Adult and adolescent antipsychotic exposure increases delay discounting and diminishes behavioral flexibility in male C57BL/6 mice.

Second-generation antipsychotics are frequently prescribed to adolescents, but the long-term consequences of their use remain understudied. These medications work via monoamine neurotransmitter systems, especially dopamine and serotonin, which undergo considerable development and pruning during adolescence. Dopamine and serotonin are linked to a wide host of behaviors, including impulsive choice and behavioral plasticity. In a murine model of adolescent antipsychotic use, male C57BL/6 mice were exposed to either 2.5 mg/kg/day risperidone or 5 mg/kg/day olanzapine via drinking water from postnatal days 22-60. To determine whether the adolescent period was uniquely sensitive to antipsychotic exposure, long-term effects on behavior were compared to an equivalently exposed group of adults where mice were exposed to 2.5 mg/kg risperidone from postnatal days 101-138. Motor activity and body weight in adolescent animals were assessed. Thirty days after exposure terminated animal's behavioral flexibility and impulsive choice were assessed using spatial discrimination reversal and delay discounting. Antipsychotic exposure produced a modest change in behavior flexibility during the second reversal. There was a robust and reproducible difference in impulsive choice: exposed animals devalued the delayed alternative reward substantially more than controls. This effect was observed both following adolescent and adult exposure, indicating that an irreversible change in impulsive choice occurs regardless of the age of exposure.

Effects of chlordiazepoxide on pausing during rich-to-lean transitions.

Extended pausing during discriminable transitions from rich-to-lean conditions can be viewed as escape (i.e., rich-to-lean transitions function aversively). Thus, an anxiolytic drug would be predicted to mitigate the aversiveness and decrease pausing. In the current experiment, pigeons' key pecking was maintained by a multiple fixed-ratio fixed-ratio schedule of rich (i.e., larger) or lean (i.e., smaller) reinforcers. Intermediate doses (3.0-10.0 mg/kg) of chlordiazepoxide differentially decreased median pauses during rich-to-lean transitions. Relatively small decreases in pauses occurred during lean-to-lean and rich-to-rich transitions. Effects of chlordiazepoxide on pausing occurred without appreciable effects on run rates. These findings suggest that signaled rich-to-lean transitions function aversively.