Abstract
A reversible neuronal inactivation procedure was used to study the role of the medial orbital cortex (MO) and medial tip of the subthalamic nucleus (mSTN) in maintenance of cocaine self-administration studied under a second-order schedule of drug and cue presentation. Lidocaine or vehicle was infused 5-min before 1-h self-administration test sessions, using bilateral, asymmetric or unilateral manipulations. The results demonstrated that whether the MO was inactivated bilaterally, unilaterally or asymmetrically (with contralateral mSTN inactivation), cocaine seeking and cocaine intake were reduced. In contrast, bilateral mSTN inactivation did not impact cocaine seeking or cocaine intake, suggesting that the reductions in these measures following asymmetric inactivation may have been due to a unilateral influence of lidocaine in MO. Expression of c-Fos protein was measured in sites downstream of the STN to ensure that the lidocaine inactivation procedure was effective in selectively altering activity of neurons in mSTN. Cocaine-induced c-Fos protein expression was augmented only in the ipsilateral nucleus accumbens core after mSTN lidocaine pretreatment, consistent with the expectation that inactivation of mSTN would disinhibit nucleus accumbens core, but not shell, activity. The present investigation shows the critical importance of the MO for maintaining cocaine seeking and cocaine intake in rats, though its projections to mSTN appear to be unimportant for this purpose. Because cocaine seeking was impacted to such a great extent (45% of baseline, on average), it is likely that MO inactivation exerts its influence on maintenance of cocaine self-administration by interfering primarily with cue-controlled behavior rather than by modifying the reinforcing effects of cocaine.