Sex differences in methylphenidate-induced dopamine increases in ventral striatum.

Sex differences in the prevalence of dopamine-related neuropsychiatric diseases and in the sensitivity to dopamine-boosting drugs such as stimulants is well recognized. Here we assessed whether there are sex differences in the brain dopamine system in humans that could contribute to these effects. We analyzed data from two independent [11C]raclopride PET brain imaging studies that measured methylphenidate-induced dopamine increases in the striatum using different routes of administration (Cohort A = oral 60 mg; Cohort B = intravenous 0.5 mg/kg; total n = 95; 65 male, 30 female), in blinded placebo-controlled designs. Females when compared to males reported stronger feeling of "drug effects" and showed significantly greater dopamine release in the ventral striatum (where nucleus accumbens is located) to both oral and intravenous methylphenidate. In contrast, there were no significant differences in methylphenidate-induced increases in dorsal striatum for either oral or intravenous administration nor were there differences in levels of methylphenidate in plasma. The greater dopamine increases with methylphenidate in ventral but not dorsal striatum in females compared to males suggests an enhanced sensitivity specific to the dopamine reward system that might underlie sex differences in the vulnerability to substance use disorders and to attention-deficit/hyperactivity disorder (ADHD).

Inflammatory Markers in Substance Use and Mood Disorders: A Neuroimaging Perspective.

Chronic exposure to addictive drugs in substance use disorders and stressors in mood disorders render the brain more vulnerable to inflammation. Inflammation in the brain, or neuroinflammation, is characterized by gliosis, microglial activation, and sustained release of cytokines, chemokines, and pro-inflammatory factors compromising the permeability of the blood-brain barrier. There is increased curiosity in understanding how substance misuse and/or repeated stress exposure affect inflammation and contribute to abnormal neuronal activity, altered neuroplasticity, and impaired cognitive control, which eventually promote compulsive drug-use behaviors and worsen mood disorders. This review will emphasize human imaging studies to explore the link between brain function and peripheral markers of inflammation in substance use disorders and mood disorders.

Striatal D1 and D2 receptor availability are selectively associated with eye-blink rates after methylphenidate treatment.

Eye-blink rate has been proposed as a biomarker of the brain dopamine system, however, findings have not been consistent. This study assessed the relationship between blink rates, measured after oral placebo) (PL) and after a challenge with oral methylphenidate (MP; 60 mg) and striatal D1 receptor (D1R) (measured at baseline) and D2 receptor (D2R) availability (measured after PL and after MP) in healthy participants. PET measures of baseline D1R ([11C]NNC112) (BL-D1R) and D2R availability ([11C]raclopride) after PL (PL-D2R) and after MP (MP-D2R) were quantified in the striatum as non-displaceable binding potential. MP reduced the number of blinks and increased the time participants kept their eyes open. Correlations with dopamine receptors were only significant for the eye blink measures obtained after MP; being positive for BL-D1R in putamen and MP-D2R in caudate (PL-D2R were not significant). MP-induced changes in blink rates (PL minus MP) were negatively correlated with BL-D1R in caudate and putamen. Our findings suggest that eye blink measures obtained while stressing the dopamine system might provide a more sensitive behavioral biomarker of striatal D1R or D2R in healthy volunteers than that obtained at baseline or after placebo.

Cortical D1 and D2 dopamine receptor availability modulate methylphenidate-induced changes in brain activity and functional connectivity.

Dopamine signaling plays a critical role in shaping brain functional network organization and behavior. Prominent theories suggest the relative expression of D1- to D2-like dopamine receptors shapes excitatory versus inhibitory signaling, with broad consequences for cognition. Yet it remains unknown how the balance between cortical D1R versus D2R signaling coordinates the activity and connectivity of functional networks in the human brain. To address this, we collected three PET scans and two fMRI scans in 36 healthy adults (13 female/23 male; average age 43 ± 12 years), including a baseline D1R PET scan and two sets of D2R PET scans and fMRI scans following administration of either 60 mg oral methylphenidate or placebo (two separate days, blinded, order counterbalanced). The drug challenge allowed us to assess how pharmacologically boosting dopamine levels alters network organization and behavior in association with D1R-D2R ratios across the brain. We found that the relative D1R-D2R ratio was significantly greater in high-level association cortices than in sensorimotor cortices. After stimulation with methylphenidate compared to placebo, brain activity (as indexed by the fractional amplitude of low frequency fluctuations) increased in association cortices and decreased in sensorimotor cortices. Further, within-network resting state functional connectivity strength decreased more in sensorimotor than association cortices following methylphenidate. Finally, in association but not sensorimotor cortices, the relative D1R-D2R ratio (but not the relative availability of D1R or D2R alone) was positively correlated with spatial working memory performance, and negatively correlated with age. Together, these data provide a framework for how dopamine-boosting drugs like methylphenidate alter brain function, whereby regions with relatively higher inhibitory D2R (i.e., sensorimotor cortices) tend to have greater decreases in brain activity and connectivity compared to regions with relatively higher excitatory D1R (i.e., association cortices). They also support the importance of a balanced interaction between D1R and D2R in association cortices for cognitive function and its degradation with aging.