Mapping reward mechanisms by intracerebral self-stimulation in the rhesus monkey (Macaca mulatta).

The objective of the study was to identify brain structures that mediate reward as evidenced by positive reinforcing effects of stimuli on behavior. Testing by intracerebral self-stimulation enabled monkeys to inform whether activation of ~2900 sites in 74 structures of 4 sensorimotor pathways and 4 modulatory loop pathways was positive, negative or neutral. Stimulation was rewarding at 30% of sites, negative at 17%, neutral at 52%. Virtually all (99%) structures yielded some positive or negative sites, suggesting a ubiquitous distribution of pathways transmitting valence information. Mapping of sites to structures with dense versus sparse dopaminergic (DA) or noradrenergic (NA) innervation showed that stimulation of DA-pathways was rewarding or neutral. Stimulation of NA-pathways was not rewarding. Stimulation of association areas was generally rewarding; stimulation of purely sensory or motor structures was generally negative. Reward related more to structures' sensorimotor function than to density of DA-innervation. Stimulation of basal ganglia loop pathways was rewarding except in lateral globus pallidus, an inhibitory structure in the negative feedback loop; stimulation of the cerebellar loop was rewarding in anterior vermis and the spinocerebellar pathway; and stimulation of the hippocampal CA1 loop was rewarding. While most positive sites were in the DA reward system, numerous sites in sparsely DA-innervated posterior cingulate and parietal cortices may represent a separate reward system. DA-density represents concentrations of plastic synapses that mediate acquisition of new synaptic connections. DA-sparse areas may represent innate, genetically programmed reward-associated pathways. Implications of findings in regard to response habituation and addiction are discussed.