118 results on '"Benkelfat, C."'
Search Results
2. Tryptophan hydroxylase2 gene polymorphisms predict brain serotonin synthesis in the orbitofrontal cortex in humans
- Author
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Booij, L, Turecki, G, Leyton, M, Gravel, P, Lopez De Lara, C, Diksic, M, and Benkelfat, C
- Published
- 2012
- Full Text
- View/download PDF
3. Patterns of gene expression in the limbic system of suicides with and without major depression
- Author
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Sequeira, A, Klempan, T, Canetti, L, ffrench-Mullen, J, Benkelfat, C, Rouleau, G A, and Turecki, G
- Published
- 2007
- Full Text
- View/download PDF
4. A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: II. Suicidal behavior
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Anguelova, M, Benkelfat, C, and Turecki, G
- Published
- 2003
- Full Text
- View/download PDF
5. A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: I. Affective disorders
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Anguelova, M, Benkelfat, C, and Turecki, G
- Published
- 2003
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- View/download PDF
6. TPH and suicidal behavior: a study in suicide completers
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Turecki, G, Zhu, Z, Tzenova, J, Lesage, A, Séguin, M, Tousignant, M, Chawky, N, Vanier, C, Lipp, O, Alda, M, Joober, R, Benkelfat, C, and Rouleau, G A
- Published
- 2001
- Full Text
- View/download PDF
7. Association between the methylenetetrahydrofolate reductase 677C→T missense mutation and schizophrenia
- Author
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Joober, R, Benkelfat, C, Lal, S, Bloom, D, Labelle, A, Lalonde, P, Turecki, G, Rozen, R, and Rouleau, G A
- Published
- 2000
- Full Text
- View/download PDF
8. Polyglutamine-containing proteins in schizophrenia
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Joober, R, Benkelfat, C, Jannatipour, M, Turecki, G, Lal, S, Mandel, J-L, Bloom, D, Lalonde, P, Lopes-Cendes, I, Fortin, D, and Rouleau, G
- Published
- 1999
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- View/download PDF
9. Elevated dopa decarboxylase activity in living brain of patients with psychosis
- Author
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Benkelfat, C., Reith, J., Sherwin, A., Yasuhara, Y., Kuwabara, H., Andermann, F., Bachneff, S., Cumming, P., Diksic, M., Dyve, S.E., Etienne, P., Evans, A.C., Lal, S., Shevell, M., Savard, G., Wong, D.F., Chouinard, G., and Gjedde, A.
- Subjects
Schizophrenia -- Research ,Dopa -- Psychological aspects ,Science and technology - Abstract
Specific assay for psychosis in schizophrenic patients reveals a marked increase in the metabolic rate of an exogenous dopa tracer (6-(18F)fluoro-L-dopa) in the striatum of these patients. Basic dopamine deficiency in the striatum is balanced by an excess of episodic dopamine, giving rise to psychosis. Cortical deficiency regulates the enzymes that catalyze dopa metabolism in the striatum and the receptors that regulate dopaminergic neurotransmission.
- Published
- 1994
10. Effects on Mood of Acute Phenylalanine/Tyrosine Depletion in Healthy Women
- Author
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Leyton, M., Young, S.N., Pihl, R.O., Etezadi, S., Lauze, C., Blier, P., Baker, G.B., and Benkelfat, C.
- Published
- 2000
- Full Text
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11. Dopamine cross-sensitization between psychostimulant drugs and stress in healthy male volunteers
- Author
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Booij, L, primary, Welfeld, K, additional, Leyton, M, additional, Dagher, A, additional, Boileau, I, additional, Sibon, I, additional, Baker, G B, additional, Diksic, M, additional, Soucy, J-P, additional, Pruessner, J C, additional, Cawley-Fiset, E, additional, Casey, K F, additional, and Benkelfat, C, additional
- Published
- 2016
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- View/download PDF
12. Mood-elevating effects of d-amphetamine and incentive salience: The effect of acute dopamine precursor depletion
- Author
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Leyton, M., Aan het Rot, M., Booij, L., Baker, G.B., Young, S.N., Benkelfat, C., and Heymans Institute for Psychological Research
- Published
- 2007
13. Suicide and tryptophan hydroxylase: An investigation in completers
- Author
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Turecki, G, Tzenova, J, Lesage, A, Seguin, M, Tousignant, M, Benkelfat, C, and Rouleau, G
- Published
- 2001
14. Statistical mapping analysis of serotonin synthesis images generated in healthy volunteers using positron-emission tomography and alpha-[11C]methyl-L-tryptophan
- Author
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Okazawa, H, Leyton, M, Benkelfat, C, Mzengeza, S, and Diksic, M
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Research Article - Abstract
OBJECTIVES: To assess the suitability of analyzing functional images of brain serotonin (5-HT) synthesis with statistical parametric mapping (SPM), and to investigate further possible sex-related regional differences. DESIGN: Prospective study. PARTICIPANTS: Six healthy men and 5 healthy women. INTERVENTION: Participants' brains were scanned with positron-emission tomography (PET) after intravenous injection of alpha-[11C]methyl-L-tryptophan (alpha-[11C]MTrp). OUTCOME MEASURES: Tissue radioactivity images were converted into functional images using the Patlak plot approach, and analyzed with 2 methods for global normalization in the SPM program: proportional scaling and analysis of covariance (ANCOVA). RESULTS: The data structure suggests that PET alpha-[11C]MTrp data meet the criteria for analysis with SPM, and that the proportional scaling method is more appropriate than the ANCOVA method for normalization. Regional differences in 5-HT synthesis were identified between men and women, and the significance of these findings was supported by region of interest (ROI) analyses. CONCLUSION: SPM analyses of PET alpha-[11C]MTrp data may be of value for identifying regional differences in brain 5-HT synthesis between groups, and in investigating the effects of psychotropic drugs. Since we found regional differences between male and female subjects, men and women should not be grouped for data analysis in PET alpha-[11C]MTrp studies.
- Published
- 2000
15. T102C polymorphism in the 5HT2A gene and schizophrenia: relation to phenotype and drug response variability
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Alda, M., Benkelfat, C., Bloom, D., Brisebois, K., Fortin, D., Joober, R., Labelle, A., Lal, S., Lalonde, P., Palmour, R., Rouleau, G. A., Andre Toulouse, and Turecki, G.
- Subjects
Adult ,Male ,Phenotype ,Polymorphism, Genetic ,Receptors, Serotonin ,Schizophrenia ,Humans ,Female ,Receptor, Serotonin, 5-HT2A ,Middle Aged ,Alleles ,Research Article - Abstract
Although genes play a major role in the etiology of schizophrenia, no major genes involved in this disease have been identified. However, several genes with small effect have been reported, though inconsistently, to increase the risk for schizophrenia. Recently, the 5HT2A 2 allele (T102C polymorphism) was reported to be over-represented in patients with schizophrenia. Other reports have found an excess of allele 2(C) only in schizophrenic patients who are resistant to clozapine, not in those who respond to clozapine. In this study, the 5HT2A receptor allele 2 frequencies were compared between 2 groups of patients with schizophrenia (39 responders and 63 nonresponders) based on long-term outcome and response to typical neuroleptics. A control group of 90 healthy volunteers screened for mental disorders was also included. Genotype 2/2 tended to be more frequent in patients with schizophrenia with poor long-term outcome and poor response to typical neuroleptics (Bonferroni corrected p = 0.09). This difference was significant in men (Bonferroni corrected p = 0.054) but not in women. In addition, the age at first contact with psychiatric care was significantly younger in the patients with schizophrenia with genotype 2/2 than in patients with genotype 1/1. These result suggest that the 5HT2A-receptor gene may play a role in a subset of schizophrenia characterized by poor long-term outcome and poor response to neuroleptics.
