Glutamatergic drugs exacerbate symptomatic behavior in a transgenic model of comorbid Tourette's syndrome and obsessive-compulsive disorder

We previously created a transgenic mouse model of comorbid Tourette's syndr ome and obsessive-compulsive disorder (TS+OCD), by expressing a neuropotent iating cholera toxin (CT) transgene in a subset of dopamine D1 receptor-exp ressing (D1+) neurons thought to induce cortical and amygdalar glutamate ou tput. To test glutamate's role in the TS+OCD-like disorder of these transge nic mice (D1CT-7 line), the effects of glutamate receptor-binding drugs on their behavior were examined. MK-801, a non-competitive NMDA receptor antag onist that indirectly stimulates cortical-limbic glutamate output, aggravat ed a transgene-dependent abnormal behavior (repetitive climbing and leaping ) in the D1CT-7 mice at doses insufficient to induce stereotypies, and more readily induced stereotypies and limbic seizure behaviors at high doses. N BQX, a seizure-inhibiting AMPA receptor antagonist, reduced only the MK-801 -dependent stereotypic and limbic seizure behavior of D1CT-7 mice, but not their transgene-dependent behaviors. These data imply that TS+OCD-like beha vior is mediated by cortical-limbic glutamate, but that AMPA glutamate rece ptors are not an essential part of this behavioral circuit. Our findings le ad to the prediction that the symptoms of human Tourette's syndrome and obs essive-compulsive disorder are elicited by excessive forebrain glutamate ou tput. (C) 2000 Elsevier Science B.V. All rights reserved.