevant finding is the region-specific hypersensitivity of postsynaptic 5-HT(1A) receptors, in the hippocampus but not in entorhinal cortex, following chronic fluoxetine. These differential adaptive changes in brain 5-HT(1A) receptors could underlie the mechanism of action of antidepressants and also contribute to their clinical effects.

[1]  L. Lanfumey,et al.  Early desensitization of somato-dendritic 5-HT1A autoreceptors in rats treated with fluoxetine or paroxetine , 1995, Naunyn-Schmiedeberg's Archives of Pharmacology.

[2]  Victoria Arango,et al.  Serotonin 1A Receptors, Serotonin Transporter Binding and Serotonin Transporter mRNA Expression in the Brainstem of Depressed Suicide Victims , 2001, Neuropsychopharmacology.

[3]  G. Rajkowska,et al.  Increase in Serotonin-1A Autoreceptors in the Midbrain of Suicide Victims with Major Depression—Postmortem Evidence for Decreased Serotonin Activity , 1998, The Journal of Neuroscience.

[4]  G. Aghajanian,et al.  Electrophysiological responses of serotoninergic dorsal raphe neurons to 5‐HT1A and 5‐HT1B agonists , 1987, Synapse.

[5]  J. Bockaert,et al.  5-HT1A-sensitive adenylyl cyclase of rodent hippocampal neurons: effects of antidepressant treatments and chronic stimulation with agonists. , 1991, The Journal of pharmacology and experimental therapeutics.

[6]  R. Duman.  Novel therapeutic approaches beyond the serotonin receptor , 1998, Biological Psychiatry.

[7]  S. Childers,et al.  In Vitro Autoradiographic Localization of 5-HT1A Receptor-Activated G-Proteins in the Rat Brain , 1997, Brain Research Bulletin.

[8]  D. Hoyer,et al.  Molecular pharmacology of 5-HT1 and 5-HT2 recognition sites in rat and pig brain membranes: radioligand binding studies with [3H]5-HT, [3H]8-OH-DPAT, (-)[125I]iodocyanopindolol, [3H]mesulergine and [3H]ketanserin. , 1985, European journal of pharmacology.

[9]  S. Beck,et al.  Fluoxetine selectively alters 5-hydroxytryptamine1A and gamma-aminobutyric acidB receptor-mediated hyperpolarization in area CA1, but not area CA3, hippocampal pyramidal cells. , 1997, The Journal of pharmacology and experimental therapeutics.

[10]  C. Montigny,et al.  Presynaptic and postsynaptic modifications of the serotonin system by long-term administration of antidepressant treatments. An in vivo electrophysiologic study in the rat. , 1991, Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology.

[11]  R. Samanin,et al.  Chronic treatment with citalopram facilitates the effect of a challenge dose on cortical serotonin output: role of presynaptic 5-HT1A receptors. , 1994, European journal of pharmacology.

[12]  M. De Vivo,et al.  Characterization of the 5-hydroxytryptamine1a receptor-mediated inhibition of forskolin-stimulated adenylate cyclase activity in guinea pig and rat hippocampal membranes. , 1986, The Journal of pharmacology and experimental therapeutics.

[13]  P M Whitaker-Azmitia,et al.  Role of serotonin and other neurotransmitter receptors in brain development: basis for developmental pharmacology. , 1991, Pharmacological reviews.

[14]  Yogesh K. Dwivedi,et al.  Effects of subchronic administration of antidepressants and anxiolytics on levels of the α subunits of G proteins in the rat brain , 2005, Journal of Neural Transmission.

[15]  C. Montigny,et al.  Current advances and trends in the treatment of depression. , 1994, Trends in pharmacological sciences.

[16]  L. Vogt,et al.  Region-specific changes in 5-HT(1A) receptor-activated G-proteins in rat brain following chronic buspirone. , 2000, European journal of pharmacology.

[17]  J. Hensler,et al.  Regulation of 5‐HT1A receptor‐stimulated [35S]‐GTPγS binding as measured by quantitative autoradiography following chronic agonist administration , 2001, British journal of pharmacology.

