The Serotonin-1A Receptor in Anxiety Disorders
2009; Elsevier BV; Volume: 66; Issue: 7 Linguagem: Inglês
10.1016/j.biopsych.2009.03.012
ISSN1873-2402
AutoresElena Akimova, Rupert Lanzenberger, Siegfried Kasper,
Tópico(s)Nicotinic Acetylcholine Receptors Study
ResumoThe serotonin system plays an important role in the neural processing of anxiety. The involvement of the main inhibitory serotonergic receptor, the serotonin-1A (5-HT1A) subtype, in dysfunctional forms of anxiety has been supported by findings from a wide range of preclinical research and clinical trials, including treatment studies, genetic research, and neuroimaging data. The following article summarizes preclinical results with a focus on 5-HT1A receptor knockout and transgenic mice as genetic models of anxiety. Behavioral, autonomic, and endocrinological changes in these mice are reported. This article also presents genetic polymorphisms in humans associated with increased anxiety scores and pharmacological data focused on 5-HT1A receptor agonists and antagonists. Furthermore, molecular neuroimaging results are presented. Recent positron emission tomography (PET) studies have reported reduced 5-HT1A receptor binding in patients with panic disorder and social anxiety disorder, but not in posttraumatic stress disorder. In healthy subjects, increased anxiety scores might be associated with lower 5-HT1A receptor binding. This overview of preclinical and clinical data provides strong evidence for the key role of the 5-HT1A receptor in the serotonergic dysregulation of anxiety disorders. The serotonin system plays an important role in the neural processing of anxiety. The involvement of the main inhibitory serotonergic receptor, the serotonin-1A (5-HT1A) subtype, in dysfunctional forms of anxiety has been supported by findings from a wide range of preclinical research and clinical trials, including treatment studies, genetic research, and neuroimaging data. The following article summarizes preclinical results with a focus on 5-HT1A receptor knockout and transgenic mice as genetic models of anxiety. Behavioral, autonomic, and endocrinological changes in these mice are reported. This article also presents genetic polymorphisms in humans associated with increased anxiety scores and pharmacological data focused on 5-HT1A receptor agonists and antagonists. Furthermore, molecular neuroimaging results are presented. Recent positron emission tomography (PET) studies have reported reduced 5-HT1A receptor binding in patients with panic disorder and social anxiety disorder, but not in posttraumatic stress disorder. In healthy subjects, increased anxiety scores might be associated with lower 5-HT1A receptor binding. This overview of preclinical and clinical data provides strong evidence for the key role of the 5-HT1A receptor in the serotonergic dysregulation of anxiety disorders. Brain serotonin (5-HT) plays a major role in a number of physiological processes and pathological conditions. Serotonin neurotransmission is involved in the regulation of mood, impulse control, sleep, vigilance, eating, libido, and cognitive functions, such as memory and learning. In addition, serotonin is important in the modulation of anxiety and fear, as well as impulsiveness in suicidal and other violent acts (1Arango V. Underwood M.D. Boldrini M. Tamir H. Kassir S.A. Hsiung S. et al.Serotonin 1A receptors, serotonin transporter binding and serotonin transporter mRNA expression in the brainstem of depressed suicide victims.Neuropsychopharmacology. 2001; 25: 892-903Crossref PubMed Scopus (315) Google Scholar, 2Lemonde S. Turecki G. Bakish D. Du L. Hrdina P.D. Bown C.D. et al.Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide.J Neurol Sci. 2003; 23: 8788-8799Google Scholar). These effects are mediated by at least 14 different 5-HT receptors (3Barnes N.M. Sharp T. A review of central 5-HT receptors and their function.Neuropharmacology. 1999; 38: 1083-1152Crossref PubMed Scopus (2689) Google Scholar). Among them, the serotonin-1A (5-HT1A) receptor in particular is thought to play an important role in the etiology of anxiety disorders, supported by the fact that partial 5-HT1A receptor agonists are anxiolytics (4Goldberg H.L. Finnerty R.J. The comparative efficacy of buspirone and diazepam in the treatment of anxiety.Am J Psychiatry. 1979; 136: 1184-1187PubMed Google Scholar).Nonpsychotic and nonorganic anxiety is part of the following disorders: phobic anxiety disorders, general anxiety disorder (GAD), panic disorder (PD), obsessive-compulsive disorder (OCD), reaction to severe stress as acute stress reaction, and posttraumatic stress disorder (PTSD). Pathological harm avoidance, induced by conflict and fear, is a dimension of anxiety-related responses and may also be associated with increased 5-HT functional activity (5Cloninger C.R. A systematic method for clinical description and classification of personality variants A proposal.Arch Gen Psychiatry. 1987; 44: 573-588Crossref PubMed Scopus (2909) Google Scholar, 6Bailer U.F. Price J.C. Meltzer C.C. Mathis C.A. Frank G.K. Weissfeld L. et al.Altered 5-HT(2A) receptor binding after recovery from bulimia-type anorexia nervosa: Relationships to harm avoidance and drive for thinness.Neuropsychopharmacology. 2004; 29: 1143-1155Crossref PubMed Scopus (147) Google Scholar, 7Bailer U.F. Frank G.K. Henry S.E. Price J.C. Meltzer C.C. Mathis C.A. et al.Exaggerated 5-HT1A but normal 5-HT2A receptor activity in individuals ill with anorexia nervosa.Biol Psychiatry. 2007; 61: 1090-1099Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar). All of these disorders have common behavioral and physiological characteristics that respond to similar pharmacological treatment. Selective serotonin reuptake inhibitors (SSRIs) have become the first-line treatment for anxiety disorders. They act by selectively blocking the reuptake of 5-HT following its release from neurons, thereby changing 5-HT neurotransmission in the brain, including binding on the 5-HT1A receptor (8Spindelegger C. Lanzenberger R. Wadsak W. Mien L.K. Stein P. Mitterhauser M. et al.Influence of escitalopram treatment on 5-HT(1A) receptor binding in limbic regions in patients with anxiety disorders.Mol Psychiatry. 2008; ([published online ahead of print March 25])PubMed Google Scholar, 9Sibon I. Benkelfat C. Gravel P. Aznavour N. Costes N. Mzengeza S. et al.Decreased [18F]MPPF binding potential in the dorsal raphe nucleus after a single oral dose of fluoxetine: A positron-emission tomography study in healthy volunteers.Biol Psychiatry. 2008; 63: 1135-1140Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar).Due to the high density of the 5-HT1A receptor subtype in several cortical and subcortical areas, this receptor is considered the major inhibitory serotonergic receptor (10Varnas K. Halldin C. Hall H. Autoradiographic distribution of serotonin transporters and receptor subtypes in human brain.Hum Brain Mapp. 2004; 22: 246-260Crossref PubMed Scopus (264) Google Scholar). See Figure 1 for the distribution of 5-HT1A receptors in the human brain. The 5-HT1A receptor is expressed in high concentration in limbic, temporal, and prefrontal cortices, while having low density in the primary sensory areas. It is not yet certain how 5-HT1A alterations in different human brain areas are specifically associated with dysfunctions in anxiety processing. However, the topology of 5-HT1A alterations is a relevant factor. Given its broad distribution within the cortex, it is important to consider