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The Journal of Neuroscience, June 15, 1999, 19(12):5044-5053

OCD-Like Behaviors Caused by a Neuropotentiating Transgene Targeted to Cortical and Limbic D1+ Neurons

Keith M. Campbell¹, Luis de Lecea², Diana M. Severynse³, Marc G. Caron³, Michael J. McGrath¹, Sheldon B. Sparber¹, Li-Yan Sun¹, and Frank H. Burton¹

¹ Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455, ² Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, and ³ Howard Hughes Medical Institute, Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710

To study the behavioral role of neurons containing the D1 dopamine receptor (D1+), we have used a genetic neurostimulatory approach. We generated transgenic mice that express an intracellular form of cholera toxin (CT), a neuropotentiating enzyme that chronically activates stimulatory G-protein (G_s) signal transduction and cAMP synthesis, under the control of the D1 promoter. Because the D1 promoter, like other CNS-expressed promoters, confers transgene expression that is regionally restricted to different D1+ CNS subsets in different transgenic lines, we observed distinct but related psychomotor disorders in different D1CT-expressing founders. In a D1CT line in which transgene expression was restricted to the following D1+ CNS regionsthe piriform cortex layer II, layers II-III of somatosensory cortical areas, and the intercalated nucleus of the amygdalaD1CT mice showed normal CNS and D1+ neural architecture but increased cAMP content in whole extracts of the piriform and somatosensory cortex. These mice also exhibited a constellation of compulsive behavioral abnormalities that strongly resembled human cortical-limbic-induced compulsive disorders such as obsessive-compulsive disorder (OCD). These compulsive behaviors included episodes of perseverance or repetition of any and all normal behaviors, repetitive nonaggressive biting of siblings during grooming, and repetitive leaping. These results suggest that chronic potentiation of cortical and limbic D1+ neurons thought to induce glutamatergic output to the striatum causes behaviors reminiscent of those in human cortical-limbic-induced compulsive disorders.

Key words: transgenic mice; cholera toxin; dopamine; D1 receptor; obsessive-compulsive disorder; cAMP; G-proteins; stereotypy; piriform; somatosensory; intercalated nucleus

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19125044-10$05.00/0

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