title: "Hyperglutamatergic cortico-striato-thalamo-cortical circuit" breaker drugs alleviate tics in a transgenic circuit model of Tourette׳s syndrome.
abstract: The brain circuits underlying tics in Tourette׳s syndrome (TS) are unknown but thought to involve cortico/amygdalo-striato-thalamo-cortical (CSTC) loop hyperactivity. We previously engineered a transgenic mouse "circuit model" of TS by expressing an artificial neuropotentiating transgene (encoding the cAMP-elevating, intracellular A1 subunit of cholera toxin) within a small population of dopamine D1 receptor-expressing somatosensory cortical and limbic neurons that hyperactivate cortico/amygdalostriatal glutamatergic output circuits thought to be hyperactive in TS and comorbid obsessive-compulsive (OC) disorders. As in TS, these D1CT-7 ("Ticcy") transgenic mice׳s tics were alleviated by the TS drugs clonidine and dopamine D2 receptor antagonists; and their chronic glutamate-excited striatal motor output was unbalanced toward hyperactivity of the motoric direct pathway and inactivity of the cataleptic indirect pathway. Here we have examined whether these mice׳s tics are countered by drugs that "break" sequential elements of their hyperactive cortical/amygdalar glutamatergic and efferent striatal circuit: anti-serotonoceptive and anti-noradrenoceptive corticostriatal glutamate output blockers (the serotonin 5-HT2a,c receptor antagonist ritanserin and the NE alpha-1 receptor antagonist prazosin); agmatinergic striatothalamic GABA output blockers (the presynaptic agmatine/imidazoline I1 receptor agonist moxonidine); and nigrostriatal dopamine output blockers (the presynaptic D2 receptor agonist bromocriptine). Each drug class alleviates tics in the Ticcy mice, suggesting a hyperglutamatergic CSTC "tic circuit" could exist in TS wherein cortical/amygdalar pyramidal projection neurons׳ glutamatergic overexcitation of both striatal output neurons and nigrostriatal dopaminergic modulatory neurons unbalances their circuit integration to excite striatothalamic output and create tics, and illuminating new TS drug strategies.
authors.affiliation: Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church St SE, Minneapolis, MN 55455-0217, USA; Minneapolis Medical Research Foundation, Hennepin County Medical Center, 701 Park Ave, Shapiro S3.111, Minneapolis, MN 55415-1623, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nordstrom
authors.affiliation: Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church St SE, Minneapolis, MN 55455-0217, USA.
authors.forename: Katie C
authors.initials: KC
authors.lastname: Bittner
authors.affiliation: Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church St SE, Minneapolis, MN 55455-0217, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McGrath
authors.affiliation: Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church St SE, Minneapolis, MN 55455-0217, USA.
authors.forename: Clinton R
authors.initials: CR
authors.lastname: Parks
authors.affiliation: Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church St SE, Minneapolis, MN 55455-0217, USA; Minneapolis Medical Research Foundation, Hennepin County Medical Center, 701 Park Ave, Shapiro S3.111, Minneapolis, MN 55415-1623, USA. Electronic address: burto006@umn.edu.
authors.forename: Frank H
authors.initials: FH
authors.lastname: Burton
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009415:Nerve Net / Q000187:drug effects / Q000378:metabolism; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D013003:Somatosensory Cortex / Q000187:drug effects / Q000378:metabolism*; D013787:Thalamic Nuclei / Q000187:drug effects / Q000378:metabolism*; D020323:Tics / Q000188:drug therapy / Q000378:metabolism*; D005879:Tourette Syndrome / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D018491:Dopamine Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D018698:Glutamic Acid
keywords: Cortex; Dopamine; Glutamate; Somatosensory; Striatum; Tourette