Differential Pharmacological Profiles of Operant Acquisition, Operant Expression, and Decision-Making Performance As Tested By Antipsychotics and Other Dopaminergic Drugs

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Baker, Tyson William
Operant Acquisition , Iowa Gambling Task , Dopamine , Decision-Making , Antipsychotic , Amphetamine , Rodent Gambling Task , Haloperidol , Risperidone , Operant Expression , Metoclopramide , Clozapine , Instrumental , Incentive Learning , Reinforcement Blunting , Operant
Operant acquisition, operant expression, and decision-making differentially rely on brain areas that are differentially affected by antipsychotic and other dopaminergic drugs. The purpose of this thesis was to test if the known differential pharmacological and location of action of antipsychotic and other dopaminergic drugs predict the drug effects on operant acquisition, operant expression, and decision-making. Clozapine and to a lesser extent, risperidone but not metoclopramide or haloperidol affect the prefrontal cortex (PFC); haloperidol, metoclopramide, and to a lesser extent, risperidone affect the dorsolateral striatum (DLS). We used amphetamine as a broadly-acting indirect dopamine (DA), serotonin (5-HT), and norepinephrine agonist. We found that all antagonists altered operant acquisition and expression, but in different ways. The DA D2-like receptor antagonists blunted reinforcement impact during operant acquisition and induced an extinction-like decline in expression whereas the atypical antipsychotics with high PFC 5-HT-2A affinity maintained inactive lever presses during acquisition, but produced tolerance in expression. Curiously, risperidone and metoclopramide, but not clozapine or haloperidol, more potently suppressed lever pressing in acquisition than expression. In contrast, amphetamine suppressed operant expression, but not acquisition, at a dose range that increased locomotion and induced conditioned place preference. Amphetamine decreased sensitivity to reward presentation and inactive lever pressing during operant acquisition, but had the opposite effects during expression. A very different pattern was found in the rodent gambling task (rGT), a model of the 4- choice (deck) Iowa Gambling Task used in humans. The rGT puts small, immediate rewards that are advantageous in the long-term due to generally fewer and shorter associated penalties in conflict with large, immediate rewards that are disadvantageous in the long-term due to generally more and longer associated penalties. Two antipsychotics (risperidone, haloperidol) but not the anti-emetic (metoclopramide) enhanced performance by shifting preferences towards advantageous options, but the antipsychotic that induces PFC Fos (clozapine) impaired performance. Amphetamine decreased discrimination among different decks in the rGT. These data demonstrate the differential effects of clinically relevant drugs on decision-making and different stages of operant learning. The differential effects on operant responding and decision-making of different antipsychotic drugs provide important information regarding their therapeutic and side-effect profiles.
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