Stress-induced dorsal striatal dopamine release is associated with changes in functional connectivity to the prefrontal cortex in nicotine-dependent individuals—a preliminary report

Introduction The neural mechanism linking stress to addiction pathophysiology remains unclear. A proposed pathway involves stress-induced dopamine (DA) transmission impairing inhibitory control, leading to relapse. Lipopolysaccharide (LPS), a biological stressor inducing systemic inflammation, amplifies DA release. Our prior study demonstrated this effect in smokers. Using the same cohort, we investigated whether DA transmission mediates acute stress effects and impacts striatal-prefrontal functional connectivity (FC) in brain regions governing reward, inhibition, and decision-making. Methods Using a within-subject, multimodal design, we collected PET and resting-state functional MRI (rs-fMRI) scans in 8 smokers (6 females; mean age: 32 ± 3.6 years). Stress was induced using LPS; plasma cortisol indexed level of stress. DA release was measured in striatal subregions using [ 11 C]raclopride PET before and after methylphenidate administration, while striatal–prefrontal functional connectivity was assessed using seed-based rs-fMRI. Each participant completed three PET scans (one baseline and two post-methylphenidate scans following LPS or placebo [PCBO] pretreatment) and two rs-fMRI scans (LPS and PCBO), resulting in a total of 24 PET scans and 16 rs-fMRI scans. Results LPS elevated cortisol and DA release in striatum compared to Placebo ( p < 0.05). Cortisol increases correlated with dorsal striatal DA release ( r = 0.708, p = 0.04). FC analyses revealed enhanced FC between dorsal striatum and ventral medial prefrontal cortex (vmPFC) ( p < 0.001, FDR-corrected), and between whole striatum and dorsal lateral PFC (dlPFC) ( p < 0.001, FDR-corrected). Nonlinear associations showed FC initially increased with stress but plateaued at higher stress levels. Conclusion Stress-induced changes in DA release within dorsal striatum influence stress-related alterations in frontal-striatal FC. Our present findings in a limited cohort lead us to hypothesize more broadly that stress alterations in frontal-striatal FC reflect adaptation, whereas excessive stress may disrupt circuits, potentially contributing to addictive behaviors such as smoking. While the present pilot study demonstrates the potential value of PET and rs-fMRI to connect neurotransmitter action to downstream cortical activity future work will be essential to confirm the reproducibility and relevance of the observed associations.