- Published
- 1999
16. Individual Differences in Frontal Cortical Thickness Correlate with the d-Amphetamine-Induced Striatal Dopamine Response in Humans
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Casey, K. F., primary, Cherkasova, M. V., additional, Larcher, K., additional, Evans, A. C., additional, Baker, G. B., additional, Dagher, A., additional, Benkelfat, C., additional, and Leyton, M., additional
- Published
- 2013
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17. Tryptophan hydroxylase2 gene polymorphisms predict brain serotonin synthesis in the orbitofrontal cortex in humans
- Author
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Booij, L, primary, Turecki, G, additional, Leyton, M, additional, Gravel, P, additional, Lopez De Lara, C, additional, Diksic, M, additional, and Benkelfat, C, additional
- Published
- 2011
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18. Conditioned Dopamine Release in Humans: A Positron Emission Tomography [11C]Raclopride Study with Amphetamine
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Boileau, I., primary, Dagher, A., additional, Leyton, M., additional, Welfeld, K., additional, Booij, L., additional, Diksic, M., additional, and Benkelfat, C., additional
- Published
- 2007
- Full Text
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19. TPH and suicidal behavior: a study in suicide completers
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Turecki, G, primary, Zhu, Z, additional, Tzenova, J, additional, Lesage, A, additional, Séguin, M, additional, Tousignant, M, additional, Chawky, N, additional, Vanier, C, additional, Lipp, O, additional, Alda, M, additional, Joober, R, additional, Benkelfat, C, additional, and Rouleau, G A, additional
- Published
- 2000
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20. Serotonin1A Receptor Activation by Flesinoxan in Humans
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Seletti, B, primary, Benkelfat, C, additional, Blier, P, additional, Annable, L, additional, Gilbert, F, additional, and de Montigny, C, additional
- Published
- 1995
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21. Elevated dopa decarboxylase activity in living brain of patients with psychosis.
- Author
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Reith, J, primary, Benkelfat, C, additional, Sherwin, A, additional, Yasuhara, Y, additional, Kuwabara, H, additional, Andermann, F, additional, Bachneff, S, additional, Cumming, P, additional, Diksic, M, additional, and Dyve, S E, additional
- Published
- 1994
- Full Text
- View/download PDF
22. Tryptophan hydroxylase2 gene polymorphisms predict brain serotonin synthesis in the orbitofrontal cortex in humans.
- Author
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Booij, L, Turecki, G, Leyton, M, Gravel, P, Lopez De Lara, C, Diksic, M, and Benkelfat, C
- Subjects
TRYPTOPHAN hydroxylase ,GENETIC polymorphisms ,SEROTONIN ,NEURAL development ,MENTAL depression ,SUICIDE - Abstract
Brain regional serotonin synthesis can be estimated in vivo using positron emission tomography (PET) and α-[(
11 )C]methyl-L-tryptophan (11 C-AMT) trapping (K* ) as a proxy. Recently, we reported evidence of lower normalized11 C-AMT trapping in the orbitofrontal cortex (OBFC) of subjects meeting the criteria for an impulsive and/or aggressive behavioral phenotype. In this study, we examined whether part of the variance in OBFC serotonin synthesis is related to polymorphisms of the gene that encodes for the indoleamine's rate-limiting enzyme in the brain, tryptophan hydroxylase-2 (TPH2 ). In all, 46 healthy controls had PET11 C-AMT scans and were genotyped for 11 single-nucleotide polymorphisms (SNPs) distributed across the TPH2 gene and its 5′ upstream region. Several TPH2 SNPs were associated with lower normalized blood-to-brain clearance of11 C-AMT in the OBFC. Dose-effect relationships were found for two variants (rs6582071 and rs4641527, respectively, located in the 5′ upstream region and intron 1) that have previously been associated with suicide. Associations in the OBFC remained statistically significant in a mixed larger sample of patients and controls. These results suggest that in humans, genetic factors might partly account for variations in serotonin synthesis in the OBFC. [ABSTRACT FROM AUTHOR]- Published
- 2012
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23. Mood-elevating effects of d-amphetamine and incentive salience: the effect of acute dopamine precursor depletion.
- Author
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Leyton M, Het Rot MA, Booij L, Baker GB, Young SN, and Benkelfat C
- Abstract
OBJECTIVE: Midbrain dopamine transmission is thought to regulate responses to rewarding drugs and drug-paired stimuli; however, the exact contribution, particularly in humans, remains unclear. In the present study, we tested whether decreasing dopamine synthesis, as produced by acute phenylalanine/tyrosine depletion (APTD), would alter responses to the stimulant drug, d-amphetamine. METHODS: On 3 separate days, 14 healthy men received d-amphetamine (0.3 mg/kg, given orally) plus a nutritionally balanced amino acid mixture, the phenylalanine/tyrosine-deficient mixture or the phenylalanine/tyrosine-deficient mixture followed by the immediate dopamine precursor, L-DOPA (Sinemet, 2 x 100 mg/25 mg). Responses to these treatments were assessed with visual analog scales, the Profile of Mood States, and a computerized Go/No-Go task. RESULTS: d-Amphetamine elicited its prototypical subjective effects, but these were not altered by APTD. In comparison, APTD significantly increased commission errors on the Go/No-Go task and did so uniquely in conditions where subjects were rewarded for making correct responses; this effect of APTD was prevented by L-DOPA. CONCLUSIONS: Together these results support the hypothesis that, in healthy men, dopamine is not closely linked to euphorogenic effects of abused substances but does affect the salience of reward-related cues and the ability to respond to them preferentially. [ABSTRACT FROM AUTHOR]
- Published
- 2007
24. A new method for rapidly and simultaneously decreasing serotonin and catecholamine synthesis in humans.
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Leyton M, Pun VK, Benkelfat C, and Young SN
- Abstract
OBJECTIVE: The administration of amino acid (AA) mixtures that are selectively deficient either in tryptophan or phenylalanine plus tyrosine can decrease serotonin or catecholamine synthesis, respectively. In the present study, we assessed whether a mixture that was simultaneously deficient in tryptophan, phenylalanine and tyrosine could induce sufficient protein synthesis that plasma levels of all 3 monoamine precursors would decrease. DESIGN: Ten healthy volunteers (5 male, 5 female) were administered a tryptophan/phenylalanine/tyrosine-deficient AA mixture in an open-label study. Plasma concentrations of large neutral AAs were measured before and 5 hours after mixture ingestion. RESULTS: The tryptophan/phenylalanine/tyrosine-deficient mixture lowered plasma concentrations of the 3 AAs by 67;, 78% and 77%, respectively (p < or = 0.001); their ratio to other large neutral AAs was decreased more, namely, by 87%, 90% and 90% (p < or = 0.001). Mood lowering was seen on 3 subscales of the bipolar Profile of Mood States, that is, elated-depressed, composed-anxious and clearheaded-confused, as well as 2 visual analog scales, bored and irritated (p < or = 0.05). CONCLUSIONS: Acute tryptophan/phenylalanine/tyrosine depletion may be a suitable new method for rapidly decreasing serotonin and catecholamine transmission simultaneously. [ABSTRACT FROM AUTHOR]
- Published
- 2003
25. Association between the methylenetetrahydrofolate reductase 677C--T missense mutation and schizophrenia.
- Author
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Joober, R., Benkelfat, C., Lal, S., Bloom, D., Labelle, A., Lalonde, P., Turecki, G., Rozen, R., and Rouleau, G.A.
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SCHIZOPHRENIA ,GENETIC mutation ,ENZYMES - Abstract
The schizophrenia phenotype is heterogeneous with respect to clinical presentation, long-term response to medication, and outcome, possibly reflecting genetic heterogeneity and/or the presence of modifier genes. Compared to non-responders, schizophrenic patients who are responders to neuroleptic medications are characterized by a high female/male ratio, a better longterm outcome and more frequently disturbed dopamine neurotransmission. In this study, we compared two groups of schizophrenic patients selected on the basis of their long-term response to neuroleptics (excellent responders and non-responders) and a group of healthy volunteers, with regard to a missense mutation (677C→T) in the methylenetetrahydrofolate reductase (MTHFR) gene. This polymorphism was chosen because it is functional5 and was previously associated with schizophrenia. The present study revealed a significant association between schizophrenia and allele T of this gene. This association was entirely due to an over-representation of allele T in responder patients compared to controls; nonresponder patients did not differ from controls. Genotype TT was more frequent in responder patients compared to controls, thus replicating the findings of Arinami et al. These results strongly suggest that the MTHFR gene is involved in the pathogenesis of schizophrenia characterized by a rapid and sustained therapeutic response to typical neuroleptics and/or a good long-term prognosis/favorable therapeutic outcome. [ABSTRACT FROM AUTHOR]
- Published
- 2000
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26. Serotonin1AReceptor Activation by Flesinoxan in Humans.
