Differential Impairments in Incentive Learning Caused by First‐ and Second‐ Generation Antipsychotic Drugs

Abstract

Schizophrenia is a neuropsychiatric disorder characterized by increased function of dopamine in the brain. Dopamine release is a natural response to reward. It promotes incentive learning (IL), a process by which neutral stimuli acquire the ability to elicit approach and other responses. A recent model characterizes dopamine‐mediated IL as a progressive process with early and late stages accompanied by a shift in neural control from the nucleus accumbens (NAc) to the dorsolateral striatum (DLS). A parallel can be drawn to differences in regionally specific neural responses generated by first‐ and second‐generation antipsychotic drugs (APDs) used to treat schizophrenia. APDs are dopamine receptor antagonists, but first‐generation APDs affect the NAc and DLS while second‐generation APDs affect primarily the NAc. We compared the effects of APDs on IL. Rats (N = 48) were trained to press a lever forfood pellets in an operant chamber. Intraperitoneal injections (1 hr before testing) of the first‐generation APD haloperidol (0,0.05,0.10,0.20 mg/kg) or of the second‐generation APD risperidone (0,0.20,0.40,0.80 mg/kg) induced dose‐dependent suppression of lever pressing on days 1‐4, with the highest dose groups failing to demonstrate any evidence of previous learning on day 5 when tested drug‐free. On days 16‐20 haloperidol induced a day‐to‐day suppression not seen with risperidone. The results suggest that the effects of first‐ and second‐generation APDs on learning processes putatively mediated by the NAc and DLS can be differentiated experimentally. The findings imply that APDs may differentially affect IL inpatients with schizophrenia.