| Dopamine signaling in the striatum delivers information about past experience that is integrated with cortical and thalamic information about the internal and external environment to enable the selection of appropriate actions. Alterations in dopamine signaling, as occur in schizophrenia and Parkinson's disease, result in the disruption of this system.;Typical antipsychotic drugs are widely thought to alleviate the positive symptoms of schizophrenia by antagonizing dopamine D2 receptors expressed by striatal spiny projection neurons (SPNs). What is less clear is why antipsychotics have a therapeutic latency of weeks. Additionally, the extrapyramidal side effects (EPS) of these drugs develop over weeks, months and years. The hypothesis of this dissertation is that these time-dependent phenomena occur as a result of cellular and circuit adaptations to continued dopamine D2 receptor antagonism by haloperidol. Using a combination of physiological, anatomical, and optogenetic approaches in ex vivo brain slices from transgenic mice, it was found that two weeks of haloperidol treatment induced both intrinsic and synaptic adaptations specifically within indirect pathway SPNs (iSPNs) and that the timing of these adaptations correlates with the emergence of tolerance to catalepsy, an animal model of EPS. Some of these adaptations were homeostatic, including a drop in intrinsic excitability. However, haloperidol treatment also led to strengthening of a subset of excitatory corticostriatal synapses. This slow remodeling of corticostriatal iSPN circuitry is likely to play a role in mediating the delayed therapeutic action of neuroleptics and the generation of EPS. |
