A challenge in treating drug addicts is preventing their pathological motivation for the drug without impairing their general affective state toward natural reinforcers. Here we have shown that discrete lesions of the subthalamic nucleus greatly decreased the motivation of rats for cocaine while increasing it for food reward. The subthalamic nucleus, a key structure controlling basal ganglia outputs, is therefore able to oppositely modulate the effect of 'natural' rewards and drugs of abuse on behavior. Modulating the activity of the subthalamic nucleus might prove to be a new target for the treatment of cocaine addiction.

Lesions of the subthalamic nucleus (STN) have been found to reduce the severe akinetic motor symptom produced in animal models of Parkinson's disease, such as in monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or in monoamine-depleted rats. However, little is known about the effect of STN exclusion on subtle motor deficits induced by moderate dopaminergic lesions in complex motor tasks. The present study was thus performed on rats trained in a reaction time (RT) task known to be extremely sensitive to variations of dopamine transmission in the striatum. Animals were trained to release a lever after the onset of a visual stimulus within a time limit to obtain a food reward. Discrete dopamine depletion produced by infusing the neurotoxin 6-hydroxydopamine (6-OHDA) bilaterally into the dorsal part of the striatum, produced motor initiation deficits which were revealed by an increase in the number of delayed responses (lever release after the time limit) and a lengthening of RTs. In contrast, bilateral excitotoxic lesion of the STN with ibotenic acid induced severe behavioral deficits which were opposite to those produced by the dopaminergic lesion, as shown by an increase in the number of premature responses (lever release before the onset of the visual stimulus) and a decrease of RTs. Surprisingly, the performance of the animals bearing a double lesion (striatal dopaminergic lesion followed 14 d later by STN ibotenic lesion) was still impaired 40 d after the ibotenic lesion. As expected, the 6-OHDA-induced motor initiation deficits were reversed by a subsequent STN lesion. However, the dramatic increase of premature responses contributing to major behavioral deficits induced by the STN lesion remained unchanged. Thus, the bilateral lesion of the STN was found to alleviate the motor deficits in this model of parkinsonism, but essentially produced over time, long lasting deficits that might be related to dyskinesia or cognitive impairment. The present results strongly support the recent concept of a predominant control of the STN on basal ganglia output structures.

Although inactivation of the subthalamic nucleus (STN) has beneficial effects on motor symptoms of parkinsonism, little is known of possible actions on nonmotor symptoms of cognition or mood. Here, we used several forms of converging evidence to show that STN lesions can enhance behavioral motivation. Thus, bilateral fiber-sparing lesions of the STN in rats reduced the time required to eat a standard number of food reward pellets, without affecting food intake, and altered performance on a number of behavioral measures consistent with enhanced motivation for food. Thus, STN-lesioned rats showed greater levels of locomotor activity conditioned to food presentation, enhanced control over responding by food-related conditioned reinforcers, and a higher breaking point associated with elevated rate of lever press under a progressive ratio schedule of reinforcement. These results reveal a new functional role schedule for STN, possibly because of its involvement in ventral, as well as dorsal, striatal circuitry and are relevant to the therapeutic effects of STN stimulation in Parkinson's disease.