The effects of medial prefrontal cortex infusions of cocaine in a runway model of drug self-administration: evidence of reinforcing but not anxiogenic actions

Abstract

In previous work we have shown that rats running a straight alley for intravenous (i.v.) or intracerebroventricular (i.c.v.) injections of cocaine develop an ambivalence about entering the goal box that results from cocaine's mixed reinforcing and anxiogenic properties. What remains unclear is whether or not cocaine's opposing properties stem from actions on a common neuronal system or from dual actions on separate systems - one related to reward and another to anxiogenic responses. One way to address this question is to deliver cocaine into discrete brain areas as a means of assessing whether or not the positive and negative effects of the drug can be spatially dissociated. Given the putative role of mesocorticolimbic dopamine pathways in the mediation of cocaine-reinforced behavior, the current study examined the cocaine-seeking behavior of rats permitted to run an alley once each day for bilateral medial prefrontal cortex microinjections of cocaine (0.0, 12.5, 25 or 50 microg/0.5 microl per side) delivered upon goal-box entry. The results demonstrated that undrugged animals are highly motivated to seek medial prefrontal cortex cocaine without any evidence of negative or anxiogenic effects at any dose. These results are therefore consistent with suggestions of a medial prefrontal cortex involvement in the reinforcing actions of cocaine, and indicate that the dual and opposing actions of the drug can be dissociated and hence may be mediated by the drug's actions on separate neuronal systems.

Figure 1

Panel A -- Mean (+S.E.M.) run times per group expressed per trial during the 15 days of runway testing. For clarity, each data point was plotted from the average of two successive days/trials. The doses represent the bilateral infusions of intra-mPFC cocaine that were delivered once a day upon the animal’s entry into the goal box. Panel B – Mean (+S.E.M.) run times per group per trial averaged over the entire two weeks of testing. All three cocaine groups entered the goal box more quickly than the non-reinforced 0μg control animals (*P<.05).

Figure 2

Panel A -- Mean (+S.E.M.) retreat frequency per group over each two-day period of the test session (i.e., each data point represents the average 2-day retreat total made by animals in each group). Panel B -- Mean (+S.E.M.) total retreat frequency exhibited by each group over the entire two-week test period. The doses represent the bilateral infusions of intra-mPFC cocaine that were delivered once a day upon the animal’s entry into the goal box. All three cocaine groups exhibited fewer retreats compared to the non-reinforced 0μg control animals (*P < .05).