[18]  J. Hensler,et al.  Differential Regulation of 5-HT1A Receptor-G Protein Interactions in Brain Following Chronic Antidepressant Administration , 2002, Neuropsychopharmacology.

[19]  B. Jacobs,et al.  Adult brain neurogenesis and psychiatry: a novel theory of depression , 2000, Molecular Psychiatry.

[20]  D. Kendall,et al.  Serotonin 5‐HT1A Receptor Activation Increases Cyclic AMP Formation in the Rat Hippocampus In Vivo , 1994, Journal of neurochemistry.

[21]  K. Vinod,et al.  Modulation of 5-HT1A receptor mediated response by fluoxetine in rat brain , 2000, Journal of Neural Transmission.

[22]  B. Lerer,et al.  Chronic clomipramine alters presynaptic 5-HT1B and postsynaptic 5-HT1A receptor sensitivity in rat hypothalamus and hippocampus, respectively , 2000, Neuropharmacology.

[23]  J. Palacios,et al.  Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors , 1985, Brain Research.

[24]  Trevor Sharp,et al.  A review of central 5-HT receptors and their function , 1999, Neuropharmacology.

[25]  R. Nicoll,et al.  A G protein couples serotonin and GABAB receptors to the same channels in hippocampus. , 1986, Science.

[26]  B. Lerer,et al.  Regulation of 5-hydroxytryptamine1A receptor function in rat hippocampus by short- and long-term administration of 5-hydroxytryptamine1A agonist and antidepressants. , 1992, The Journal of pharmacology and experimental therapeutics.

[27]  G. Aghajanian,et al.  Electrophysiology of the Central Serotonin System: Receptor Subtypes and Transducer Mechanisms a , 1990, Annals of the New York Academy of Sciences.

[28]  G. Aghajanian,et al.  Pertussis toxin blocks 5-HT1A and GABAB receptor-mediated inhibition of serotonergic neurons. , 1987, European journal of pharmacology.

[29]  F. Artigas,et al.  Chronic treatment with fluvoxamine increases extracellular serotonin in frontal cortex but not in raphe nuclei , 1993, Synapse.

[30]  D. Selley,et al.  In vitro autoradiography of receptor-activated G proteins in rat brain by agonist-stimulated guanylyl 5'-[gamma-[35S]thio]-triphosphate binding. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[31]  P A Sargent,et al.  Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment. , 2000, Archives of general psychiatry.

[32]  G. Mengod,et al.  Desensitization of 5-HT1A Autoreceptors by a Low Chronic Fluoxetine Dose Effect of the Concurrent Administration of WAY-100635 , 2001, Neuropsychopharmacology.

[33]  V. Klimek,et al.  EFFECTS OF REPEATED TREATMENT WITH FLUOXETINE AND CITALOPRAM, A 5‐HT UPTAKE INHIBITORS ON 5‐HT1A AND 5‐HT2 RECEPTORS IN THE RAT BRAIN. , 1994, Journal of psychiatry & neuroscience : JPN.

[34]  W. Foote,et al.  Action of psychotogenic drugs on single midbrain raphe neurons. , 1970, The Journal of pharmacology and experimental therapeutics.

[35]  C. de Montigny,et al.  Long-Term Antidepressant Treatments Result in a Tonic Activation of Forebrain 5-HT1A Receptors , 1998, The Journal of Neuroscience.

[36]  G. Aghajanian,et al.  Tricyclic antidepressants: long-term treatment increases responsivity of rat forebrain neurons to serotonin. , 1978, Science.

[37]  Claudette Boni,et al.  Differential adaptation of brain 5-HT1A and 5-HT1B receptors and 5-HT transporter in rats treated chronically with fluoxetine , 2000, Neuropharmacology.

[38]  M. Hamon,et al.  Quantitative autoradiography of multiple 5-HT1 receptor subtypes in the brain of control or 5,7-dihydroxytryptamine-treated rats , 1986, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[39]  L. D. van de Kar,et al.  Chronic fluoxetine induces a gradual desensitization of 5-HT1A receptors: reductions in hypothalamic and midbrain Gi and G(o) proteins and in neuroendocrine responses to a 5-HT1A agonist. , 1996, The Journal of pharmacology and experimental therapeutics.