Prefrontal activity during working memory is modulated by the interaction of variation in CB1 and COX2 coding genes and correlates with frequency of cannabis use.
The CB1 cannabinoid receptor is targeted in the brain by endocannabinoids under physiological conditions as well as by delta9-tetrahydrocannabinol under cannabis use. Furthermore, its signaling appears to affect brain cognitive processing. Recent findings highlight a crucial role of cyclooxygenase-2 (COX-2) in the mechanism of intraneuronal CB1 signaling transduction, while others indicate that two single nucleotide polymorphisms (SNPs) (rs1406977 and rs20417) modulate expression of CB1 (CNR1) and COX-2 (PTGS2) coding genes, respectively. Here, our aim was to use fMRI to investigate in healthy humans whether these SNPs interact in modulating prefrontal activity during working memory processing and if this modulation is linked with cannabis use. We recruited 242 healthy subjects genotyped for CNR1 rs1406977 and PTGS2 rs20417 that performed the N-back working memory task during fMRI and were interviewed using the Cannabis Experience Questionnaire (CEQ). We found that the interaction between CNR1 rs1406977 and PTGS2 rs20417 is associated with dorsolateral prefrontal cortex (DLPFC) activity such that specific genotype configurations (CNR1 C carriers/PTGS2 C carriers and CNR1 TT/PTGS2 GG) predict lower cortical response versus others in spite of similar behavioral accuracy. Furthermore, DLPFC activity in the cluster associated with the CNR1 by PTGS2 interaction was negatively correlated with behavioral efficiency and positively correlated with frequency of cannabis use in cannabis users. These results suggest that a genetically modulated balancing of signaling within the CB1-COX-2 pathway may reflect on more or less efficient patterns of prefrontal activity during working memory. Frequency of cannabis use may be a factor for further modulation of CNR1/PTGS2-mediated cortical processing associated with this cognitive process.
Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy; IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Foggia, Italy.
Paolo
P
Taurisano
Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy; Department of Educational Sciences, Psychology and Communication Science, University of Bari 'Aldo Moro', Bari, Italy.
Linda A
LA
Antonucci
Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy; IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Foggia, Italy.
Leonardo
L
Fazio
Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.
Antonio
A
Rampino
Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.
Raffaella
R
Romano
Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.
Annamaria
A
Porcelli
Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.
Rita
R
Masellis
Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Marco
M
Colizzi
Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy; Cognitive Brain Research Unit, Institute of Behavioral Science, University of Helsinki, Finland.
Tiziana
T
Quarto
Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.
Silvia
S
Torretta
IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Foggia, Italy.
Annabella
A
Di Giorgio
Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.
Giulio
G
Pergola
Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy; pRED, NORD DTA, Hoffman-La Roche, Ltd., Basel, Switzerland. Electronic address: alessandro.bertolino@uniba.it.
Alessandro
A
Bertolino
Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy. Electronic address: blasi.seppe@gmail.com.
Giuseppe
G
Blasi
D000328:Adult; D002188:Cannabis / Q000009:adverse effects; D051546:Cyclooxygenase 2 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017397:Prefrontal Cortex / Q000502:physiology*; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics*; D055815:Young Adult
D043884:Receptor, Cannabinoid, CB1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human
CB1; COX2; Cannabis; DLPFC; Working memory