Linking animal models of psychosis to computational models of dopamine function.
Psychosis is linked to dysregulation of the neuromodulator dopamine and antipsychotic drugs (APDs) work by blocking dopamine receptors. Dopamine-modulated disruption of latent inhibition (LI) and conditioned avoidance response (CAR) have served as standard animal models of psychosis and antipsychotic action, respectively. Meanwhile, the 'temporal difference' algorithm (TD) has emerged as the leading computational model of dopamine neuron firing. In this report TD is extended to include action at the level of dopamine receptors in order to explain a number of behavioral phenomena including the dose-dependent disruption of CAR by APDs, the temporal dissociation of the effects of APDs on receptors vs behavior, the facilitation of LI by APDs, and the disruption of LI by amphetamine. The model also predicts an APD-induced change to the latency profile of CAR--a novel prediction that is verified experimentally. The model's primary contribution is to link dopamine neuron firing, receptor manipulation, and behavior within a common formal framework that may offer insights into clinical observations.
Smith
Andrew J
AJ
Bentley Heath, Solihull, West Midlands, UK.
Li
Ming
M
Becker
Suzanna
S
Kapur
Shitij
S
D000200:Action Potentials / Q000187:drug effects; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D003198:Computer Simulation; D003214:Conditioning, Classical / Q000187:drug effects; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology*; D018491:Dopamine Agonists / Q000627:therapeutic use; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D007859:Learning Disabilities / Q000188:drug therapy / Q000209:etiology; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects; D011237:Predictive Value of Tests; D011618:Psychotic Disorders / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D000661:Amphetamine; D006220:Haloperidol; D004298:Dopamine