that 5-HT1A plays a role not only in anxiety and affective disorders, but also in the regulation of a variety of physiological states and behaviors, including fear, aggression, and impulsivity, as recently demonstrated by Witte et al. (11Witte A.V. Floel A. Stein P. Savli M. Mien L.K. Wadsak W. et al.Aggression is related to frontal serotonin-1A receptor distribution as revealed by PET in healthy subjects.Hum Brain Mapp. 2008; ([published online ahead of print December 11])Google Scholar). Several human positron emission tomography (PET) studies showed that the lower tracer binding of the receptor observed in patients with psychiatric disorders, when compared with control subjects, was limited to distinct regions of the brain (12Drevets W.C. Thase M.E. Moses-Kolko E.L. Price J. Frank E. Kupfer D.J. et al.Serotonin-1A receptor imaging in recurrent depression: Replication and literature review.Nucl Med Biol. 2007; 34: 865-877Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar). Brain 5-HT1A receptors are located both presynaptically and postsynaptically. Presynaptic 5-HT1A receptors are present on serotonergic neurons in the dorsal and medial raphe nuclei and act as somatodendritic autoreceptors. The activation of these receptors by 5-HT causes a reduction in the firing rate of the serotonergic neurons and suppression of 5-HT synthesis, 5-HT turnover, and 5-HT release in projection areas. Postsynaptic 5-HT1A receptors are mainly located on glutamatergic and GABAergic (gamma-aminobutyric acid) pyramidal neurons in limbic regions and in the frontal and entorhinal cortices (13Artigas F. Adell A. Celada P. Pindolol augmentation of antidepressant response.Curr Drug Targets. 2006; 7: 139-147Crossref PubMed Scopus (101) Google Scholar, 14Palchaudhuri M. Flugge G. 5-HT1A receptor expression in pyramidal neurons of cortical and limbic brain regions.Cell Tissue Res. 2005; 321: 159-172Crossref PubMed Scopus (59) Google Scholar, 15Azmitia E.C. Gannon P.J. Kheck N.M. Whitaker-Azmitia P.M. Cellular localization of the 5-HT1A receptor in primate brain neurons and glial cells.Neuropsychopharmacology. 1996; 14: 35-46Crossref PubMed Scopus (247) Google Scholar). They modulate serotonergic sensitivity and are involved in emotional and cognitive processes (10Varnas K. Halldin C. Hall H. Autoradiographic distribution of serotonin transporters and receptor subtypes in human brain.Hum Brain Mapp. 2004; 22: 246-260Crossref PubMed Scopus (264) Google Scholar, 16Hall H. Lundkvist C. Halldin C. Farde L. Pike V.W. McCarron J.A. et al.Autoradiographic localization of 5-HT1A receptors in the post-mortem human brain using [3H]WAY-100635 and [11C]WAY-100635.Brain Res. 1997; 745: 96-108Crossref PubMed Scopus (255) Google Scholar).This overview aims to present the most important literature currently available on clinical and preclinical findings demonstrating the pivotal role of the 5-HT1A receptor in anxiety disorders.Results in Animal StudiesPrevious results in rats (17Overstreet D.H. Commissaris R.C. De La Garza 2nd, R. File S.E. Knapp D.J. Seiden L.S. Involvement of 5-HT1A receptors in animal tests of anxiety and depression: Evidence from genetic models.Stress. 2003; 6: 101-110Crossref PubMed Scopus (95) Google Scholar, 18Knapp D.J. Overstreet D.H. Crews F.T. Brain 5-HT1A receptor autoradiography and hypothermic responses in rats bred for differences in 8-OH-DPAT sensitivity.Brain Res. 1998; 782: 1-10Crossref PubMed Scopus (35) Google Scholar), knockout mice (19Toth M. 5-HT1A receptor knockout mouse as a genetic model of anxiety.Eur J Pharmacol. 2003; 463: 177-184Crossref PubMed Scopus (142) Google Scholar), and nonhuman primates (20Bethea C.L. Pau F.K. Fox S. Hess D.L. Berga S.L. Cameron J.L. Sensitivity to stress-induced reproductive dysfunction linked to activity of the serotonin system.Fertil Steril. 