Sex differences in VTA GABA transmission and plasticity during opioid withdrawal

• Published in: Scientific reports Vol. 13; no. 1; pp. 8460 - 10
• Main Authors: Kalamarides, Daniel J., Singh, Aditi, Wolfman, Shannon L., Dani, John A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.05.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 631/378/1689/5; 631/378/1697/1691; 631/378/2591/2592; 631/378/548/1964; 631/443/376; Analgesics, Opioid - pharmacology; Animals; Dopamine; Drug abuse; Drug addiction; Drug withdrawal; Female; Females; gamma-Aminobutyric Acid - pharmacology; Gender differences; Humanities and Social Sciences; Long-term potentiation; Male; Males; Mice; Morphine; Morphine - adverse effects; multidisciplinary; Narcotics; Narcotics - pharmacology; Neuronal Plasticity; Opioids; Physiology; Plasticity; Science; Science (multidisciplinary); Sex Characteristics; Sex differences; Substance Withdrawal Syndrome; Synapses; Synaptic plasticity; Ventral Tegmental Area; Ventral tegmentum; γ-Aminobutyric acid
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-023-35673-9

The effectiveness of current treatments for opioid use disorder (OUD) varies by sex. Our understanding of the neurobiological mechanisms mediating negative states during withdrawal is lacking, particularly with regard to sex differences. Based on preclinical research in male subjects, opioid withdrawal is accompanied by increased gamma-aminobutyric acid (GABA) release probability at synapses onto dopamine neurons in the ventral tegmental area (VTA). It is unclear, however, if the physiological consequences of morphine that were originally elucidated in male rodents extend to females. The effects of morphine on the induction of future synaptic plasticity are also unknown. Here, we show that inhibitory synaptic long-term potentiation (LTP GABA ) is occluded in the VTA in male mice after repeated morphine injections and 1 day of withdrawal, while morphine-treated female mice maintain the ability to evoke LTP GABA and have basal GABA activity similar to controls. Our observation of this physiological difference between male and female mice connects previous reports of sex differences in areas upstream and downstream of the GABA-dopamine synapse in the VTA during opioid withdrawal. The sex differences highlight the mechanistic distinctions between males and females that can be targeted when designing and implementing treatments for OUD.