Original Article

Neuropsychopharmacology (2012) 37, 1773–1783; doi:10.1038/npp.2012.24; published online 21 March 2012

Chronic Adolescent Exposure to Delta-9-Tetrahydrocannabinol in COMT Mutant Mice: Impact on Indices of Dopaminergic, Endocannabinoid and GABAergic Pathways

Áine T Behan1, Magdalena Hryniewiecka1, Colm M P O'Tuathaigh2,6, Anthony Kinsella2, Mary Cannon1, Maria Karayiorgou3, Joseph A Gogos4,5, John L Waddington2 and David R Cotter1

  1. 1Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland
  2. 2Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland
  3. 3Department of Psychiatry and Genetics & Development, Columbia University, NY, USA
  4. 4Department of Physiology and Cellular Biophysics, Columbia University, NY, USA
  5. 5Department of Neuroscience, Columbia University, NY, USA

Correspondence: Dr ÁT Behan, Current address: Department of Physiology, Royal College of Surgeons in Ireland, 123 St Stephens Green, Dublin 2, Ireland. Tel: +353 1 402 8579, Fax: +353 1 402 2447, E-mail: abehan@rcsi.ie

6Current address: School of Medicine, University College Cork, Cork, Ireland.

Received 9 September 2011; Revised 30 January 2012; Accepted 6 February 2012
Advance online publication 21 March 2012



Cannabis use confers a two-fold increase in risk for psychosis, with adolescent use conferring an even greater risk. A high-low activity polymorphism in catechol-O-methyltransferase (COMT), a gene encoding the COMT enzyme involved in dopamine clearance in the brain, may interact with adolescent cannabis exposure to increase risk for schizophrenia. The impact of such an interaction on central neurotransmitter pathways implicated in schizophrenia is unknown. Male mice with knockout of the COMT gene were treated chronically with delta-9-tetrahydrocannabinol (THC) during adolescence (postnatal day 32–52). We measured the size and density of GABAergic cells and the protein expression of cannabinoid receptor 1 (CB1R) in the prefrontal cortex (PFC) and hippocampus (HPC) in knockout mice relative to heterozygous mutants and wild-type controls. Size and density of dopaminergic neurons was also assessed in the ventral tegmental area (VTA) across the genotypes. COMT genotype × THC treatment interactions were observed for: (1) dopaminergic cell size in the VTA, (2) CB1R protein expression in the HPC, and (3) parvalbumin (PV) cell size in the PFC. No effects of adolescent THC treatment were observed for PV and dopaminergic cell density across the COMT genotypes. COMT genotype modulates the effects of chronic THC administration during adolescence on indices of neurotransmitter function in the brain. These findings illuminate how COMT deletion and adolescent cannabis use can interact to modulate the function of neurotransmitters systems implicated in schizophrenia.


delta-9-tetrahydrocannabinol; COMT; dopamine; GABA; gene × environment interaction; animal models

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