Title: Attenuation of dopamine-induced GABA release in problem gamblers Short running title: L-dopa effect on GABA release in gamblers

Introduction : We have previously shown that an interaction between medial prefrontal and parietal cortices is instrumental in promoting self-awareness via synchronizing oscillations in the gamma range. The synchronisation of these oscillations is modulated by dopamine release. Given that such oscillations result from intermittent GABA stimulation of pyramidal cells, it is of interest to determine whether the dopaminergic system regulates GABA release directly in cortical paralimbic regions. Here we test the hypothesis that the regulation of the GABA-ergic system by the dopaminergic system becomes attenuated in problem gamblers resulting in addictive behaviors and impaired self-awareness. Methods : [ 11 C] Ro15 - 4513 PET, a marker of benzodiazepine α 1/ α 5 receptor availability in the GABA receptor complex, was used to detect changes in synaptic GABA levels after oral doses of 100mg L-dopa in a double blind controlled study of male problem gamblers (N=10) and age-matched healthy male controls (N=10). Results : The mean reduction of cortical grey matter GABA/BDZ receptor availability induced by L-dopa was significantly attenuated in the problem gambling group compared to the healthy control group (p = 0.0377). Conclusions: Our findings demonstrate that: (1) Exogenous dopamine can induce synaptic GABA release in healthy controls. (2) This release is attenuated in frontal cortical areas of males suffering from problem gambling, possibly contributing to their loss of inhibitory control. This suggests that dysfunctional dopamine regulation of GABA release may contribute to problem gambling and gambling disorder.