Sex differences in methylphenidate-induced dopamine increases in ventral striatum

Peter Manza,Dana Feldman,Nora D Volkow,Dardo Tomasi,Evan Dennis,Danielle Kroll,Andrew Kelleher,Erin Biesecker,Ehsan Shokri-Kojori,Allison Johnson,Gene-Jack Wang,Katherine Mcpherson,Corinde E Wiers,Song Qu

doi:10.1038/s41380-021-01294-9

Peter Manza, Dana Feldman + Show 12 more

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https://doi.org/10.1038/s41380-021-01294-9

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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).

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Dopamine signaling in the brain is responsible for modulating functions critical for survival, including attention, memory, motor control, motivation, and reward-guided behaviors [1, 2]
Here we find that females compared to males showed larger dopamine increases in ventral striatum (NAc) when challenged with methylphenidate whether it was given orally or intravenously whereas we found no differences in the dorsal striatum
These results provide evidence of sex differences in sensitivity of the dopamine reward system with females showing greater sensitivity than males

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Introduction

Dopamine signaling in the brain is responsible for modulating functions critical for survival, including attention, memory, motor control, motivation, and reward-guided behaviors [1, 2]. Differential expression of genes in the sex chromosomes directly contributes to differences in midbrain dopaminergic signaling between men and women [3] These are thought to manifest in differences in brain structure and function that emerge in childhood, impacting behavior and vulnerability to neuropsychiatric illnesses including those associated with aberrant dopaminergic function [4]. Preclinical studies have corroborated significant sex differences in the response to stimulant drugs including locomotor and rewarding effects [13, 14] These findings underscore the need to better understand sex differences in the brain’s responses to dopamine-enhancing drugs in humans that might help clarify sex differences in vulnerability to SUD and other neuropsychiatric disorders that involve the dopaminergic system (e.g., ADHD, schizophrenia, mood disorders, and Parkinson’s disease)

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