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The Journal of Neuroscience, January 14, 2004, 24(2):412-419; doi:10.1523/JNEUROSCI.2806-03.2004

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Neurobiology of Disease
Attenuated Response to Stress and Novelty and Hypersensitivity to Seizures in 5-HT₄ Receptor Knock-Out Mice

Valérie Compan,¹ Mingming Zhou,⁶ Régis Grailhe,³ Russell A. Gazzara,⁴ Renee Martin,⁵ Jay Gingrich,⁶ Aline Dumuis,¹ Daniela Brunner,^4,5 Joël Bockaert,¹ and René Hen²

¹Unité Propre de Recherche Centre National de la Recherche Scientifique 2580, Génomique fonctionnelle, Montpellier 34094, France, ²Columbia University, Center for Neurobiology and Behavior, New York, New York 10032, ³Institut Pasteur, Récepteurs et cognition, Paris 75724 Cédex 15, France, ⁴PsychoGenics, Hawthorne, New York 10532, ⁵Roche Palo Alto, Palo Alto, California 94304, and ⁶Department of Psychiatry, Columbia University, New York, New York 10032

To study the functions of 5-HT₄ receptors, a null mutation was engineered in the corresponding gene. 5-HT₄ receptor knock-out mice displayed normal feeding and motor behaviors in baseline conditions but abnormal feeding and locomotor behavior in response to stress and novelty. Specifically, stress-induced hypophagia and novelty-induced exploratory activity were attenuated in the knock-out mice. In addition, pentylenetetrazol-induced convulsive responses were enhanced in the knock-out mice, suggesting an increase in neuronal network excitability. These results provide the first example of a genetic deficit that disrupts the ability of stress to reduce feeding and body weight and suggest that 5-HT₄ receptors may be involved in stress-induced anorexia and seizure susceptibility.

Key words: anorexia; stress; locomotion; epilepsy; 5-HT₄ receptor; knock-out

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Received June 4, 2003; revised October 27, 2003; accepted October 27, 2003.

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