In vivo evidence for greater amphetamine-induced dopamine release in pathological gambling: a positron emission tomography study with [[sup.11]C]--PHNO

Drug addiction has been associated with deficits in mesostriatal dopamine (DA) function, but whether this state extends to behavioral addictions such as pathological gambling (PG) is unclear. Here we used positron emission tomography and the [D.sub.3] receptor-preferring radioligand [[sup.11]C]-(+)-PHNO during a dual-scan protocol to investigate DA release in response to oral amphetamine in pathological gamblers (n = 12) and healthy controls (n = 11). In contrast with human neuroimaging findings in drug addiction, we report the first evidence that PG is associated with greater DA release in dorsal striatum (54-63% greater [[sup.11]C]-(+)-PHNO displacement) than controls. Importantly, dopaminergic response to amphetamine in gamblers was positively predicted by [D.sub.3] receptor levels (measured in substantia nigra), and related to gambling severity, allowing for construction of a mechanistic model that could help explain DA contributions to PG. Our results are consistent with a hyperdopaminergic state in PG, A and support the hypothesis that dopaminergic sensitization involving [D.sub.3]-related mechanisms might contribute to the pathophysiology of behavioral addictions. Molecular Psychiatry (2014) 19, 1305-1313; doi: 10.1038/mp.2013.163; published online 10 December 2013 Keywords: [[sup.11]C]-(+)-PHNO; amphetamine; dopamine; positron emission tomography; pathological gambling; sensitization