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Seletti, B, Benkelfat, C, Blier, P, Annable, L, Gilbert, F, and de Montigny, C
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- 1995
- Full Text
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27. Serotonin1AReceptor Activation by Flesinoxan in Humans
- Author
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Seletti, B, Benkelfat, C, Blier, P, Annable, L, Gilbert, F, and de Montigny, C
- Abstract
The effects of the selective 5-HT1Areceptor agonist flesinoxan on neuroendocrine function, temperature, and behavior were assessed in male healthy volunteers using a double-blind, placebo-controlled crossover design. Flexinoxan (7 and 14 μg/kg), administered intravenously in 11 healthy volunteers, elicited a dose-related decrease in body temperature and increases in growth hormone, adrenocorticotropic hormone (ACTH), cortisol, and prolactin plasma levels. In a second independent study, 12 healthy volunteers were pretreated sequentially, at one-week intervals, with either the 5-HT1Aantagonist pindolol (30 mg, PO), the nonselective 5-HT1 2antagonist methysergide (4 mg, PO), or placebo, prior to being administered flesinoxan (1 mg, IV). The growth hormone response to flesinoxan was blocked by pindolol but not by methysergide, whereas the prolactin response was blocked by methysergide but not by pindolol. The ACTH and cortisol responses to flesinoxan were potentiated by methysergide. The flesinoxan-induced hypothermia was attenuated by both methysergide and pindolol, although the latter effects did not reach statistical significance. The present results suggest that the growth hormone response and the hypothermic response to the intravenous infusion of flesinoxan may serve as a valid index of 5-HT1Areceptor function in humans.
- Published
- 1995
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28. Suicide and the serotonin transporter gene.
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Fitch, D., Lesage, A., Seguin, M., Tousignant, M., Benkelfat, C., Rouleau, G.A., and Turecki, G.
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SUICIDE ,SEROTONIN ,GENETIC psychology - Abstract
Verifies evidence that a genetic component may increase the predisposition to suicide and that deficiencies of the serotonin system play a significant role. Effort to replicate findings reported by Bondy and associates; Investigation of a large sample of suicide completers.
- Published
- 2001
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29. Externalizing Risk Pathways for Adolescent Substance Use and Its Developmental Onset: A Canadian Birth Cohort Study: Trajectoires de comportements extériorisés et le risque pour l'initiation et l'usage de substances des adolescents : Une étude de cohorte de naissance canadienne.
- Author
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Cox SML, Castellanos-Ryan N, Parent S, Benkelfat C, Vitaro F, Pihl RO, Boivin M, Tremblay RE, Leyton M, and Séguin JR
- Subjects
- Adolescent, Canada epidemiology, Child, Child, Preschool, Cohort Studies, Female, Humans, Infant, Pregnancy, Prospective Studies, Birth Cohort, Substance-Related Disorders epidemiology
- Abstract
Objective: Only a minority of drug and alcohol users develops a substance use disorder. Previous studies suggest that this differential vulnerability commonly reflects a developmental trajectory characterized by diverse externalizing behaviors. In this study, we examined the relation between child and adolescent externalizing behaviors and adolescent substance use in a prospectively followed Canadian birth cohort, accounting for the temporal sequence of a wide variety of contributing factors., Methods: Two hundred and forty-two adolescents followed since birth (date range: 1996 to 2012) were assessed on externalizing behavior (age 17 months to 16 years), alcohol and cannabis use at age 16, age of alcohol use onset, family history of substance use problems, family functioning (age 11 to 15), sensation seeking (age 16), prenatal substance exposure, socioeconomic status (age 1 to 9), and sex., Results: Age of alcohol use onset was predicted by a family history of substance use problems, externalizing traits from ages 6 to 10 and 11 to 16, sensation seeking at age 16, prenatal alcohol and tobacco exposure and family functioning at ages 11 to 15. High frequencies of alcohol and cannabis use at age 16 were both predicted by externalizing traits from ages 11 to 16, a family history of substance use problems and sensation seeking after controlling for other individual, environmental and familial variables. The association between familial substance use problems and substance use during adolescence was partially mediated by externalizing traits from age 11 to 16., Conclusions: The present findings provide prospective evidence for a developmental risk pathway for adolescent substance use, potentially identifying those who could benefit from early interventions.
- Published
- 2021
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30. Metabotropic glutamate type 5 receptor binding availability during dextroamphetamine sensitization in mice and humans.
- Author
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Smart K, Nagano-Saito A, Milella MS, Sakae DY, Favier M, Vigneault E, Louie L, Hamilton A, Ferguson SSG, Rosa-Neto P, Narayanan S, El Mestikawy S, Leyton M, and Benkelfat C
- Subjects
- Adult, Animals, Behavior, Animal drug effects, Central Nervous System Stimulants administration & dosage, Dextroamphetamine administration & dosage, Female, Fluorescent Antibody Technique, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Oximes pharmacokinetics, Positron-Emission Tomography, Pyridines pharmacokinetics, Receptor, Metabotropic Glutamate 5 antagonists & inhibitors, Central Nervous System Sensitization drug effects, Central Nervous System Stimulants pharmacology, Corpus Striatum diagnostic imaging, Corpus Striatum drug effects, Corpus Striatum metabolism, Dextroamphetamine pharmacology, Locomotion drug effects, Prefrontal Cortex diagnostic imaging, Prefrontal Cortex drug effects, Prefrontal Cortex metabolism, Psychomotor Performance drug effects, Receptor, Metabotropic Glutamate 5 drug effects, Receptor, Metabotropic Glutamate 5 metabolism
- Abstract
Background: Glutamate transmission is implicated in drug-induced behavioural sensitization and the associated long-lasting increases in mesolimbic output. Metabotropic glutamate type 5 (mGlu5) receptors might be particularly important, but most details are poorly understood., Methods: We first assessed in mice (n = 51, all male) the effects of repeated dextroamphetamine administration (2.0 mg/kg, i.p.) on locomotor activity and binding of the mGlu5 ligand [3H]ABP688. In a parallel study, in 19 stimulant-drug-naïve healthy human volunteers (14 female) we administered 3 doses of dextroamphetamine (0.3 mg/kg, p.o.) or placebo, followed by a fourth dose 2 weeks later. We measured [11C]ABP688 binding using positron emission tomography before and after the induction phase. We assessed psychomotor and behavioural sensitization using speech rate, eye blink rate and self-report. We measured the localization of mGlu5 relative to synaptic markers in mouse striatum using immunofluorescence., Results: We observed amphetamine-induced psychomotor sensitization in mice and humans. We did not see group differences in mGlu5 availability following 3 pre-challenge amphetamine doses, but group differences did develop in mice administered 5 doses. In mice and humans, individual differences in mGlu5 binding after repeated amphetamine administration were negatively correlated with the extent of behavioural sensitization. In drug-naïve mice, mGlu5 was expressed at 67% of excitatory synapses on dendrites of striatal medium spiny neur., Limitations: Correlational results should be interpreted as suggestive because of the limited sample size. We did not assess sex differences., Conclusion: Together, these results suggest that changes in mGlu5 availability are not part of the earliest neural adaptations in stimulant-induced behavioural sensitization, but low mGlu5 binding might identify a higher propensity for sensitization., Competing Interests: M. Leyton is an associate editor of JPN. He was not involved in reviewing or the decision to accept this paper for publication., (© 2021 Joule Inc. or its licensors.)
- Published
- 2021
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31. mGlu5 receptor availability in youth at risk for addictions: effects of vulnerability traits and cannabis use.
