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

Abstract

Initiating drug use during adolescence increases the risk of developing addiction and psychiatric disorders later in life, with long-term outcomes varying according to sex and exact timing of use. Even though most individuals begin experimenting with drugs of abuse in adolescence, to date, the cellular and molecular underpinnings explaining differential sensitivity to detrimental drug effects remain unknown. The Netrin-1/DCC guidance cue system plays a critical role in the adolescent development of mesocorticolimbic dopamine circuitry, segregating the cortical and limbic pathways. Adolescent experiences, including exposure to drugs of abuse, can regulateDccexpression in male mice, placing Netrin-1/DCC signaling as a potential molecular link between experience and enduring changes to circuitry and behavior. Here we show that exposure to a recreational-like regimen of amphetamine (AMPH) in adolescence induces sex- and age-specific alterations inDccexpression in the ventral tegmental area. Female mice are protected against the deleterious long-term effects of AMPH-inducedDccregulation by compensatory changes in the expression of its binding partner, Netrin-1. AMPH induces targeting errors in mesolimbic dopamine axons and triggers their ectopic growth to the prefrontal cortex, only in early-adolescent male mice, underlying a male-specific vulnerability to its enduring cognitive effects. Upregulating DCC receptor expression in dopamine neurons in adolescent males using a neuron-optimized CRISPR/dCas9 Activation System induces female-like protection against the persistent effects of AMPH in early adolescence on inhibitory control. Netrin-1/DCC signaling is therefore a molecular switch which can be differentially regulated in response to the same experience as function of age and sex of the individual, leading to divergent long-term outcomes associated with vulnerable or resilient phenotypes.

Nicotine in adolescence freezes dopamine circuits in an immature state

“…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.…”

“…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.…”

We’re not in Kansas anymore: ectopic dopaminergic terminals as an explanation for the positive symptoms in psychiatric pathology

“… 7 , 25 – 29 Ectopic dopamine terminals would no longer be available to synapse their intended target, as in the neurotypical brain, since they would now innervate an erroneous brain region. We suggest that the intended target of these terminals will have reduced dopamine innervation and present its own dysfunction, 7 , 8 an additional insult stemming from the rerouting phenomenon, although some degree of compensation in local circuitry may occur. This interpretation is intriguing as it could help explain the dichotomy of symptoms often seen in some psychiatric disorders, namely positive and negative symptoms or, more simply, domains of hyperfunction and hypofunction.…”

“… 4 – 6 These mechanistic interpretations were developed under the assumption that long-distance axonal pathfinding, most of which occurs during embryonic and fetal development, has ended by early childhood, generally before the onset of the first symptoms in any of the psychiatric disorders mentioned above. Recently, Reynolds and colleagues 7 , 8 and Hoops and colleagues 9 were able to demonstrate that, in mice, anterograde axon pathfinding of mesocortical dopamine neurons continues throughout adolescence, a finding not yet directly replicated in humans, but likely only because of the difficulty of doing equivalent experiments with human participants. In line with these findings, there has been some indirect evidence from nonhuman primates that showed the number of dopaminergic inputs in the prefrontal cortex (PFC) increases from adolescence to adulthood.…”

“…It is conceivable that a number of these terminals can deviate from this intended target, either for genetic or environmental reasons, and synapse in unintended locations. 7 , 8 At these aberrant sites, where dopaminergic axons are normally scarce or absent, there is now abnormal and elevated dopamine release. Khlghatyan and colleagues 22 used a high-sensitivity approach to map D2 receptors in the human cortex and showed both widespread low-level cortical expression and multiple foci of D2 receptor clustering in areas not previously considered for significant dopamine signalling (insula, somatosensory, visual and auditory cortices).…”