Unravelling the Role of the Dopamine D1 Receptor in Anhedonia, Asociality, and Avolition

Despite major advances in neuroscience, there has been limited progress in improving pharmacological treatment for neuropsychiatric disorders. Neuropsychiatric disorders are heterogenous with variance in symptoms within disorders and partial overlap in symptoms between disorders, leading to symptoms that remain untreated. To improve treatment outcomes, the Research Domain Criteria (RDoC) was created to provide researchers a framework for examining the neurobiological mechanisms underlying individual components, or dysfunctions, across disorders. Anhedonia, asociality and avolition are three excellent examples of prominent symptoms associated with poor functional outcome across disorders.

This thesis aimed to use an RDoC approach to investigate the neurobiological mechanisms underlying anhedonia, asociality and avolition. To this aim, rats with a selective genetic reduction in the dopamine D1 receptor (DAD1-/- mutants) underwent a series of five studies across their lifespan that examined the role of the D1 receptor in anticipatory and consummatory pleasure, social play behaviour, socio-emotional communication, and motivation. Additionally, previous research with DAD1-/- mutants used only males; this thesis expanded on that work by including both sexes and explored the possibility for sex differences in each study. The overall hypothesis was that the D1 receptor is implicated in anticipatory anhedonia, asociality and avolition, therefore DAD1-/- mutant rats were predicted to exhibit reduced socio-emotional communication, anticipation of rewards, engagement in social play and exertion of effort across their lifespan. The results showed that genetic reduction in the dopamine D1 receptor led to blunted motivation and diminished anticipatory pleasure, while consummatory pleasure and social play were not impacted. There were marked sex differences in some measures such as stability of social play across sessions and exertion of effort. Ultimately, this thesis furthered pharmacological research, implicating a clear role for the dopamine D1 receptor in motivation and anticipatory pleasure which could be targeted for treatment. In addition, this thesis supported the vital importance of including both sexes in animal research to address the strong focus of males in neuroscience research and in the role of D1 receptors in general.