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Cox SML, Tippler M, Jaworska N, Smart K, Castellanos-Ryan N, Durand F, Allard D, Benkelfat C, Parent S, Dagher A, Vitaro F, Boivin M, Pihl RO, Côté S, Tremblay RE, Séguin JR, and Leyton M
- Subjects
- Adolescent, Adult, Brain diagnostic imaging, Brain metabolism, Carbon Radioisotopes, Humans, Longitudinal Studies, Positron-Emission Tomography, Receptor, Metabotropic Glutamate 5 metabolism, Young Adult, Cannabis metabolism
- Abstract
The excitatory neurotransmitter glutamate has been implicated in experience-dependent neuroplasticity and drug-seeking behaviors. Type 5 metabotropic glutamate (mGlu5) receptors might be particularly important. They are critically involved in synaptic plasticity and their availability has been reported to be lower in people with alcohol, tobacco, and cocaine use disorders. Since these reductions could reflect effects of drug use or pre-existing traits, we used positron emission tomography to measure mGlu5 receptor availability in young adults at elevated risk for addictions. Fifty-nine participants (age 18.5 ± 0.6) were recruited from a longitudinal study that has followed them since birth. Based on externalizing traits that predict future substance use problems, half were at low risk, half were at high risk. Cannabis use histories varied markedly and participants were divided into three subgroups: zero, low, and high use. Compared to low risk volunteers, those at elevated risk had lower [
11 C]ABP688 binding potential (BPND ) values in the striatum, amygdala, insula, and orbitofrontal cortex (OFC). Cannabis use by risk group interactions were observed in the striatum and OFC. In these regions, low [11 C]ABP688 BPND values were only seen in the high risk group that used high quantities of cannabis. When these high risk, high cannabis use individuals were compared to all other participants, [11 C]ABP688 BPND values were lower in the striatum, OFC, and insula. Together, these results provide evidence that mGlu5 receptor availability is low in youth at elevated risk for addictions, particularly those who frequently use cannabis.- Published
- 2020
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32. Extra-striatal D 2/3 receptor availability in youth at risk for addiction.
- Author
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Jaworska N, Cox SML, Tippler M, Castellanos-Ryan N, Benkelfat C, Parent S, Dagher A, Vitaro F, Boivin M, Pihl RO, Côté SM, Tremblay RE, Séguin JR, and Leyton M
- Subjects
- Adolescent, Humans, Impulsive Behavior, Positron-Emission Tomography, Receptors, Dopamine D3 metabolism, Corpus Striatum diagnostic imaging, Corpus Striatum metabolism, Receptors, Dopamine D2 metabolism
- Abstract
The neurobiological traits that confer risk for addictions remain poorly understood. However, dopaminergic function throughout the prefrontal cortex, limbic system, and upper brainstem has been implicated in behavioral features that influence addiction vulnerability, including poor impulse control, and altered sensitivity to rewards and punishments (i.e., externalizing features). To test these associations in humans, we measured type-2/3 dopamine receptor (DA
2/3 R) availability in youth at high vs. low risk for substance use disorders (SUDs). In this study, N = 58 youth (18.5 ± 0.6 years) were recruited from cohorts that have been followed since birth. Participants with either high (high EXT; N = 27; 16 F/11 M) or low pre-existing externalizing traits (low EXT; N = 31; 20 F/11 M) underwent a 90-min positron emission tomography [18 F]fallypride scan, and completed the Barratt Impulsiveness Scale (BIS-11), Substance Use Risk Profile scale (SURPS), and Sensitivity to Punishment (SP) and Sensitivity to Reward (SR) questionnaire. We found that high vs. low EXT trait participants reported elevated substance use, BIS-11, SR, and SURPS impulsivity scores, had a greater prevalence of psychiatric disorders, and exhibited higher [18 F]fallypride binding potential (BPND ) values in prefrontal, limbic and paralimbic regions, even when controlling for substance use. Group differences were not evident in midbrain dopamine cell body regions, but, across all participants, low midbrain BPND values were associated with low SP scores. Together, the results suggest that altered DA2/3 R availability in terminal extra-striatal and dopamine cell body regions might constitute biological vulnerability traits, generating an EXT trajectory for addictions with and without co-occurring alterations in punishment sensitivity (i.e., an internalizing feature).- Published
- 2020
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33. Dopaminergic Plasticity in the Bilateral Hippocampus Following Threat Reversal in Humans.
- Author
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Lissemore JI, Nagano-Saito A, Smart K, Gravel P, Leyton M, and Benkelfat C
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- Adult, Conditioning, Psychological, Cues, Female, Healthy Volunteers, Hippocampus diagnostic imaging, Hippocampus physiology, Humans, Male, Positron-Emission Tomography, Dopamine metabolism, Hippocampus metabolism, Neuronal Plasticity
- Abstract
When a cue no longer predicts a threat, a diminished ability to extinguish or reverse this association is thought to increase risk for stress-related disorders. Despite the clear clinical relevance, the mediating neurochemical mechanisms of threat reversal have received relatively little study. One neurotransmitter implicated in rodent research of changing associations with threat is dopamine. To study whether dopamine is involved in threat reversal in humans, we used high-resolution positron emission tomography (PET) coupled with
18 F-fallypride. Twelve healthy volunteers (6 F/6 M) underwent three PET scans: (i) at baseline, (ii) following threat conditioning (the response to a cue associated with electric wrist shock), and (iii) following threat reversal (the response to the same cue now associated with safety). We observed moderate evidence of reduced dopamine D2/3 receptor availability, consistent with greater dopamine release, in the bilateral anterior hippocampus following threat reversal, in response to a safety cue that was previously associated with threat, as compared to both baseline and during exposure to the same cue prior to threat reversal. These findings offer the first preliminary evidence that the response to a previously threatening cue that has since become associated with safety involves dopaminergic neurotransmission within the hippocampus in healthy humans.- Published
- 2020
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34. Why Is Aging a Risk Factor for Cognitive Impairment in Parkinson's Disease?-A Resting State fMRI Study.
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Nagano-Saito A, Bellec P, Hanganu A, Jobert S, Mejia-Constain B, Degroot C, Lafontaine AL, Lissemore JI, Smart K, Benkelfat C, and Monchi O
- Abstract
Using resting-state functional MRI (rsfMRI) data of younger and older healthy volunteers and patients with Parkinson's disease (PD) with and without mild cognitive impairment (MCI) and applying two different analytic approaches, we investigated the effects of age, pathology, and cognition on brain connectivity. When comparing rsfMRI connectivity strength of PD patients and older healthy volunteers, reduction between multiple brain regions in PD patients with MCI (PD-MCI) compared with PD patients without MCI (PD-non-MCI) was observed. This group difference was not affected by the number and location of clusters but was reduced when age was included as a covariate. Next, we applied a graph-theory method with a cost-threshold approach to the rsfMRI data from patients with PD with and without MCI as well as groups of younger and older healthy volunteers. We observed decreased hub function (measured by degree and betweenness centrality) mainly in the medial prefrontal cortex (mPFC) in older healthy volunteers compared with younger healthy volunteers. We also found increased hub function in the posterior medial structure (precuneus and the cingulate cortex) in PD-non-MCI patients compared with older healthy volunteers and PD-MCI patients. Hub function in these posterior medial structures was positively correlated with cognitive function in all PD patients. Together these data suggest that overlapping patterns of hub modifications could mediate the effect of age as a risk factor for cognitive decline in PD, including age-related reduction of hub function in the mPFC, and recruitment availability of the posterior medial structure, possibly to compensate for impaired basal ganglia function.
- Published
- 2019
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35. Mesocorticolimbic Connectivity and Volumetric Alterations in DCC Mutation Carriers.
