title: Chronic adolescent exposure to Δ-9-tetrahydrocannabinol in COMT mutant mice: impact on psychosis-related and other phenotypes.
abstract: Cannabis use confers a two-fold increase in the risk for psychosis, with adolescent use conferring even greater risk. A high-low activity catechol-O-methyltransferase (COMT) polymorphism may modulate the effects of adolescent Δ-9-tetrahydrocannabinol (THC) exposure on the risk for adult psychosis. Mice with knockout of the COMT gene were treated chronically with THC (4.0 and 8.0 mg/kg over 20 days) during either adolescence (postnatal days (PDs) 32-52) or adulthood (PDs 70-90). The effects of THC exposure were then assessed in adulthood across behavioral phenotypes relevant for psychosis: exploratory activity, spatial working memory (spontaneous and delayed alternation), object recognition memory, social interaction (sociability and social novelty preference), and anxiety (elevated plus maze). Adolescent THC administration induced a larger increase in exploratory activity, greater impairment in spatial working memory, and a stronger anti-anxiety effect in COMT knockouts than in wild types, primarily among males. No such effects of selective adolescent THC administration were evident for other behaviors. Both object recognition memory and social novelty preference were disrupted by either adolescent or adult THC administration, independent of genotype. The COMT genotype exerts specific modulation of responsivity to chronic THC administration during adolescence in terms of exploratory activity, spatial working memory, and anxiety. These findings illuminate the interaction between genes and adverse environmental exposures over a particular stage of development in the expression of the psychosis phenotype.
authors.affiliation: Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland. cotuathaigh@rcsi.ie
authors.forename: Colm M P
authors.initials: CM
authors.lastname: O'Tuathaigh
authors.forename: Magdalena
authors.initials: M
authors.lastname: Hryniewiecka
authors.forename: Aine
authors.initials: A
authors.lastname: Behan
authors.forename: Orna
authors.initials: O
authors.lastname: Tighe
authors.forename: Catherine
authors.initials: C
authors.lastname: Coughlan
authors.forename: Lieve
authors.initials: L
authors.lastname: Desbonnet
authors.forename: Mary
authors.initials: M
authors.lastname: Cannon
authors.forename: Maria
authors.initials: M
authors.lastname: Karayiorgou
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Gogos
authors.forename: David R
authors.initials: DR
authors.lastname: Cotter
authors.forename: John L
authors.initials: JL
authors.lastname: Waddington
mesh_terms: D000367:Age Factors; D000818:Animals; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D013759:Dronabinol / Q000008:administration & dosage*; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011618:Psychotic Disorders / Q000201:enzymology* / Q000235:genetics*; D011897:Random Allocation
chemical_list: D013759:Dronabinol; D002394:Catechol O-Methyltransferase