The 2010 Young Investigator Award was presented to Dr. Jean Martin Beaulieu and Dr. Cecilia Flores at the 33rd Annual Meeting of the Canadian College of Neuropsychopharmacology in Ottawa, Ontario,. The Young Investigator Award, sponsored by AstraZeneca Canada, is designed to recognize outstanding contributions in the field of research in neuropsychopharmacology by a young basic or clinical investigator in Canada.

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Dr. Jean Martin Beaulieu

Abstract

TARGETING NETWORKS, AKT/GSK3 SIGNALING IN THE ACTIONS OF PSYCHIATRIC DRUGS

Departments of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval-CRULRG, Québec, Québec, Canada.

Psychotropic drugs acting on monoamine neurotransmission remain the principal form of pharmacological treatments for neuropsychiatric conditions such as schizophrenia, depression, ADHD and bipolar disorder. Several lines of research involving behavioral and biochemical approaches in normal and/or genetically modified mice provide evidence for an involvement of the protein kinases glycogen syntase kinase-3 (GSK3) and Akt in the behavioral functions of dopamine and serotonin (5-HT). These kinases have also received attention for their role in the actions of psychoactive drugs including lithium, antidepressants and antipsychotics. Furthermore, investigations of the mechanism by which D2 dopamine receptors regulate Akt/GSK3 signaling strongly support the physiological relevance of a new modality of G protein-coupled receptor (GPCR) signaling involving the multifunctional scaffolding protein beta-arrestin 2. Here we provide an overview of how this dual function of components of the GPCR desensitization machinery relates to the mechanism of action of several psychoactive drugs and summarize recent insights into the relevance of the Akt-GSK-3 signaling cascade for the expression of monoamine-associated behaviors.

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Dr. Cecilia Flores

Abstract

ROLE OF NETRIN-1 IN THE ORGANIZATION AND FUNCTION OF DOPAMINE SYSTEMS. IMPLICATIONS FOR PSYCHOPATHOLOGY.

Dysfunctions of the mesocorticolimbic dopamine system are implicated in the psychopathology of schizophrenia and other disorders including drug addiction. Abnormalities in brain development and connectivity play an etiological role in schizophrenia leading to altered dopamine function and increased vulnerability to the effects of stimulant drugs in adulthood. Netrins, are proteins that organize neuronal networks during development. We have shown that netrin-1 and its receptors are highly expressed by dopamine neurons in the rodent brain. Interestingly, the expression of netrin-1 receptors by dopamine neurons varies from embryonic life to adulthood, with a dramatic shift in expression pattern occurring during the peripubertal period. Moreover, we find that adult netrin-1 receptor deficient mice display altered mesocorticolimbic dopamine function and related behaviors and modifications in mesocortical dopamine circuitry. These changes appear opposite to those observed in developmental animal models of schizophrenia or following chronic use of drugs of abuse. Significantly, the signs of this apparently 'protective' phenotype is not evident before puberty (i.e., before the maturation of the mesocortical DA system). We propose that variations in netrin-1 and netrin-1 receptor function in selective populations of dopamine neurons and their target regions, and at specific critical periods during development, contribute to individual differences in susceptibility to psychopathology.

Consistent with the expression of netrin-1 and netrin-1 receptors within the midbrain dopamine system in the adult brain, we have also identified a critical role for netrin-1 in the behavioral plasticity induced by repeated exposure to stimulant drugs in adulthood. Our studies suggest netrin-1 signaling in the dopamine somatodendritic region as a novel mechanism in the series of cellular processes that lead to the reorganization of neuronal circuitry by drugs of abuse.