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Vosberg DE, Zhang Y, Menegaux A, Chalupa A, Manitt C, Zehntner S, Eng C, DeDuck K, Allard D, Durand F, Dagher A, Benkelfat C, Srour M, Joober R, Lepore F, Rouleau G, Théoret H, Bedell BJ, Flores C, and Leyton M
- Subjects
- Adult, Aging psychology, Animals, Axons, Exploratory Behavior, Female, Heterozygote, Humans, Limbic System diagnostic imaging, Magnetic Resonance Imaging, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Neural Pathways diagnostic imaging, Personality Disorders genetics, Personality Disorders psychology, Prefrontal Cortex diagnostic imaging, Substance-Related Disorders genetics, Substance-Related Disorders psychology, Substantia Nigra diagnostic imaging, Substantia Nigra physiopathology, Ventral Tegmental Area diagnostic imaging, Ventral Tegmental Area physiopathology, Young Adult, DCC Receptor genetics, Limbic System physiopathology, Neural Pathways physiopathology, Prefrontal Cortex physiopathology
- Abstract
The axon guidance cue receptor DCC (deleted in colorectal cancer) plays a critical role in the organization of mesocorticolimbic pathways in rodents. To investigate whether this occurs in humans, we measured (1) anatomical connectivity between the substantia nigra/ventral tegmental area (SN/VTA) and forebrain targets, (2) striatal and cortical volumes, and (3) putatively associated traits and behaviors. To assess translatability, morphometric data were also collected in Dcc -haploinsufficient mice. The human volunteers were 20 DCC
+/- mutation carriers, 16 DCC+/+ relatives, and 20 DCC+/+ unrelated healthy volunteers (UHVs; 28 females). The mice were 11 Dcc+/- and 16 wild-type C57BL/6J animals assessed during adolescence and adulthood. Compared with both control groups, the human DCC+/- carriers exhibited the following: (1) reduced anatomical connectivity from the SN/VTA to the ventral striatum [ DCC+/+ : p = 0.0005, r ( effect size ) = 0.60; UHV: p = 0.0029, r = 0.48] and ventral medial prefrontal cortex ( DCC+/+ : p = 0.0031, r = 0.53; UHV: p = 0.034, r = 0.35); (2) lower novelty-seeking scores ( DCC+/+ : p = 0.034, d = 0.82; UHV: p = 0.019, d = 0.84); and (3) reduced striatal volume ( DCC+/+ : p = 0.0009, d = 1.37; UHV: p = 0.0054, d = 0.93). Striatal volumetric reductions were also present in Dcc+/- mice, and these were seen during adolescence ( p = 0.0058, d = 1.09) and adulthood ( p = 0.003, d = 1.26). Together these findings provide the first evidence in humans that an axon guidance gene is involved in the formation of mesocorticolimbic circuitry and related behavioral traits, providing mechanisms through which DCC mutations might affect susceptibility to diverse neuropsychiatric disorders. SIGNIFICANCE STATEMENT Opportunities to study the effects of axon guidance molecules on human brain development have been rare. Here, the identification of a large four-generational family that carries a mutation to the axon guidance molecule receptor gene, DCC , enabled us to demonstrate effects on mesocorticolimbic anatomical connectivity, striatal volumes, and personality traits. Reductions in striatal volumes were replicated in DCC -haploinsufficient mice. Together, these processes might influence mesocorticolimbic function and susceptibility to diverse neuropsychiatric disorders., (Copyright © 2018 the authors 0270-6474/18/384655-11$15.00/0.)- Published
- 2018
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36. Brain serotonin synthesis capacity in obsessive-compulsive disorder: effects of cognitive behavioral therapy and sertraline.
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Lissemore JI, Sookman D, Gravel P, Berney A, Barsoum A, Diksic M, Nordahl TE, Pinard G, Sibon I, Cottraux J, Leyton M, and Benkelfat C
- Subjects
- Adult, Brain diagnostic imaging, Combined Modality Therapy, Female, Humans, Male, Middle Aged, Obsessive-Compulsive Disorder diagnostic imaging, Positron-Emission Tomography, Treatment Outcome, Young Adult, Brain metabolism, Cognitive Behavioral Therapy, Obsessive-Compulsive Disorder drug therapy, Obsessive-Compulsive Disorder metabolism, Serotonin biosynthesis, Selective Serotonin Reuptake Inhibitors therapeutic use, Sertraline therapeutic use
- Abstract
Cognitive behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs) are both effective treatments for some patients with obsessive-compulsive disorder (OCD), yet little is known about the neurochemical changes related to these treatment modalities. Here, we used positron emission tomography and the α-[
11 C]methyl-L-tryptophan tracer to examine the changes in brain regional serotonin synthesis capacity in OCD patients following treatment with CBT or SSRI treatment. Sixteen medication-free OCD patients were randomly assigned to 12 weeks of either CBT or sertraline treatment. Pre-to-post treatment changes in the α-[11 C]methyl-L-tryptophan brain trapping constant, K* (ml/g/min), were assessed as a function of symptom response, and correlations with symptom improvement were examined. Responders/partial responders to treatment did not show significant changes in relative regional tracer uptake; rather, in responders/partial responders, 12 weeks of treatment led to serotonin synthesis capacity increases that were brain-wide. Irrespective of treatment modality, baseline serotonin synthesis capacity in the raphe nuclei correlated positively with clinical improvement. These observations suggest that, for some patients, successful remediation of OCD symptoms might be associated with greater serotonergic tone.- Published
- 2018
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37. Differential Associations between Cortical Thickness and Striatal Dopamine in Treatment-Naïve Adults with ADHD vs. Healthy Controls.
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Cherkasova MV, Faridi N, Casey KF, Larcher K, O'Driscoll GA, Hechtman L, Joober R, Baker GB, Palmer J, Evans AC, Dagher A, Benkelfat C, and Leyton M
- Abstract
Alterations in catecholamine signaling and cortical morphology have both been implicated in the pathophysiology of attention deficit/hyperactivity disorder (ADHD). However, possible links between the two remain unstudied. Here, we report exploratory analyses of cortical thickness and its relation to striatal dopamine transmission in treatment-naïve adults with ADHD and matched healthy controls. All participants had one magnetic resonance imaging (MRI) and two [
11 C]raclopride positron emission tomography scans. Associations between frontal cortical thickness and the magnitude of d -amphetamine-induced [11 C]raclopride binding changes were observed that were divergent in the two groups. In the healthy controls, a thicker cortex was associated with less dopamine release; in the ADHD participants the converse was seen. The same divergence was seen for baseline D2/3 receptor availability. In healthy volunteers, lower D2/3 receptor availability was associated with a thicker cortex, while in the ADHD group lower baseline D2/3 receptor availability was associated with a thinner cortex. Individual differences in cortical thickness in these regions correlated with ADHD symptom severity. Together, these findings add to the evidence of associations between dopamine transmission and cortical morphology, and suggest that these relationships are altered in treatment-naïve adults with ADHD.- Published
- 2017
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38. Cocaine Cue-Induced Dopamine Release in Recreational Cocaine Users.
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Cox SML, Yau Y, Larcher K, Durand F, Kolivakis T, Delaney JS, Dagher A, Benkelfat C, and Leyton M
- Subjects
- Adolescent, Adult, Behavior, Addictive diagnostic imaging, Carbon Radioisotopes chemistry, Cocaine-Related Disorders diagnostic imaging, Corpus Striatum diagnostic imaging, Corpus Striatum metabolism, Cues, Dopamine Uptake Inhibitors pharmacology, Humans, Male, Positron-Emission Tomography methods, Raclopride chemistry, Surveys and Questionnaires, Young Adult, Cocaine pharmacology, Corpus Striatum drug effects, Dopamine metabolism, Drug-Seeking Behavior drug effects
- Abstract
It has been proposed that the acquisition of drug seeking is related to the development of conditioned dopamine responses in the ventral striatum. As drug use continues and becomes habit-like, conditioned responses have been shown to shift to the dorsal striatum. Here, using the PET [
11 C]raclopride method and highly personalized cocaine cues, we report the first evidence in humans of the dorsal dopamine response prior to the onset of addiction.- Published
- 2017
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39. Is there a relation between novelty seeking, striatal dopamine release and frontal cortical thickness?
