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Dr. Paul J. Fletcher
Biopsychology Section Centre for Addiction and Mental Health 250 College Street Toronto, Ontario M5S 2S1 (416) 535-8501 ext. 4058 paul_fletcher@camh.net
Dr. Paul Fletcher is a Research Scientist and Head of the Biopsychology Section in the Neuroscience Research Department. He is an Associate Professor of Psychology at the University of Toronto.
Dr. Fletcher and his team use preclinical models to investigate the neurochemical bases of behaviours relevant to addictions and psychiatric disorders, and to identify the mechanisms of action of drugs used to treat these disorders. Current research under Dr. Fletcher’s direction has: 1. Demonstrated differing roles of two serotonin receptor subtypes, (5-HT2A and 5-HT2C) in modulating effects of cocaine, and perhaps other drugs of abuse. For example, activating the 5-HT2C receptor reduces the locomotor stimulant and reinforcing effects of cocaine, while blocking this receptor leads to the opposite profile of effects. These data implicate the 5-HT2C receptor in particular as a contributory factor in the development of addiction, and suggest that this might be a fruitful target for treating addiction.
2. Shown that depletion of serotonin in the nucleus accumbens, but not the prefrontal cortex, leads to difficulties in inhibiting responding. In collaboration with Dr. Guy Higgins (NPS Pharmaceuticals in Salt Lake City, Utah), we have found that 5-HT2A receptor antagonists reduce such impulsive-like behaviour, but 5-HT2C receptor antagonists enhance this behaviour. Overall, our findings suggest that the relationship between 5-HT activity and impulsivity is complex, and may depend on which brain areas and which receptor subtypes are affected.
3. Shown that the amphetamine-induced sensitised state (AISS) also leads to cognitive deficits that are similar to those observed in schizophrenia. The most pronounced deficits are in sustained visual attention, and attentional set-shifting. Both of these deficits are reversed by infusing a dopamine D1 receptor agonist into the prefrontal cortex. Our future plans involve using this model to test potential treatments, including D1 receptor agonists, for cognitive disturbances in schizophrenia.
Publications
Fletcher PJ, Tenn CC, Sinyard J, Rizos Z, Kapur S. A sensitizing regimen of amphetamine impairs visual attention in the 5-choice serial reaction time test: reversal by a D1 receptor agonist injected into the medial prefrontal. Neuropsychopharmacology. In press.
Fletcher PJ, Sinyard J, Higgins GA. The effects of the 5-HT2C receptor antagonist SB242084 on locomotor activity induced by selective, or mixed, indirect serotonergic and dopaminergic agonists. Psychopharmacology (Berl). 2006;187: 515-525.
Fletcher PJ, Tenn CC, Lovic, V, Rizos Z, Kapur S. Sensitization to amphetamine but not PCP impairs attentional set-shifting: reversal by a D1 receptor agonist injected into the medial prefrontal cortex. Psychopharmacology. 2005;183: 190-200.
Fletcher PJ, Chintoh AF, Sinyard J, Higgins GA. (2004) Injection of the 5-HT2C receptor agonist Ro60-0175 into the ventral tegmental area reduces cocaine-induced locomotor activity and cocaine self-administration. Neuropyschopharmacology. 2004;29:308-318.
Higgins GA, Enderlin M, Haman M, Fletcher PJ. The 5-HT2A receptor antagonist M100,907 attenuates motor and “impulsive-types” behaviours produced by NMDA receptor antagonism. Psychopharmacology. 2003;170: 309-319.
Centre for Addiction