2005; 83: 148-155Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar) showed the key role of the 5-HT1A receptor in the modulation of behavioral correlates, anxiety and fear, that may have counterparts to anxiety and fear in humans (Table 1).Table 15-HT1A and Transgenic Mice as Genetic Models of Anxiety DisordersBehavioral FeaturesKnockout 5-HT1A−/−Heterozygote 5-HT1A+/−Overexpression 5-HT1A TransgenicRescue-Turned Off in the AdultRescue-Turned Off During DevelopmentReferencesAnxiety-Related Responses↑↑↓=↑22Heisler L.K. Chu H.M. Brennan T.J. Danao J.A. Bajwa P. Parsons L.H. et al.Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice.Proc Natl Acad Sci U S A. 1998; 95: 15049-15054Crossref PubMed Scopus (604) Google Scholar, 23Parks C.L. Robinson P.S. Sibille E. Shenk T. Toth M. Increased anxiety of mice lacking the serotonin1A receptor.Proc Natl Acad Sci U S A. 1998; 95 (10734–10734)Crossref Scopus (598) Google Scholar, 24Ramboz S. Oosting R. Amara D.A. Kung H.F. Blier P. Mendelsohn M. et al.Serotonin receptor 1A knockout: An animal model of anxiety-related disorder.Proc Natl Acad Sci U S A. 1998; 95: 14476-14781Crossref PubMed Scopus (709) Google Scholar, 25Gross C. Zhuang X. Stark K. Ramboz S. Oosting R. Kirby L. et al.Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult.Nature. 2002; 416: 396-400Crossref PubMed Scopus (753) Google Scholar, 28Kusserow H. Davies B. Hortnagl H. Voigt I. Stroh T. Bert B. et al.Reduced anxiety-related behaviour in transgenic mice overexpressing serotonin 1A receptors.Brain Res Mol Brain Res. 2004; 129: 104-116Crossref PubMed Scopus (99) Google Scholar, 37Olivier B. Pattij T. Wood S.J. Oosting R. Sarnyai Z. Toth M. The 5-HT(1A) receptor knockout mouse and anxiety.Behav Pharmacol. 2001; 12: 439-450Crossref PubMed Scopus (83) Google Scholar, 91Zhuang X. Gross C. Santarelli L. Compan V. Trillat A.C. Hen R. Altered emotional states in knockout mice lacking 5-HT1A or 5-HT1B receptors.Neuropsychopharmacology. 1999; 21: 52S-60SCrossref PubMed Scopus (248) Google ScholarHarm Avoidance↑↑↓=↑22Heisler L.K. Chu H.M. Brennan T.J. Danao J.A. Bajwa P. Parsons L.H. et al.Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice.Proc Natl Acad Sci U S A. 1998; 95: 15049-15054Crossref PubMed Scopus (604) Google Scholar, 23Parks C.L. Robinson P.S. Sibille E. Shenk T. Toth M. Increased anxiety of mice lacking the serotonin1A receptor.Proc Natl Acad Sci U S A. 1998; 95 (10734–10734)Crossref Scopus (598) Google Scholar, 24Ramboz S. Oosting R. Amara D.A. Kung H.F. Blier P. Mendelsohn M. et al.Serotonin receptor 1A knockout: An animal model of anxiety-related disorder.Proc Natl Acad Sci U S A. 1998; 95: 14476-14781Crossref PubMed Scopus (709) Google Scholar, 25Gross C. Zhuang X. Stark K. Ramboz S. Oosting R. Kirby L. et al.Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult.Nature. 2002; 416: 396-400Crossref PubMed Scopus (753) Google Scholar, 28Kusserow H. Davies B. Hortnagl H. Voigt I. Stroh T. Bert B. et al.Reduced anxiety-related behaviour in transgenic mice overexpressing serotonin 1A receptors.Brain Res Mol Brain Res. 2004; 129: 104-116Crossref PubMed Scopus (99) Google Scholar, 37Olivier B. Pattij T. Wood S.J. Oosting R. Sarnyai Z. Toth M. The 5-HT(1A) receptor knockout mouse and anxiety.Behav Pharmacol. 2001; 12: 439-450Crossref PubMed Scopus (83) Google Scholar, 91Zhuang X. Gross C. Santarelli L. Compan V. Trillat A.C. Hen R. Altered emotional states in knockout mice lacking 5-HT1A or 5-HT1B receptors.Neuropsychopharmacology. 1999; 21: 52S-60SCrossref PubMed Scopus (248) Google ScholarAggression==↑n.t.n.t.91Zhuang X. Gross C. Santarelli L. Compan V. Trillat A.C. Hen R. Altered emotional states in knockout mice lacking 5-HT1A or 5-HT1B receptors.Neuropsychopharmacology. 