Abnormal frontostriatal connectivity and serotonin function in gambling disorder: A preliminary exploratory study

Background: The neurobiological mechanisms of gambling disorder are not yet fully characterized, limiting the development of treatments. Defects in frontostriatal connections have been shown to play a major role in substance use disorders, but data on behavioral addictions, such as gambling disorder, are scarce. The aim of this study was to 1) investigate whether gambling disorder is associated with abnormal frontostriatal connectivity and 2) characterize the key neurotransmitter systems underlying the connectivity abnormalities. Methods: Fifteen individuals with gambling disorder and 17 matched healthy controls were studied with resting-state functional connectivity MRI and three brain positron emission tomography scans, investigating dopamine (F-18-FDOPA), opioid (C-11-carfentanil) and sero-tonin (C-11-MADAM) function. Frontostriatal connectivity was investigated using striatal seed-to-voxel connectivity and compared between the groups. Neurotransmitter systems underlying the identified connectivity differences were investigated using region-of-interest and voxelwise approaches. Results: Individuals with gambling disorder showed loss of functional connectivity between the right nucleus accumbens (NAcc) and a region in the right dorsolateral prefrontal cortex (DLPFC) (P-FWE <0.05). Similarly, there was a significant Group x right NAcc interaction in right DLPFC C-11-MADAM binding (p = 0.03) but not in F-18-FDOPA uptake or C-11-carfentanil binding. This was confirmed in voxelwise analyses showing a widespread Group x right NAcc interaction in the prefrontal cortex C-11-MADAM binding (PFWE <0.05). Right NAcc C-11-MADAM binding potential correlated with attentional impul-sivity in individuals with gambling disorder (r = -0.73, p = 0.005). Discussion: Gambling disorder is associated with right hemisphere abnormal frontostriatal connectivity and serotonergic function. These findings will contribute to understanding the neurobiological mechanism and may help identify po-tential treatment targets for gambling disorder.