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Jaworska N, Cox SM, Casey KF, Boileau I, Cherkasova M, Larcher K, Dagher A, Benkelfat C, and Leyton M
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- Adult, Female, Frontal Lobe anatomy & histology, Humans, Magnetic Resonance Imaging, Male, Organ Size, Positron-Emission Tomography, Young Adult, Corpus Striatum physiology, Dopamine metabolism, Exploratory Behavior, Frontal Lobe physiology
- Abstract
Background: Novelty-seeking (NS) and impulsive personality traits have been proposed to reflect an interplay between fronto-cortical and limbic systems, including the limbic striatum (LS). Although neuroimaging studies have provided some evidence for this, most are comprised of small samples and many report surprisingly large effects given the challenges of trying to relate a snapshot of brain function or structure to an entity as complex as personality. The current work tested a priori hypotheses about associations between striatal dopamine (DA) release, cortical thickness (CT), and NS in a large sample of healthy adults., Methods: Fifty-two healthy adults (45M/7F; age: 23.8±4.93) underwent two positron emission tomography scans with [11C]raclopride (specific for striatal DA D2/3 receptors) with or without amphetamine (0.3 mg/kg, p.o.). Structural magnetic resonance image scans were acquired, as were Tridimensional Personality Questionnaire data. Amphetamine-induced changes in [11C]raclopride binding potential values (ΔBPND) were examined in the limbic, sensorimotor (SMS) and associative (AST) striatum. CT measures, adjusted for whole brain volume, were extracted from the dorsolateral sensorimotor and ventromedial/limbic cortices., Results: BPND values were lower in the amphetamine vs. no-drug sessions, with the largest effect in the LS. When comparing low vs. high LS ΔBPND groups (median split), higher NS2 (impulsiveness) scores were found in the high ΔBPND group. Partial correlations (age and gender as covariates) yielded a negative relation between ASTS ΔBPND and sensorimotor CT; trends for inverse associations existed between ΔBPND values in other striatal regions and frontal CT. In other words, the greater the amphetamine-induced striatal DA response, the thinner the frontal cortex., Conclusions: These data expand upon previously reported associations between striatal DA release in the LS and both NS related impulsiveness and CT in the largest sample reported to date. The findings add to the plausibility of these associations while suggesting that the effects are likely weaker than has been previously proposed.
- Published
- 2017
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40. Cocaine cue-induced dopamine release in the human prefrontal cortex.
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Milella MS, Fotros A, Gravel P, Casey KF, Larcher K, Verhaeghe JA, Cox SM, Reader AJ, Dagher A, Benkelfat C, and Leyton M
- Subjects
- Adult, Benzamides, Brain Mapping, Cocaine administration & dosage, Cocaine-Related Disorders diagnostic imaging, Cocaine-Related Disorders psychology, Corpus Striatum diagnostic imaging, Corpus Striatum metabolism, Cues, Dopamine D2 Receptor Antagonists, Dopamine Uptake Inhibitors administration & dosage, Female, Fluorine Radioisotopes, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Neuropsychological Tests, Positron-Emission Tomography, Prefrontal Cortex diagnostic imaging, Radiopharmaceuticals, Cocaine-Related Disorders metabolism, Craving physiology, Dopamine metabolism, Prefrontal Cortex metabolism
- Abstract
Background: Accumulating evidence indicates that drug-related cues can induce dopamine (DA) release in the striatum of substance abusers. Whether these same cues provoke DA release in the human prefrontal cortex remains unknown., Methods: We used high-resolution positron emission tomography with [18F]fallypride to measure cortical and striatal DA D2/3 receptor availability in the presence versus absence of drug-related cues in volunteers with current cocaine dependence., Results: Twelve individuals participated in our study. Among participants reporting a craving response (9 of 12), exposure to the cocaine cues significantly decreased [18F]fallypride binding potential (BPND) values in the medial orbitofrontal cortex and striatum. In all 12 participants, individual differences in the magnitude of craving correlated with BPND changes in the medial orbitofrontal cortex, dorsolateral prefrontal cortex, anterior cingulate, and striatum. Consistent with the presence of autoreceptors on mesostriatal but not mesocortical DA cell bodies, midbrain BPND values were significantly correlated with changes in BPND within the striatum but not the cortex. The lower the midbrain D2 receptor levels, the greater the striatal change in BPND and self-reported craving., Limitations: Limitations of this study include its modest sample size, with only 2 female participants. Newer tracers might have greater sensitivity to cortical DA release., Conclusion: In people with cocaine use disorders, the presentation of drug-related cues induces DA release within cortical and striatal regions. Both effects are associated with craving, but only the latter is regulated by midbrain autoreceptors. Together, the results suggest that cortical and subcortical DA responses might both influence drug-focused incentive motivational states, but with separate regulatory mechanisms.
- Published
- 2016
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41. Genetic and early environmental influences on the serotonin system: consequences for brain development and risk for psychopathology.
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Booij L, Tremblay RE, Szyf M, and Benkelfat C
- Subjects
- Animals, Environment, Epigenesis, Genetic, Genetic Predisposition to Disease, Humans, Brain growth & development, Brain physiopathology, Gene-Environment Interaction, Mental Disorders physiopathology, Serotonin genetics, Serotonin metabolism
- Abstract
Background: Despite more than 60 years of research in the role of serotonin (5-HT) in psychopathology, many questions still remain. From a developmental perspective, studies have provided more insight into how 5-HT dysfunctions acquired in utero or early in life may modulate brain development. This paper discusses the relevance of the developmental role of 5-HT for the understanding of psychopathology. We review developmental milestones of the 5-HT system, how genetic and environmental 5-HT disturbances could affect brain development and the potential role of DNA methylation in 5-HT genes for brain development., Methods: Studies were identified using common databases (e.g., PubMed, Google Scholar) and reference lists., Results: Despite the widely supported view that the 5-HT system matures in early life, different 5-HT receptors, proteins and enzymes have different developmental patterns, and development is brain region-specific. A disruption in 5-HT homeostasis during development may lead to structural and functional changes in brain circuits that modulate emotional stress responses, including subcortical limbic and (pre)frontal areas. This may result in a predisposition to psychopathology. DNA methylation might be one of the underlying physiologic mechanisms., Limitations: There is a need for prospective studies. The impact of stressors during adolescence on the 5-HT system is understudied. Questions regarding efficacy of drugs acting on 5-HT still remain., Conclusion: A multidisciplinary and longitudinal approach in designing studies on the role of 5-HT in psychopathology might help to bring us closer to the understanding of the role of 5-HT in psychopathology.
- Published
- 2015
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42. Amphetamine-induced dopamine release and neurocognitive function in treatment-naive adults with ADHD.
- Author
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Cherkasova MV, Faridi N, Casey KF, O'Driscoll GA, Hechtman L, Joober R, Baker GB, Palmer J, Dagher A, Leyton M, and Benkelfat C
- Subjects
- Adult, Attention Deficit Disorder with Hyperactivity psychology, Brain Mapping, Corpus Striatum diagnostic imaging, Dextroamphetamine blood, Dopamine Antagonists pharmacokinetics, Dopamine Uptake Inhibitors blood, Executive Function physiology, Humans, Inhibition, Psychological, Male, Neuropsychological Tests, Psychiatric Status Rating Scales, Raclopride pharmacokinetics, Radionuclide Imaging, Task Performance and Analysis, Attention Deficit Disorder with Hyperactivity drug therapy, Attention Deficit Disorder with Hyperactivity metabolism, Corpus Striatum metabolism, Dextroamphetamine pharmacology, Dopamine metabolism, Dopamine Uptake Inhibitors pharmacology
- Abstract
Converging evidence from clinical, preclinical, neuroimaging, and genetic research implicates dopamine neurotransmission in the pathophysiology of attention deficit hyperactivity disorder (ADHD). The in vivo neuroreceptor imaging evidence also suggests alterations in the dopamine system in ADHD; however, the nature and behavioral significance of those have not yet been established. Here, we investigated striatal dopaminergic function in ADHD using [(11)C]raclopride PET with a d-amphetamine challenge. We also examined the relationship of striatal dopamine responses to ADHD symptoms and neurocognitive function. A total of 15 treatment-free, noncomorbid adult males with ADHD (age: 29.87 ± 8.65) and 18 healthy male controls (age: 25.44 ± 6.77) underwent two PET scans: one following a lactose placebo and the other following d-amphetamine (0.3 mg/kg, p.o.), administered double blind and in random order counterbalanced across groups. In a separate session without a drug, participants performed a battery of neurocognitive tests. Relative to the healthy controls, the ADHD patients, as a group, showed greater d-amphetamine-induced decreases in striatal [(11)C]raclopride binding and performed more poorly on measures of response inhibition. Across groups, a greater magnitude of d-amphetamine-induced change in [(11)C]raclopride binding potential was associated with poorer performance on measures of response inhibition and ADHD symptoms. Our findings suggest an augmented striatal dopaminergic response in treatment-naive ADHD. Though in contrast to results of a previous study, this finding appears consistent with a model proposing exaggerated phasic dopamine release in ADHD. A susceptibility to increased phasic dopamine responsivity may contribute to such characteristics of ADHD as poor inhibition and impulsivity.
