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 D-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.

Spontaneous object recognition and its relevance to schizophrenia: a review of findings from pharmacological, genetic, lesion and developmental rodent models

“…Male and female mice with a heterozygous deletion of COMT were significantly impaired in SOR with a 5-min delay, while males but not females were impaired with a 1-h delay (Babovic et al 2008). In a subsequent study using an apparently identical protocol, however, the same group found no effect of sex and no impairment at either delay (O'Tuathaigh et al 2010). In the latter study, the animals had received chronic vehicle injections for 20 days prior to the SOR test.…”

AKT1 Moderation of Cannabis-Induced Cognitive Alterations in Psychotic Disorder

“…This is especially interesting, as COMT, another gene important in prefrontal dopamine availability, was also suggested to moderate the effects of cannabis use on expression of psychosis and cognitive performance in previous studies (Caspi et al, 2005;Henquet et al, 2006;O'Tuathaigh et al, 2010). Although the reported cognitive effects of cannabis use were subtle, the present findings are important as they suggest that the psychosis-inducing effects of cannabis may be driven by dopamine-related prefrontal-striatal interactions and that genetic variation in this brain circuit may determine the vulnerability to these effects.…”

Acute and long-term effects of Δ9-tetrahydrocannabinol on object recognition and anxiety-like activity are age- and strain-dependent in mice

“…In the NOR task, acute THC did not alter object discrimination in adolescent or adult rats (Ciccocioppo et al, 2002; Swartzwelder et al, 2012). Conversely, a repeated adolescent history of THC exposure was shown to reduce novel object discrimination in rats (Quinn et al, 2008; Realini et al, 2011; Zamberletti et al, 2012; but see O’Tuathaigh et al, 2010). However, of these studies, only Quinn et al (2008) utilized an adult control and found no effect of adult THC history on later object discrimination.…”