Investigations into the role of the metabotropic glutamate receptor, mGluR5, in incentive learning and some behavioural and neurobiological effects of cocaine

The metabotropic glutamate receptor, mGluR5, is densely expressed in brain regions involved in incentive learning processes. There is considerable evidence to suggest that following exposure to addictive drugs such as cocaine, adaptations in these brain areas may underlie the development and maintenance of behavioural responses related to addictive processes. The present thesis examines the role of mGluR5 in both incentive learning processes and some behavioural and neurobiological effects of cocaine. First, using a novel mutant mouse line in which mGluR5 is selectively knocked down in cells that express dopamine D1 receptors (D1R), I argue that this mGluR5 population is critically important for specific incentive learning processes. By blocking mGluR5 in wild-type mice with a selective antagonist, I then propose mGluR5 as necessary for the acquisition, but not the expression of an incentive association. Next, I present data showing that mGluR5 on dopaminoceptive neurons are not necessary for the „conditioned rewarding‟ properties of cocaine, measured in the conditioned place preference model, but do contribute to the psychomotor activating effects of cocaine. Finally, I present an immunohistochemistry study that examines cocaine-induced activation of the extracellular-signal related kinase (ERK) pathway. In the mGluR5 knock-down mice, activation of the ERK pathway in the striatum is disrupted following an acute injection of cocaine. Given the importance of the ERK pathway in establishing and maintaining long term memories, I propose that disruption of this pathway could contribute, in part, to some findings reported in the present thesis. Taken together, this thesis will argue that signalling through mGluR5 on D1R expressing neurons is important for the formation of incentive associations, and may contribute to neural adaptations necessary for the development and maintenance of behavioural responses related to addictive processes.