1999; 21: 52S-60SCrossref PubMed Scopus (248) Google Scholar, 90Sarnyai Z. Sibille E.L. Pavlides C. Fenster R.J. McEwen B.S. Toth M. Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin (1A) receptors.Proc Natl Acad Sci U S A. 2000; 97: 14731-14736Crossref PubMed Scopus (292) Google ScholarFear Conditioning↑n.t.n.t.n.t.n.t.92Klemenhagen K.C. Gordon J.A. David D.J. Hen R. Gross C.T. Increased fear response to contextual cues in mice lacking the 5-HT1A receptor.Neuropsychopharmacology. 2006 Jan; 31: 101-111PubMed Google ScholarExploratory Activity↓↓↑=↓22Heisler L.K. Chu H.M. Brennan T.J. Danao J.A. Bajwa P. Parsons L.H. et al.Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice.Proc Natl Acad Sci U S A. 1998; 95: 15049-15054Crossref PubMed Scopus (604) Google Scholar, 23Parks C.L. Robinson P.S. Sibille E. Shenk T. Toth M. Increased anxiety of mice lacking the serotonin1A receptor.Proc Natl Acad Sci U S A. 1998; 95 (10734–10734)Crossref Scopus (598) Google Scholar, 24Ramboz S. Oosting R. Amara D.A. Kung H.F. Blier P. Mendelsohn M. et al.Serotonin receptor 1A knockout: An animal model of anxiety-related disorder.Proc Natl Acad Sci U S A. 1998; 95: 14476-14781Crossref PubMed Scopus (709) Google Scholar, 25Gross C. Zhuang X. Stark K. Ramboz S. Oosting R. Kirby L. et al.Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult.Nature. 2002; 416: 396-400Crossref PubMed Scopus (753) Google Scholar, 28Kusserow H. Davies B. Hortnagl H. Voigt I. Stroh T. Bert B. et al.Reduced anxiety-related behaviour in transgenic mice overexpressing serotonin 1A receptors.Brain Res Mol Brain Res. 2004; 129: 104-116Crossref PubMed Scopus (99) Google Scholar, 37Olivier B. Pattij T. Wood S.J. Oosting R. Sarnyai Z. Toth M. The 5-HT(1A) receptor knockout mouse and anxiety.Behav Pharmacol. 2001; 12: 439-450Crossref PubMed Scopus (83) Google Scholar, 91Zhuang X. Gross C. Santarelli L. Compan V. Trillat A.C. Hen R. Altered emotional states in knockout mice lacking 5-HT1A or 5-HT1B receptors.Neuropsychopharmacology. 1999; 21: 52S-60SCrossref PubMed Scopus (248) Google ScholarLearning Deficit↑n.t.n.t.n.t.n.t.90Sarnyai Z. Sibille E.L. Pavlides C. Fenster R.J. McEwen B.S. Toth M. Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin (1A) receptors.Proc Natl Acad Sci U S A. 2000; 97: 14731-14736Crossref PubMed Scopus (292) Google ScholarFreezing Response After Shock↑n.t.n.t.n.t.n.t.92Klemenhagen K.C. Gordon J.A. David D.J. Hen R. Gross C.T. Increased fear response to contextual cues in mice lacking the 5-HT1A receptor.Neuropsychopharmacology. 2006 Jan; 31: 101-111PubMed Google Scholar5-HT1A, serotonin-1A; ↑, significant increase; ↓, significant decrease; =, changes were not significant; n.t., not tested. Open table in a new tab In our overview, we focus on transgenic and knockout mice models of the 5-HT1A receptor, which represent a genetic model of anxiety and are useful in explaining pathogenetic pathways leading to this disorder (21Lesch K.P. Mouse anxiety: The power of knockout.Pharmacogenomics J. 2001; 1: 187-192Crossref PubMed Scopus (16) Google Scholar). A significant increase in the anxiety level and anxious behavior is present not only in homozygote but also in heterozygote 5-HT1A receptor knockout mice, indicating that a partial receptor deficit is sufficient to elicit the phenotype. Therefore, receptor downregulation may be an important risk factor in psychiatric disorders. Table 1, Table 2, Table 3 summarize preclinical results described in detail below.Table 2Behavioral Conflict Tests on 5-HT1A Knockout and Transgenic MiceConflict Tests, Anxiety ParadigmsKnockout 5-HT1A−/−Heterozygote 5-HT1A+/−Overexpression 5-HT1A TransgenicRescue-Turned Off in the AdultRescue-Turned Off During DevelopmentReferencesHome Cage Activity==↓n.t.n.t.22Heisler L.K. Chu H.M. Brennan T.J. Danao J.A. Bajwa P. Parsons L.H. et al.Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice.Proc Natl Acad Sci U S A. 1998; 95: 15049-15054Crossref PubMed Scopus (604) Google Scholar, 28Kusserow H. Davies B. Hortnagl H. Voigt I. Stroh T. Bert B. et al.Reduced anxiety-related behaviour in transgenic mice overexpressing serotonin 1A receptors.Brain Res Mol Brain Res. 2004; 129: 104-116Crossref PubMed Scopus (99) Google ScholarLight-Dark Test↓n.t.n.t.n.t.n.t.90Sarnyai Z. Sibille E.L. Pavlides C. Fenster R.J. McEwen B.S. Toth M. Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin (1A) receptors.Proc Natl Acad Sci U S A. 2000; 97: 14731-14736Crossref PubMed Scopus (292) Google ScholarOpen Field↓↓==↓22Heisler L.K. Chu H.M. Brennan T.J. Danao J.A. Bajwa P. Parsons L.H. et al.Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice.Proc Natl Acad Sci U S A. 1998; 95: 15049-15054Crossref PubMed Scopus (604) Google Scholar, 23Parks C.L. Robinson P.S. Sibille E. Shenk T. Toth M. Increased anxiety of mice lacking the serotonin1A receptor.Proc Natl Acad Sci U S A. 1998; 95 (10734–10734)Crossref Scopus (598) Google Scholar, 24Ramboz S. Oosting R. Amara D.A. Kung H.F. Blier P. Mendelsohn M. et al.Serotonin receptor 1A knockout: An animal model of anxiety-related disorder.Proc Natl Acad Sci U S A. 1998; 95: 14476-14781Crossref PubMed Scopus (709) Google Scholar, 25Gross C. Zhuang X. Stark K. Ramboz S. Oosting R. Kirby L. et al.Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult.Nature. 2002; 416: 396-400Crossref PubMed Scopus (753) Google Scholar, 28Kusserow H. Davies B. Hortnagl H. Voigt I. Stroh T. Bert B. et al.Reduced anxiety-related behaviour in transgenic mice overexpressing serotonin 1A receptors.Brain Res Mol Brain Res. 2004; 129: 104-116Crossref PubMed Scopus (99) Google Scholar, 37Olivier B. Pattij T. Wood S.J. Oosting R. Sarnyai Z. Toth M. The 5-HT(1A) receptor knockout mouse and anxiety.Behav Pharmacol. 2001; 12: 439-450Crossref PubMed Scopus (83) Google ScholarElevated-Plus Maze↓↓↑=↓22Heisler L.K. Chu H.M. Brennan T.J. Danao J.A. Bajwa P. Parsons L.H. et al.Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice.Proc Natl Acad Sci U S A. 1998; 95: 15049-15054Crossref PubMed Scopus (604) Google Scholar, 23Parks C.L. Robinson P.S. Sibille E. Shenk T. Toth M. Increased anxiety of mice lacking the serotonin1A receptor.Proc Natl Acad Sci U S A. 1998; 95 (10734–10734)Crossref Scopus (598) Google Scholar, 24Ramboz S. Oosting R. Amara D.A. Kung H.F. Blier P. Mendelsohn M. et al.Serotonin receptor 1A knockout: An animal model of anxiety-related disorder.Proc Natl Acad Sci U S A. 1998; 95: 14476-14781Crossref PubMed Scopus (709) Google Scholar, 25Gross C. Zhuang X. Stark K. Ramboz S. Oosting R. Kirby L. et al.Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult.Nature. 2002; 416: 396-400Crossref PubMed Scopus (753) Google Scholar, 28Kusserow H. Davies B. Hortnagl H. Voigt I. Stroh T. Bert B. et al.Reduced anxiety-related behaviour in transgenic mice overexpressing serotonin 1A receptors.Brain Res Mol Brain Res. 2004; 129: 104-116Crossref PubMed Scopus (99) Google Scholar, 37Olivier B. Pattij T. Wood S.J. Oosting R. Sarnyai Z. Toth M. The 5-HT(1A) receptor knockout mouse and anxiety.Behav Pharmacol. 2001; 12: 439-450Crossref PubMed Scopus (83) Google ScholarNovel Object↓=n.t.n.t.n.t.22Heisler L.K. Chu H.M. Brennan T.J. Danao J.A. Bajwa P. Parsons L.H. et al.Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice.Proc Natl Acad Sci U S A. 1998; 95: 15049-15054Crossref PubMed Scopus (604) Google ScholarTail Suspension↓↓n.t.n.t.n.t.22Heisler L.K. Chu H.M. Brennan T.J. Danao J.A. Bajwa P. Parsons L.H. et al.Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice.Proc Natl Acad Sci U S A. 1998; 95: 15049-15054Crossref PubMed Scopus (604) Google ScholarForced Swim Test↑↑n.t.n.t.n.t.23Parks C.L. Robinson P.S. Sibille E. Shenk T. Toth M. Increased anxiety of mice lacking the serotonin1A receptor.Proc Natl Acad Sci U S A. 1998; 95 (10734–10734)Crossref Scopus (598) Google Scholar, 24Ramboz S. Oosting R. Amara D.A. Kung H.F. Blier P. Mendelsohn M. et al.Serotonin receptor 1A knockout: An animal model of anxiety-related disorder.Proc Natl Acad Sci U S A. 1998; 95: 14476-14781Crossref PubMed Scopus (709) Google ScholarMorris Water Maze↑n.t.n.t.n.t.n.t.90Sarnyai Z. Sibille E.L. Pavlides C. Fenster R.J. McEwen B.S. Toth M. Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin (1A) receptors.Proc Natl Acad Sci U S A. 2000; 97: 14731-14736Crossref PubMed Scopus (292) Google ScholarNovelty Suppressed Feeding↓n.t.n.t.=↓90Sarnyai Z. Sibille E.L. Pavlides C. Fenster R.J. McEwen B.S. Toth M. Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin (1A) receptors.Proc Natl Acad Sci U S A. 2000; 97: 14731-14736Crossref PubMed Scopus (292) Google Scholar, 25Gross C. Zhuang X. Stark K. Ramboz S. Oosting R. Kirby L. et al.Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult.Nature. 2002; 416: 396-400Crossref PubMed Scopus (753) Google ScholarNovel Environment↑n.t.n.t.n.t.n.t.25Gross C. Zhuang X. Stark K. Ramboz S. Oosting R. Kirby L. et al.Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult.Nature. 2002; 416: 396-400Crossref PubMed Scopus (753) Google Scholar, 37Olivier B. Pattij T. Wood S.J. Oosting R. Sarnyai Z. Toth M. The 5-HT(1A) receptor knockout mouse and anxiety.Behav Pharmacol. 2001; 12: 439-450Crossref PubMed Scopus (83) Google ScholarFreezing Response↑n.t.n.t.n.t.n.t.90Sarnyai Z. Sibille E.L. Pavlides C. Fenster R.J. McEwen B.S. Toth M. Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin (1A) receptors.Proc Natl Acad Sci U S A. 2000; 97: 14731-14736Crossref PubMed Scopus (292) Google Scholar5-HT1A, serotonin-1A; ↑, significant increase; ↓, significant decrease; =, changes were not significant; n.t., not tested. Open table in a new tab Table 3Physiological and Autonomic Changes in 5-HT1A Knockout and Transgenic MicePhysiological Features, Autonomic ChangesKnockout 5-HT1A−/−Heterozygote 5-HT1A+/−Overexpression 5-HT1A TransgenicReferencesHeart Rate==n.t.36Pattij T. Groenink L. Hijzen T.H. Oosting R.S. Maes R.A. van der Gugten J. et al.Autonomic changes associated with enhanced anxiety in 5-HT(1A) receptor knockout mice.Neuropsychopharmacology. 2002; 27: 380-390Crossref PubMed Scopus (69) Google ScholarBasal Body Temperature==↓ (male)36Pattij T. Groenink L. Hijzen T.H. Oosting R.S. Maes R.A. van der Gugten J. et al.Autonomic changes associated with enhanced anxiety in 5-HT(1A) receptor knockout mice.Neuropsychopharmacology. 2002; 27: 380-390Crossref PubMed Scopus (69) Google Scholar, 28Kusserow H. Davies B. Hortnagl H. Voigt I. Stroh T. Bert B. et al.Reduced anxiety-related behaviour in transgenic mice overexpressing serotonin 1A receptors.Brain Res Mol Brain Res. 2004; 129: 104-116Crossref PubMed Scopus (99) Google ScholarStressed-Induced Tachycardia↑=n.t.36Pattij T. Groenink L. Hijzen T.H. Oosting R.S. Maes R.A. van der Gugten J. et al.Autonomic changes associated with enhanced anxiety in 5-HT(1A) receptor knockout mice.Neuropsychopharmacology. 2002; 27: 380-390Crossref PubMed Scopus (69) Google Scholar, 37Olivier B. Pattij T. Wood S.J. Oosting R. Sarnyai Z. Toth M. The 5-HT(1A) receptor knockout mouse and anxiety.Behav Pharmacol. 2001; 12: 439-450Crossref PubMed Scopus (83) Google ScholarStressed-Induced Hyperthermia↑=n.t.36Pattij T. Groenink L. Hijzen T.H. 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