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 syndrome and obsessive-compulsive disorder (TS+OCD), by expressing a neuropotentiating cholera toxin (CT) transgene in a subset of dopamine D1 receptor-expressing (D1+) neurons thought to induce cortical and amygdalar glutamate output. To test glutamate's role in the TS+OCD-like disorder of these transgenic mice (D1CT-7 line), the effects of glutamate receptor-binding drugs on their behavior were examined. MK-801, a non-competitive NMDA receptor antagonist that indirectly stimulates cortical-limbic glutamate output, aggravated 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. NBQX, 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 behavior is mediated by cortical-limbic glutamate, but that AMPA glutamate receptors are not an essential part of this behavioral circuit. Our findings lead to the prediction that the symptoms of human Tourette's syndrome and obsessive-compulsive disorder are elicited by excessive forebrain glutamate output.
McGrath
M J
MJ
Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church St. S.E., Minneapolis, MN 55455, USA.
Campbell
K M
KM
Parks
C R
CR
Burton
F H
FH
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D015897:Comorbidity; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000008:administration & dosage*; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage*; D006801:Humans; D008032:Limbic System / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009771:Obsessive-Compulsive Disorder / Q000503:physiopathology; D011810:Quinoxalines / Q000494:pharmacology; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology; D005879:Tourette Syndrome / Q000503:physiopathology
D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D016291:Dizocilpine Maleate