- Published
- 2014
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43. Dopamine and light: dissecting effects on mood and motivational states in women with subsyndromal seasonal affective disorder.
- Author
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Cawley EI, Park S, aan het Rot M, Sancton K, Benkelfat C, Young SN, Boivin DB, and Leyton M
- Subjects
- Adult, Affect drug effects, Dopamine deficiency, Female, Humans, Motivation drug effects, Phenylalanine blood, Phenylalanine pharmacology, Psychomotor Performance drug effects, Psychomotor Performance physiology, Reward, Seasonal Affective Disorder diagnosis, Seasonal Affective Disorder metabolism, Tyrosine blood, Tyrosine pharmacology, Affect physiology, Dopamine physiology, Light, Motivation physiology, Seasonal Affective Disorder physiopathology, Seasonal Affective Disorder psychology
- Abstract
Background: Despite evidence that bright light can improve mood, the neurobiology remains poorly understood. Some evidence implicates the catecholamines. In the present study, we measured the effects of transiently decreasing dopamine (DA) synthesis on mood and motivational states in healthy women with mild seasonal mood changes who were tested in either bright or dim light., Methods: On 2 test days, participants slept overnight in a light-controlled room. On the morning of each session, half of the participants awoke to gradual increases of bright light, up to 3000 lux, and half to dim light (10 lux). For all participants, DA was reduced on 1 of the test days using the acute phenylalanine/tyrosine depletion (APTD) method; on the other day, they ingested a nutritionally balanced control mixture (BAL). Beginning 4 hours postingestion, participants completed subjective mood questionnaires, psychological tests and a progressive ratio breakpoint task during which they worked for successive units of $5., Results: Thirty-two women participated in our study. The APTD lowered mood, agreeableness, energy and the willingness to work for monetary reward. The effects on energy and motivation were independent of light, while the effects on mood and agreeableness were seen in the dim condition only, being prevented by bright light., Limitations: Acute phenylalanine/tyrosine depletion might affect systems other than DA. The sample size was small., Conclusion: These results suggest that increased DA function may be responsible for some of the beneficial effects of light, while adding to the evidence that the neurobiology of mood and motivational states can be dissociated.
- Published
- 2013
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44. Cocaine cue-induced dopamine release in amygdala and hippocampus: a high-resolution PET [¹⁸F]fallypride study in cocaine dependent participants.
- Author
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Fotros A, Casey KF, Larcher K, Verhaeghe JA, Cox SM, Gravel P, Reader AJ, Dagher A, Benkelfat C, and Leyton M
- Subjects
- Adult, Affect, Amygdala diagnostic imaging, Behavior, Addictive diagnostic imaging, Cocaine-Related Disorders diagnostic imaging, Cocaine-Related Disorders psychology, Corpus Striatum diagnostic imaging, Corpus Striatum metabolism, Cues, Female, Fluorine Radioisotopes, Hippocampus diagnostic imaging, Humans, Male, Neuroimaging, Radionuclide Imaging, Amygdala metabolism, Behavior, Addictive metabolism, Benzamides, Cocaine-Related Disorders metabolism, Dopamine metabolism, Hippocampus metabolism
- Abstract
Drug-related cues are potent triggers for relapse in people with cocaine dependence. Dopamine (DA) release within a limbic network of striatum, amygdala and hippocampus has been implicated in animal studies, but in humans it has only been possible to measure effects in the striatum. The objective here was to measure drug cue-induced DA release in the amygdala and hippocampus using high-resolution PET with [(18)F]fallypride. Twelve cocaine-dependent volunteers (mean age: 39.6 ± 8.0 years; years of cocaine use: 15.9 ± 7.4) underwent two [(18)F]fallypride high-resolution research tomography-PET scans, one with exposure to neutral cues and one with cocaine cues. [(18)F]Fallypride non-displaceable-binding potential (BPND) values were derived for five regions of interest (ROI; amygdala, hippocampus, ventral limbic striatum, associative striatum, and sensorimotor striatum). Subjective responses to the cues were measured with visual analog scales and grouped using principal component analysis. Drug cue exposure significantly decreased BPND values in all five ROI in subjects who had a high-, but not low-, craving response (limbic striatum: p=0.019, associative striatum: p=0.008, sensorimotor striatum: p=0.004, amygdala: p=0.040, and right hippocampus: p=0.025). Individual differences in the cue-induced craving response predicted the magnitude of [(18)F]fallypride responses within the striatum (ventral limbic: r=0.581, p=0.048; associative: r=0.589, p=0.044; sensorimotor: r=0.675, p=0.016). To our knowledge this study provides the first evidence of drug cue-induced DA release in the amygdala and hippocampus in humans. The preferential induction of DA release among high-craving responders suggests that these aspects of the limbic reward network might contribute to drug-seeking behavior.
- Published
- 2013
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45. The neurobiology of depression--revisiting the serotonin hypothesis. II. Genetic, epigenetic and clinical studies.
- Author
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Albert PR and Benkelfat C
- Subjects
- Animals, Antidepressive Agents therapeutic use, Depression drug therapy, Depression genetics, Epigenesis, Genetic, Genetic Predisposition to Disease, Humans, Neuroimaging, Raphe Nuclei drug effects, Raphe Nuclei metabolism, Raphe Nuclei physiopathology, Receptors, Serotonin drug effects, Receptors, Serotonin genetics, Receptors, Serotonin metabolism, Serotonin genetics, Serotonin Plasma Membrane Transport Proteins genetics, Serotonin Plasma Membrane Transport Proteins metabolism, Depression physiopathology, Serotonin metabolism
- Abstract
The serotonin system originates from a small number of neurons (a few hundred thousand of the 100 billion in man) located in the midbrain raphe nuclei, that project widely throughout the central nervous system to influence a large array of inter-related biological functions, not least of which are circuits involved in mood and emotion. The serotonin hypothesis of depression has postulated that a reduction in serotonin leads to increased predisposition to depression. Indeed, it has become evident from therapeutic strategies that affect serotonin activity, that alterations in serotonin may not only predispose to depression, but also to aggressive behaviour, impulsivity, obsessive-compulsive behaviour and suicide. Many potential mechanisms known to alter the genes that regulate the serotonin system, including developmental epigenetic modifications, are presented, as additional evidence implicating the serotonin system. This second issue of two special issues of Philosophical Transactions B presents a series of reviews, perspectives and new findings that argue that the serotonin hypothesis remains an important idea that continues to guide research into the aetiology and treatment of depression.
- Published
- 2013
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46. The neurobiology of depression--revisiting the serotonin hypothesis. I. Cellular and molecular mechanisms.
