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Le Foll B.,Translational Addiction Research Laboratory | Le Foll B.,Alcohol Research and Treatment Clinic | Le Foll B.,Campbell Family Mental Health Research Institute | Le Foll B.,University of Toronto | Di Ciano P.,Translational Addiction Research Laboratory
European Neuropsychopharmacology | Year: 2015

Since the cloning of the D3 receptor in the early 1990s, there has been a great deal of interest in this receptor as a possible therapeutic target for drug addiction. The development of a D3 ligand suitable for use in humans has remained elusive, so the study of the function of the D3 receptor and its possible therapeutic efficacy has largely been restricted to animals. Pre-clinical studies have established that systemic administration of D3 ligands, particularly antagonists and partial agonists, can alter drug-seeking in animals. Despite over a decade of research, few studies have investigated the effects of intra-cerebral infusion of D3 ligands on drug-seeking. In the present review, these studies are summarized, which have largely focused on stimulus-controlled behaviors. Converging evidence from studies of D3 receptor expression, Fos and pharmacological Magnetic Resonance Imaging (phMRI) is also provided to delineate some of the D3 brain systems involved in drug-seeking and taking. The data so far indicate that different brain systems may be involved in different types of stimulus control as well as drug taking. © 2014 Elsevier B.V. and ECNP. Source

Tiwari A.K.,Campbell Family Mental Health Research Institute
Pharmacogenomics Journal | Year: 2015

Antipsychotic-induced weight gain (AIWG) is a common side effect with a high genetic contribution. We reanalyzed genome-wide association study (GWAS) data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) selecting a refined subset of patients most suitable for AIWG studies. The final GWAS was conducted in N=189 individuals. The top polymorphisms were analyzed in a second cohort of N=86 patients. None of the single-nucleotide polymorphisms was significant at the genome-wide threshold of 5x10-8. We observed interesting trends for rs9346455 (P=6.49x10-6) upstream of OGFRL1, the intergenic variants rs7336345 (P=1.31 × 10-5) and rs1012650 (P=1.47 × 10-5), and rs1059778 (P=1.49x10-5) in IBA57. In the second cohort, rs9346455 showed significant association with AIWG (P=0.005). The combined meta-analysis P-value for rs9346455 was 1.09 × 10-7. Our reanalysis of the CATIE GWAS data revealed interesting new variants associated with AIWG. As the functional relevance of these polymorphisms is yet to be determined, further studies are needed.The Pharmacogenomics Journal advance online publication, 1 September 2015; doi:10.1038/tpj.2015.59. © 2015 Macmillan Publishers Limited Source

Oh E.,Campbell Family Mental Health Research Institute
Nature Structural and Molecular Biology | Year: 2016

The inability to digest lactose, due to lactase nonpersistence, is a common trait in adult mammals, except in certain human populations that exhibit lactase persistence. It is not known how the lactase gene is dramatically downregulated with age in most individuals but remains active in some individuals. We performed a comprehensive epigenetic study of human and mouse small intestines, by using chromosome-wide DNA-modification profiling and targeted bisulfite sequencing. Epigenetically controlled regulatory elements accounted for the differences in lactase mRNA levels among individuals, intestinal cell types and species. We confirmed the importance of these regulatory elements in modulating lactase mRNA levels by using CRISPR–Cas9-induced deletions. Genetic factors contribute to epigenetic changes occurring with age at the regulatory elements, because lactase-persistence and lactase-nonpersistence DNA haplotypes demonstrated markedly different epigenetic aging. Thus, genetic factors enable a gradual accumulation of epigenetic changes with age, thereby influencing phenotypic outcome. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. Source

Claus E.D.,Mind Research Network and Lovelace Biomedical and Environmental Research Institute | Hendershot C.S.,Campbell Family Mental Health Research Institute | Hendershot C.S.,University of Toronto
Psychopharmacology | Year: 2015

Rationale: While alcohol intoxication is known to increase disinhibited behavior, the degree to which disinhibition occurs appears to depend on a number of factors including executive functioning ability. However, the neural mechanisms by which individual differences in executive functioning lead to variable degrees of disinhibition remain unclear. Objectives: The aim of the current study was to examine the neural mechanisms by which individual differences in working memory (WM) capacity moderate alcohol-induced disinhibition. Methods: Seventeen heavy-drinking males participated in a within-subjects design in which two sessions were completed: an alcohol session (.82 g/kg) and a control session. Participants completed a go/no-go task while undergoing functional magnetic resonance imaging (fMRI) after ingestion of the control or alcohol beverage. WM capacity was measured using an operation span task. Results: Significant interactions of session and WM capacity emerged in contrasts examining successful response inhibition within superior temporal gyrus and unsuccessful inhibition in regions within the default mode network. In all cases, individuals with low WM capacity demonstrated a relative decrease in blood oxygen level-dependent (BOLD) response during the alcohol compared to control session, whereas the high-WM-capacity group demonstrated relative increases in BOLD response in the alcohol compared to control session. Conclusions: Low WM capacity appears to be associated with decreased neural response to signals indicating a need for behavioral control, an effect that may lead to increased difficulty with inhibiting responses and increased negative consequences from alcohol intoxication. © 2014 Springer-Verlag Berlin Heidelberg. Source

Le Foll B.,Campbell Family Mental Health Research Institute
Current drug targets | Year: 2013

This review examines the growing literature on the role of peroxisome proliferator-activated receptors (PPARs) in addiction. There are two subtypes of PPAR receptors that have been studied in addiction: PPAR-α and PPAR-γ. The role of each PPAR subtype in common models of addictive behavior, mainly pre-clinical models, is summarized. In particular, studies are reviewed that investigated the effects of PPAR-α agonists on relapse, sensitization, conditioned place preference, withdrawal and drug intake, and effects of PPAR-γ agonists on relapse, withdrawal and drug intake. Finally, studies that investigated the effects of PPAR agonists on neural pathways of addiction are reviewed. Taken together these preclinical data indicate that PPAR agonists are promising new medications for drug addiction treatment. Source

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