title: Genetic vs. pharmacological inactivation of COMT influences cannabinoid-induced expression of schizophrenia-related phenotypes.
abstract: Catechol-O-methyltransferase (COMT) is an important enzyme in the metabolism of dopamine and disturbance in dopamine function is proposed to be central to the pathogenesis of schizophrenia. Clinical epidemiological studies have indicated cannabis use to confer a 2-fold increase in risk for subsequent onset of psychosis, with adolescent-onset use conveying even higher risk. There is evidence that a high activity COMT polymorphism moderates the effects of adolescent exposure to cannabis on risk for adult psychosis. In this paper we compared the effect of chronic adolescent exposure to the cannabinoid WIN 55212 on sensorimotor gating, behaviours related to the negative symptoms of schizophrenia, anxiety- and stress-related behaviours, as well as ex-vivo brain dopamine and serotonin levels, in COMT KO vs. wild-type (WT) mice. Additionally, we examined the effect of pretreatment with the COMT inhibitor tolcapone on acute effects of this cannabinoid on sensorimotor gating in C57BL/6 mice. COMT KO mice were shown to be more vulnerable than WT to the disruptive effects of adolescent cannabinoid treatment on prepulse inhibition (PPI). Acute pharmacological inhibition of COMT in C57BL/6 mice also modified acute cannabinoid effects on startle reactivity, as well as PPI, indicating that chronic and acute loss of COMT can produce dissociable effects on the behavioural effects of cannabinoids. COMT KO mice also demonstrated differential effects of adolescent cannabinoid administration on sociability and anxiety-related behaviour, both confirming and extending earlier reports of COMT×cannabinoid effects on the expression of schizophrenia-related endophenotypes.
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, St Stephen's Green, Dublin, Ireland. c.otuathaigh@ucc.ie
authors.forename: Colm M P
authors.initials: CM
authors.lastname: O'Tuathaigh
authors.forename: Gerard
authors.initials: G
authors.lastname: Clarke
authors.forename: Jeremy
authors.initials: J
authors.lastname: Walsh
authors.forename: Lieve
authors.initials: L
authors.lastname: Desbonnet
authors.forename: Emilie
authors.initials: E
authors.lastname: Petit
authors.forename: Claire
authors.initials: C
authors.lastname: O'Leary
authors.forename: Orna
authors.initials: O
authors.lastname: Tighe
authors.forename: Niamh
authors.initials: N
authors.lastname: Clarke
authors.forename: Maria
authors.initials: M
authors.lastname: Karayiorgou
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Gogos
authors.forename: Ted G
authors.initials: TG
authors.lastname: Dinan
authors.forename: John F
authors.initials: JF
authors.lastname: Cryan
authors.forename: John L
authors.initials: JL
authors.lastname: Waddington
mesh_terms: D000483:Alleles; D000818:Animals; D001007:Anxiety / Q000523:psychology; D001577:Benzophenones / Q000494:pharmacology; D048588:Benzoxazines / Q000494:pharmacology; D015306:Biogenic Monoamines / Q000378:metabolism; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology; D002186:Cannabinoids / Q000494:pharmacology*; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D065098:Catechol O-Methyltransferase Inhibitors; D002851:Chromatography, High Pressure Liquid; D003511:Cyclohexanols / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009596:Nitrophenols / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D010641:Phenotype; D013216:Reflex, Startle / Q000187:drug effects / Q000235:genetics; D012559:Schizophrenia / Q000201:enzymology / Q000235:genetics*; D012565:Schizophrenic Psychology; D012919:Social Behavior; D013550:Swimming / Q000523:psychology; D000077867:Tolcapone
chemical_list: D001577:Benzophenones; D048588:Benzoxazines; D015306:Biogenic Monoamines; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; D065098:Catechol O-Methyltransferase Inhibitors; D003511:Cyclohexanols; D004791:Enzyme Inhibitors; D009025:Morpholines; D009281:Naphthalenes; D009596:Nitrophenols; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000077867:Tolcapone; D002394:Catechol O-Methyltransferase