- Author
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Albert PR, Benkelfat C, and Descarries L
- Subjects
- Animals, Anxiety physiopathology, Depression genetics, Humans, Neurons drug effects, Neurons physiology, Serotonin genetics, Selective Serotonin Reuptake Inhibitors pharmacology, Social Behavior, Synaptic Transmission, Depression physiopathology, Serotonin physiology
- Abstract
The serotonin (5-HT) hypothesis of depression dates from the 1960s. It originally postulated that a deficit in brain serotonin, corrected by antidepressant drugs, was the origin of the illness. Nowadays, it is generally accepted that recurring mood disorders are brain diseases resulting from the combination, to various degrees, of genetic and other biological as well as environmental factors, evolving through the lifespan. All areas of neuroscience, from genes to behaviour, molecules to mind, and experimental to clinical, are actively engaged in attempts at elucidating the pathophysiology of depression and the mechanisms underlying the efficacy of antidepressant treatments. This first of two special issues of Philosophical Transactions B seeks to provide an overview of current developments in the field, with an emphasis on cellular and molecular mechanisms, and how their unravelling opens new perspectives for future research.
- Published
- 2012
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47. From anticipation to action, the role of dopamine in perceptual decision making: an fMRI-tyrosine depletion study.
- Author
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Nagano-Saito A, Cisek P, Perna AS, Shirdel FZ, Benkelfat C, Leyton M, and Dagher A
- Subjects
- Adult, Brain Mapping methods, Female, Humans, Male, Young Adult, Anticipation, Psychological physiology, Decision Making physiology, Dopamine physiology, Magnetic Resonance Imaging methods, Reward, Tyrosine metabolism, Visual Perception physiology
- Abstract
During simple sensorimotor decision making, neurons in the parietal cortex extract evidence from sensory information provided by visual areas until a decision is reached. Contextual information can bias parietal activity during the task and change the decision-making parameters. One type of contextual information is the availability of reward for correct decisions. We tested the hypothesis that the frontal lobes and basal ganglia use contextual information to bias decision making to maximize reward. Human volunteers underwent functional MRI while making decisions about the motion of dots on a computer monitor. On rewarded trials, subjects responded more slowly by increasing the threshold to decision. Rewarded trials were associated with activation in the ventral striatum and prefrontal cortex in the period preceding coherent dot motion, and the degree of activation predicted the increased decision threshold. Decreasing dopamine transmission, using a tyrosine-depleting amino acid mixture, abolished the reward-related corticostriatal activation and eliminated the correlation between striatal activity and decision threshold. These observations provide direct evidence that some reward-related functional MRI signals in the striatum are the result of dopamine neuron activity and demonstrate that mesolimbic dopamine transmission can influence perceptual and decision-making neural processes engaged to maximize reward harvest.
- Published
- 2012
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48. The dopamine augmenter L-DOPA does not affect positive mood in healthy human volunteers.
- Author
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Liggins J, Pihl RO, Benkelfat C, and Leyton M
- Subjects
- Adolescent, Adult, Dopamine metabolism, Double-Blind Method, Female, Health, Human Experimentation, Humans, Male, Synaptic Transmission drug effects, Synaptic Transmission physiology, Up-Regulation drug effects, Young Adult, Affect drug effects, Levodopa pharmacology
- Abstract
Dopamine neurotransmission influences approach toward rewards and reward-related cues. The best cited interpretation of this effect proposes that dopamine mediates the pleasure that commonly accompanies reward. This hypothesis has received support in some animal models and a few studies in humans. However, direct assessments of the effect of transiently increasing dopamine neurotransmission have been largely limited to the use of psychostimulant drugs, which elevate brain levels of multiple neurotransmitters in addition to dopamine. In the present study we tested the effect of more selectively elevating dopamine neurotransmission, as produced by administration of the immediate dopamine precursor, L-DOPA (0, 100/25, 200/50 mg, Sinemet), in healthy human volunteers. Neither dose altered positive mood. The results suggest that dopamine neurotransmission does not directly influence positive mood in humans.
- Published
- 2012
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49. Peripheral SLC6A4 DNA methylation is associated with in vivo measures of human brain serotonin synthesis and childhood physical aggression.
- Author
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Wang D, Szyf M, Benkelfat C, Provençal N, Turecki G, Caramaschi D, Côté SM, Vitaro F, Tremblay RE, and Booij L
- Subjects
- Adult, Humans, Male, Promoter Regions, Genetic genetics, Thiophenes metabolism, Aggression physiology, Brain metabolism, DNA Methylation genetics, Serotonin metabolism, Serotonin Plasma Membrane Transport Proteins genetics
- Abstract
The main challenge in addressing the role of DNA methylation in human behaviour is the fact that the brain is inaccessible to epigenetic analysis in living humans. Using positron emission tomography (PET) measures of brain serotonin (5-HT) synthesis, we found in a longitudinal sample that adult males with high childhood-limited aggression (C-LHPA) had lower in vivo 5-HT synthesis in the orbitofrontal cortex (OBFC). Here we hypothesized that 5-HT alterations associated with childhood aggression were linked to differential DNA methylation of critical genes in the 5-HT pathway and these changes were also detectable in peripheral white blood cells. Using pyrosequencing, we determined the state of DNA methylation of SLC6A4 promoter in T cells and monocytes isolated from blood of cohort members (N = 25) who underwent a PET scan, and we examined whether methylation status in the blood is associated with in vivo brain 5-HT synthesis. Higher levels of methylation were observed in both T cells and monocytes at specific CpG sites in the C-LHPA group. DNA methylation of SLC6A4 in monocytes appears to be associated more reliably with group membership than T cells. In both cell types the methylation state of these CpGs was associated with lower in vivo measures of brain 5-HT synthesis in the left and right lateral OBFC (N = 20) where lower 5-HT synthesis in C-LHPA group was observed. Furthermore, in vitro methylation of the SLC6A4 promoter in a luciferase reporter construct suppresses its transcriptional activity supporting a functional role of DNA methylation in SLC6A4 promoter regulation. These findings indicate that state of SLC6A4 promoter methylation is altered in peripheral white blood cells of individuals with physical aggression during childhood. This supports the relevance of peripheral DNA methylation for brain function and suggests that peripheral SLC6A4 DNA methylation could be a marker of central 5-HT function.
- Published
- 2012
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- View/download PDF
50. Effects of lowered serotonin transmission on cocaine-induced striatal dopamine response: PET [¹¹C]raclopride study in humans.
- Author
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Cox SM, Benkelfat C, Dagher A, Delaney JS, Durand F, Kolivakis T, Casey KF, and Leyton M
- Subjects
- Administration, Intranasal, Adult, Analysis of Variance, Cocaine administration & dosage, Cocaine metabolism, Cocaine-Related Disorders diagnostic imaging, Cocaine-Related Disorders psychology, Corpus Striatum diagnostic imaging, Corpus Striatum drug effects, Dopamine Uptake Inhibitors administration & dosage, Dopamine Uptake Inhibitors metabolism, Female, Humans, Magnetic Resonance Imaging, Male, Positron-Emission Tomography methods, Raclopride pharmacokinetics, Radiopharmaceuticals pharmacokinetics, Tryptophan administration & dosage, Tryptophan deficiency, Tryptophan metabolism, Young Adult, Cocaine pharmacology, Cocaine-Related Disorders metabolism, Corpus Striatum metabolism, Dopamine metabolism, Dopamine Uptake Inhibitors pharmacology, Serotonin metabolism
- Abstract
Background: Low serotonin transmission is thought to increase susceptibility to a wide range of substance use disorders and impulsive traits., Aims: To investigate the effects of lowered serotonin on cocaine-induced (1.0 mg/kg cocaine, self-administered intranasally) dopamine responses and drug craving., Method: In non-dependent cocaine users, serotonin transmission was reduced using the acute tryptophan depletion method. Striatal dopamine responses were measured using positron emission tomography with [(11)C]raclopride., Results: Acute tryptophan depletion increased drug craving and striatal dopamine responses to cocaine. These acute tryptophan depletion-induced increases did not occur in the absence of cocaine., Conclusions: The results suggest that low serotonin transmission can increase dopaminergic and appetitive responses to cocaine. These findings might identify a mechanism by which individuals with low serotonin are at elevated risk for both substance use disorders and comorbid conditions.
- Published
- 2011
- Full Text
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