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A neurocomputational account of catalepsy sensitization induced by D2 receptor blockade in rats: context dependency, extinction, and renewal

Thomas V. Wiecki,Katrin Riedinger,A. Ameln-Mayerhofer,Werner J. Schmidt,Michael J. Frank

Published 2009 in Psychopharmacology

ABSTRACT

RationaleRepeated haloperidol treatment in rodents results in a day-to-day intensification of catalepsy (i.e., sensitization). Prior experiments suggest that this sensitization is context-dependent and resistant to extinction training.ObjectivesThe aim of this study was to provide a neurobiological mechanistic explanation for these findings.Materials and methodsWe use a neurocomputational model of the basal ganglia and simulate two alternative models based on the reward prediction error and novelty hypotheses of dopamine function. We also conducted a behavioral rat experiment to adjudicate between these models. Twenty male Sprague–Dawley rats were challenged with 0.25 mg/kg haloperidol across multiple days and were subsequently tested in either a familiar or novel context.ResultsSimulation results show that catalepsy sensitization, and its context dependency, can be explained by “NoGo” learning via simulated D2 receptor antagonism in striatopallidal neurons, leading to increasingly slowed response latencies. The model further exhibits a non-extinguishable component of catalepsy sensitization due to latent NoGo representations that are prevented from being expressed, and therefore from being unlearned, during extinction. In the rat experiment, context dependency effects were not dependent on the novelty of the context, ruling out the novelty model’s account of context dependency.ConclusionsSimulations lend insight into potential complex mechanisms leading to context-dependent catalepsy sensitization, extinction, and renewal.

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