Amphetamine disrupts dopamine axon growth in adolescence by a sex-specific mechanism in mice

Abstract

Initiating drug use during adolescence increases the risk of developing addiction or other psychopathologies later in life, with long-term outcomes varying according to sex and exact timing of use. The cellular and molecular underpinnings explaining this differential sensitivity to detrimental drug effects remain unexplained. The Netrin-1/DCC guidance cue system segregates cortical and limbic dopamine pathways in adolescence. Here we show that amphetamine, by dysregulating Netrin-1/DCC signaling, triggers ectopic growth of mesolimbic dopamine axons to the prefrontal cortex, only in early-adolescent male mice, underlying a male-specific vulnerability to enduring cognitive deficits. In adolescent females, compensatory changes in Netrin-1 protect against the deleterious consequences of amphetamine on dopamine connectivity and cognitive outcomes. Netrin-1/DCC signaling functions as a molecular switch which can be differentially regulated by the same drug experience as function of an individual’s sex and adolescent age, and lead to divergent long-term outcomes associated with vulnerable or resilient phenotypes.

Timing of methamphetamine exposure during adolescence differentially influences parvalbumin and perineuronal net immunoreactivity in the medial prefrontal cortex of female, but not male, rats

“…Interestingly, in this study males exposed from P22-31, but not P35-44, exhibited similar changes to gene expression within the VTA [43]. This suggests that drug effects can occur at different ages in each sex.…”

Nicotine in adolescence freezes dopamine circuits in an immature state

“…This raises important questions in the cross-sensitivity and additive relationship between stress and drug use in adolescence and adulthood. Other studies have reported pathological miswiring of DA circuits after psychostimulant exposure in adolescence 55,56,100 . While our evidence does not support the idea that nicotine in early adolescence leads to the global miswiring of dopamine axons, as the innervation patterns of dopamine axons in the NAc and AMG are unchanged, we find, rather, the persistent maintenance of adolescent-like responses to an acute nicotine challenge.…”

“…We focused our nicotine treatment on the early adolescent period (~PND21-28) because not only does this correspond to the time of life when human adolescents are most likely to begin nicotine use 58,59 , but previous work in rodent models has also suggested that this is a particularly vulnerable time for DA development, 55,57 .…”

“…Importantly, marked sex differences exist in adolescent developmental trajectories 101 , including dopamine development. Recent work has shown that adolescent periods of DA circuit vulnerability to experience differ between male and female mice, and that even when the immediate effects of an experience are the same, the enduring outcomes may differ dramatically due to sex-and/or age specific compensatory processes 55 , Indeed, nicotine receptor expression and function can be modulated by female sex hormones 102 , suggesting that even the immediate experience or effects of nicotine may be sex-dependent, adding to the complexity of addressing sex and developmental interactions in its effects. Ongoing work will address whether female mice show a similar or different pattern of adolescent DA circuit "freezing" by nicotine.…”

“…Indeed, nicotine simultaneously produces both reinforcing and anxiogenic behavioral effects [49][50][51][52][53][54] , which rely on distinct DA pathways: the activation of DA neurons projecting to the nucleus accumbens (NAc) produces reinforcement, whereas the inhibition of amygdala (AMG)-projecting DA neurons produces anxiety-like behavior 53 . Dopaminergic axons are still connecting to forebrain targets in adolescence 33 , and are sensitive to disruption by other psychostimulant drugs of abuse [55][56][57] ; however whether and how nicotine may alter the development of distinct DA circuits in adolescence to drive later addiction vulnerability remains unknown.…”