Chronic adolescent exposure to delta-9-tetrahydrocannabinol in COMT mutant mice: impact on psychosis-related and other phenotypes

Colm Mp O'Tuathaigh (1) , Magdalena Hryniewiecka (1) , Aine Behan (1) , Orna Tighe (1) , Catherin Coughlan (1) , Lieve Desbonnet (1) , Mary Cannon (1) , Maria Karayiorgou (1) , Joseph A. Gogos (1) , David Cotter (1) , John L. Waddington (1)

1 Molecular and cellular Therapeutics

Cannabis use confers a two-fold increase in 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 THC exposure on risk for adult psychosis. Mice with knockout of the COMT gene were treated chronically with delta-9-tetrahydrocannabinol (THC; 4.0 and 8.0 mg/kg over 20 days) during either adolescence (postnatal day 32-52) or adulthood (postnatal day 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 wildtypes, 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. 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.

Mots clés: Animal models; Cannabinoids; Psychopharmacology; Endophenotypes; Behavior; Social behavior; Mice; Schizophrenia; Antipsychotics

Colm Mp O'Tuathaigh, Magdalena Hryniewiecka, Aine Behan, Orna Tighe, Catherin Coughlan, et al.. Chronic adolescent exposure to delta-9-tetrahydrocannabinol in COMT mutant mice: impact on psychosis-related and other phenotypes. Neuropsychopharmacology, 2010, ⟨10.1038/npp.2010.100⟩. ⟨hal-00555619⟩