Evidence for impairment of behavioural inhibition in performance of operant tasks in tPA−/− mice

Abstract

We have previously shown that mice that lack the serine protease, tissue plasminogen activator (tPA), show over-responding on the active lever during time-out periods in an I.V. cocaine self-administration task. To investigate this effect further, tPA knockout mice (tPA−/−) were tested in a number of operant paradigms for a liquid food reinforcer. tPA−/− and wild-type (WT) control mice acquired a fixed ratio (FR) and a fixed interval (FI) task equally. However, extinction from the FR schedule resulted in a significant decrease in responses on the active and inactive levers in the WT mice whilst responding on the inactive lever remained high in the tPA−/− animals. In a differential reinforcement of low rate (DRL) task, tPA−/− mice acquired the task at a slower rate than WT animals. This was characterised by high levels of responding on the active lever during the first 15 sessions in the tPA−/− mice. Burst responding on the active lever (lever press rate with an inter-response time of less than 3 s) was especially high in these animals. This behaviour pattern resulted in the animals obtaining less reinforcers than the WT controls. Acute cocaine dose-dependently shifted the pattern of behaviour on the active lever towards shorter inter-response times. However, there was no difference between the tPA−/− and WT mice in their sensitivity to cocaine on this task. Repeated administration of a low dose of cocaine did not alter performance on this task in either set of animals. When the DRL task was modified to allow the tPA−/− and WT mice an equal number of reinforced trials per session there was no difference in the ability of the animals to perform the task. This would suggest that the tPA−/− mice have a tendency to over-respond but that this can be overcome when the task is modified to allow equal opportunity to learn.