Background: Background: Previous evidence suggests an association between cognition and cannabis use in healthy subjects and in patients with schizophrenia. However, results on this association are not always consistent and they do not always indicate a deleterious effects of cannabis on cognition. Several different factors may be invoked to explain these differences, including the possibility that deleterious effects of cannabis use are best elicited on particular genetic backgrounds. A crucial determinant of cannabinoid signaling in the brain is the cannabinoid receptor 1 (CNR1), which has also been associated with schizophrenia in previous reports and is coded by the CNR1 gene. Here, our aim was to investigate in healthy subjects the association between CNR1 variation and prefrontal expression of CNR1. Once this association was established, we also studied if functional variation in CNR1 and cannabis exposure interact in modulating prefrontal functional connectivity during working memory processing, as well as related behavior. Methods: Methods: CNR1 mRNA expression as a function of genetic variation was investigated in post-mortem prefrontal human tissue using Braincloud (http://braincloud.jhmi.edu/). Based on this investigation, a single nucleotide polymorphism, rs1406977, was selected. Thus, 232 healthy subjects(125males)weregenotypedforthisSNPbyDNAdirectsequencing. Assessment of cannabis use was performed with the Cannabis Experience Questionnaire. Furthermore, all individuals performed the 2-back working memory task during functional Magnetic Resonance Imaging (fMRI). A General Linear Model and the Independent Component Analysis approach were used within SPM8 to study functional connectivity as a function of CNR1 genotype, of cannabis use and of their interaction. Results: Results: A single nucleotide polymorphism (SNP) within CNR1 (rs1406977) was associated with CNR1 prefrontal mRNA expression in prefrontal cortex. In particular, G carrier individuals had significantly lower mRNA levels than AA subjects. Moreover, rs1406977 G carrier cannabis users had greater functional connectivity in the left ventrolateral prefrontal cortex (VLPFC) compared with G carrier cannabis naïve and AA cannabis users. Furthermore, G carrier cannabis users also had lower behavioral accuracy and slower reaction time than the other groups. Discussion: Discussion: genetically mediated low levels of prefrontal CNR1 levels may modulate the association between cannabis use and working memory processing in healthy subjects. Relevance of these findings for the pathophysiology of schizophrenia should be further investigated.
Poster #M195 THE INTERACTION BETWEEN CNR1 GENETIC VARIATION AND CANNABIS EXPOSURE PREDICTS PREFRONTAL FUNCTIONAL CONNECTIVITY AND BEHAVIOR DURING WORKING MEMORY
Colizzi, Marco;
2014-01-01
Abstract
Background: Background: Previous evidence suggests an association between cognition and cannabis use in healthy subjects and in patients with schizophrenia. However, results on this association are not always consistent and they do not always indicate a deleterious effects of cannabis on cognition. Several different factors may be invoked to explain these differences, including the possibility that deleterious effects of cannabis use are best elicited on particular genetic backgrounds. A crucial determinant of cannabinoid signaling in the brain is the cannabinoid receptor 1 (CNR1), which has also been associated with schizophrenia in previous reports and is coded by the CNR1 gene. Here, our aim was to investigate in healthy subjects the association between CNR1 variation and prefrontal expression of CNR1. Once this association was established, we also studied if functional variation in CNR1 and cannabis exposure interact in modulating prefrontal functional connectivity during working memory processing, as well as related behavior. Methods: Methods: CNR1 mRNA expression as a function of genetic variation was investigated in post-mortem prefrontal human tissue using Braincloud (http://braincloud.jhmi.edu/). Based on this investigation, a single nucleotide polymorphism, rs1406977, was selected. Thus, 232 healthy subjects(125males)weregenotypedforthisSNPbyDNAdirectsequencing. Assessment of cannabis use was performed with the Cannabis Experience Questionnaire. Furthermore, all individuals performed the 2-back working memory task during functional Magnetic Resonance Imaging (fMRI). A General Linear Model and the Independent Component Analysis approach were used within SPM8 to study functional connectivity as a function of CNR1 genotype, of cannabis use and of their interaction. Results: Results: A single nucleotide polymorphism (SNP) within CNR1 (rs1406977) was associated with CNR1 prefrontal mRNA expression in prefrontal cortex. In particular, G carrier individuals had significantly lower mRNA levels than AA subjects. Moreover, rs1406977 G carrier cannabis users had greater functional connectivity in the left ventrolateral prefrontal cortex (VLPFC) compared with G carrier cannabis naïve and AA cannabis users. Furthermore, G carrier cannabis users also had lower behavioral accuracy and slower reaction time than the other groups. Discussion: Discussion: genetically mediated low levels of prefrontal CNR1 levels may modulate the association between cannabis use and working memory processing in healthy subjects. Relevance of these findings for the pathophysiology of schizophrenia should be further investigated.
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