Associations between dopaminergic and serotonergic systems in individuals with cocaine use disorder: An exploratory analysis of [¹¹C]PHNO and [¹¹C]P943 PET imaging.

BACKGROUND: [¹ ¹C]PHNO is a positron emission tomography (PET) radioligand for dopamine D2/D3 receptors (D2R/D3R), while [¹ ¹C]P943 selectively targets 5-HT1B receptors. Although prior studies have shown differences in dopaminergic and serotonergic receptor availability in people with and without cocaine use disorder (CUD), these systems have been examined in isolation across separate studies and samples. METHODS: Ten non-treatment-seeking individuals with CUD (3 women; mean [SD] age, 40.6 [7.5] years) underwent PET imaging with [¹ ¹C]PHNO and [¹ ¹C]P943 following an average of 7 ± 3 days of abstinence under inpatient monitoring. Availability of D2R- and D3R-related receptors was measured with [¹ ¹C]PHNO binding potentials (BPND) in the putamen and substantia nigra/ventral tegmental area (SN/VTA), respectively. Exploratory linear regression analyses using both D2R- and D3R-related receptor availability as independent variables were applied to 5-HT1BBPND in the medial orbitofrontal cortex (mOFC) and dorsomedial prefrontal cortex (dmPFC), with secondary analyses examining the same dopaminergic-serotonergic associations in additional addiction-related prefrontal regions. RESULTS: D2R-related receptor availability was positively associated with 5-HT1BBPND in the dmPFC (p = 0.038) but not in the mOFC (p = 0.945). Conversely, D3R-related receptor availability was positively associated with 5-HT1BBPND in the mOFC (p = 0.043) but not in the dmPFC (p = 0.850). Analyses of secondary 5-HT1B regions revealed a positive association between D3R-related receptor availability and 5-HT1BBPND in the lateral OFC (lOFC) (p = 0.050). CONCLUSIONS: In individuals with CUD, D2R- and D3R-related measures were associated with 5-HT1B binding in distinct prefrontal regions. These findings provide preliminary in vivo evidence of cross-system dopaminergic-serotonergic relationships and may inform future development efforts toward targeted treatments for CUD.