Functional abnormalities in the serotonin (5-HT) receptors have been consistently associated with anxiety. We have shown that inactivation of the 5-HTA receptor (5-HTAR) results in anxiety in mice. Surprisingly, we found that these mutant mice are insensitive to the anxiolytic effect of diazepam, a classical benzodiazepine (BZ). The importance of this finding is that a significant proportion of patients suffering from generalized anxiety do not respond to BZs. Also, BZs are not particularly effective in other forms of anxiety such as panic attacks and phobias. Since BZs bind and facilitate the function of the BZ sensitive gamma-aminobutyric acid receptors (GABAAR) receptors, abnormalities in these receptors could underlie the BZ-resistant anxiety and the anxiety-like behavior of the 5-HTAR mutant mice. Indeed, we found abnormalities in the subunit composition of GABAARs in mutant mice. Our data show that the 5-HT and GABA systems, two important neurotransmitter systems implicated in anxiety disorders, are mechanistically linked. The objective of this application is to elucidate key features of the 5-HTAR-mediated regulation of GABAAR subunits that have a relevance to the KO phenotype and that could be applied to the understanding of anxiety. We ask the following questions: 1) Is the expression of the GABAAR subunits sensitive to the dosage of the 5-HTA receptor? Anxiety in heterozygote KO mice suggests that GABAAR subunit expression is sensitive to 5-HTAR dosage. This would imply a pathogenic role for 5-HTAR hypofunction described in panic anxiety. 2) Are the abnormal GABAAR subunit levels in 5-HTAR KO mice caused by a developmental arrest in subunit expression? Dysregulation of GABAAR subunits may occur during development because 5-HTAR represents a developmental signal in brain. 3) Are particular regions within amygdala and hippocampus of 5-HTAR KO mice specifically associated with altered GABAAR subunit expression? 4) Is GABA and glutamate release altered in the amygdala and hippocampus of 5-HTAR KO mice? These changes may occur to compensate GABAAR subunit abnormalities. 5) Can 5-HTA receptor agonists alter the expression of GABAAR subunits? Increasing signaling through the 5-HTAR by agonists may elicit GABAAR subunit changes that are beneficial in anxiety.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH058669-02
Application #
6392374
Study Section
Special Emphasis Panel (ZRG1-IFCN-1 (01))
Program Officer
Winsky, Lois M
Project Start
2000-09-23
Project End
2005-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
2
Fiscal Year
2001
Total Cost
$296,625
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
Toth, Miklos (2015) Mechanisms of non-genetic inheritance and psychiatric disorders. Neuropsychopharmacology 40:129-40
Oh, J-E; Chambwe, N; Klein, S et al. (2013) Differential gene body methylation and reduced expression of cell adhesion and neurotransmitter receptor genes in adverse maternal environment. Transl Psychiatry 3:e218
Hartrampf, Steffen; Dudakov, Jarrod A; Johnson, Linda K et al. (2013) The central nervous system is a target of acute graft versus host disease in mice. Blood 121:1906-10
Zupan, Bojana; Toth, Miklos (2012) Fmr-1 as an offspring genetic and a maternal environmental factor in neurodevelopmental disease. Results Probl Cell Differ 54:243-53
Bortolozzi, A; Castañé, A; Semakova, J et al. (2012) Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects. Mol Psychiatry 17:612-23
Rajadhyaksha, Anjali M; Ra, Stephen; Kishinevsky, Sarah et al. (2012) Behavioral characterization of cereblon forebrain-specific conditional null mice: a model for human non-syndromic intellectual disability. Behav Brain Res 226:428-34
Guilloux, Jean-Philippe; David, Denis J P; Xia, Lin et al. (2011) Characterization of 5-HT(1A/1B)-/- mice: an animal model sensitive to anxiolytic treatments. Neuropharmacology 61:478-88
Hicks, Martin J; De, Bishnu P; Rosenberg, Jonathan B et al. (2011) Cocaine analog coupled to disrupted adenovirus: a vaccine strategy to evoke high-titer immunity against addictive drugs. Mol Ther 19:612-9
van Velzen, A; Toth, M (2010) Role of maternal 5-HT(1A) receptor in programming offspring emotional and physical development. Genes Brain Behav 9:877-85
Gleason, G; Liu, B; Bruening, S et al. (2010) The serotonin1A receptor gene as a genetic and prenatal maternal environmental factor in anxiety. Proc Natl Acad Sci U S A 107:7592-7

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