UC San Diego

The dopamine D3 receptor (D3R) has been implicated as a potential therapeutic target for several neuropsychiatric disorders. For example, schizophrenia is currently treated with medications that nonspecifically target D3 as well as D2 receptors. However, due to the homology between these receptor subtypes, the tools available for specifically studying the D3 system in vivo are limited. While intracellular signaling pathways of D3 receptors have been described using cell lines in vitro, the applicability of these models to intact neural systems and behavior remain unclear. This dissertation utilizes behavioral, pharmacological, genetic, and cellular/molecular techniques in mice, rats, and humans to examine the role of D3 receptors in regulating sensorimotor gating. Sensorimotor gating is the inhibition of a motor response by a sensory event and can be operationally measured with prepulse inhibition (PPI) of acoustic startle. PPI - the reduction in response to a startling stimulus when it is preceded by a weak prestimulus - is diminished in patients with schizophrenia and these deficits may be related to dopaminergic dysfunction. In animal models, PPI is disrupted acutely by dopaminergic agonists, and blockade of this effect predicts clinical efficacy of antipsychotics. After determining that the D3-preferential agonist pramipexole offers advantages for studying the PPI -disruptive effects of D3 stimulation, studies in this thesis described the stereochemical, anatomical and receptor-specific effects of this drug on PPI, and dissociated these effects from those on other behaviors. Using conditions that simulated D3R-mediated PPI deficits, brain regions relevant to PPI circuitry were analyzed for corresponding intracellular signaling changes. Specific signaling elements were altered by both D3 and D2 stimulation, but Fos expression in the nucleus accumbens appeared to be differentially suppressed by pramipexole and not the selective D2 agonist, sumanirole, and consistent findings were detected using D2- and D3- preferential antagonists. Collectively, these studies establish a strategy for parsing the anatomical, neurochemical and molecular substrates underlying the regulation of sensorimotor gating by forebrain D2 vs. D3 receptors, and identify divergent mechanisms that might be important targets for future drug development