Increased sensitivity to cocaine, and over-responding during cocaine self-administration in tPA knockout mice

Abstract

Tissue plasminogen activator, tPA, is induced in the brain by electrical activity leading to synaptic remodeling. It is also induced in the prefrontal cortex (PFC) by acute cocaine. We investigated cocaine-induced locomotor activity, the development of sensitisation to cocaine and cocaine self-administration in mice lacking the gene encoding tPA. Mice lacking tPA (tPA knockout mice, tPA−/−) showed normal spontaneous activity, exhibited cocaine-induced locomotor activity at lower doses than wild-type (WT) control mice and showed a greater degree of cocaine-induced locomotor activity following repeated administration. tPA−/− and WT mice did not differ significantly in the time to acquire self-administration of cocaine (20 μg/i.v. infusion) under an FR2 schedule. Following acquisition of this behavior, these groups also did not differ significantly in the rate of cocaine self-administration across the next three sessions. However, WT mice decreased responses on the active lever during signaled periods when reinforcer was not available; in contrast, tPA−/− mice did not. The emission of non-reinforced responses was most marked at the beginning of each 90 min daily session. This pattern of responding was not seen in tPA−/− mice pressing for food under an FR2 schedule of reinforcement. These results suggest that tPA may play a specific role either in retention of information between sessions or in behavioural inhibition in cocaine self-administration.