Adolescent nicotine exposure and persistent neurocircuitry changes: unveiling lifelong psychiatric risks

Abstract

Nicotine exposure during adolescence has emerged as a significant risk factor for later psychiatric disease. Notably, adolescence is a critical period for the maturation of acetylcholine and dopamine systems, neuromodulators which tightly regulate cognitive, motivational and emotional behaviors known to contribute to psychiatric vulnerability. This review explores whether long-lasting modifications in these neuromodulatory systems following adolescent nicotine exposure underlie the increased vulnerability to mental health disorders. We discuss evidence that nicotine in adolescence leads to enduring molecular, cellular alterations by perturbing the normal trajectory of cholinergic and dopamine systems, and link these changes with potential adverse behavioral outcomes in adulthood. We propose that persistent alterations in acetylcholine and dopamine signaling caused by adolescent nicotine exposure may contribute to the heightened risk for psychiatric disorders including substance abuse, anxio-depressive disorders, and schizophrenia for which deficits in a large spectrum of motivational domains are highly prevalent. The interaction between nicotine and these developing neurotransmitter systems during adolescence raises important questions about the mechanisms driving these changes. Finally, we discuss limitations in the current research and subsequently identify open questions in the field which will help drive forward research on the psychiatric consequences of adolescent nicotine use. Understanding these maladaptations could pave the way for targeted therapeutic strategies to mitigate the adverse effects of adolescent nicotine exposure on brain development and subsequent psychiatric outcomes.

Fig. 1. Situating adolescence in the rodent lifespan.

Adolescence can be considered to last from weaning (generally PND 21) until rodents achieve complete sexual, behavioral, and neurobiological maturity around PND 60. It can be further divided into early (~PND 21–34), middle (~PND 35–45), and late (~PND 45–60) periods where animals exhibit different epochs of sexual development and exhibit certain behavioral and neurobiological characteristics.

Fig. 2. Adolescent changes in acetylcholine and dopaminergic systems.

A ACh system changes across adolescence. Top: regional changes in nAChR subunit expression have been noted across adolescence, with a peak in late adolescence of α4 receptor expression in the VTA, as assessed with YFP tagging, and with a gradual lessening of α5, α6, and α7 receptors in the VTA between adolescence and adulthood. Dotted lines represent periods where expression has not yet been studied. Bottom: α4β2-containing nAChR function in the PFC and striatum increases from late adolescence to adulthood. ChAT function changes across adolescence in the PFC and in the midbrain, with a peak in function in mid- to late adolescence before declining to adult levels. B Dopamine system changes across adolescence. Top: In the PFC, DA innervation increases steadily across adolescence until reaching a plateau around PND 60. DA receptor expression in the PFC peaks in mid-adolescence before declining to adult levels. Bottom: DA content in the striatum increases across adolescence, while DA receptor expression peaks in mid-adolescence. This peak appears to be sex specific, as it has been confirmed in male rodents, but was not seen in females.

Fig. 3. Nicotine exposure in adolescence leads to immature response to nicotine in adulthood.

Adolescent mice show an increased rewarding effect of nicotine, paired with a blunted anxiogenic effect of the drug in comparison to adults. These differences result from an imbalance in dopamine neuron response to nicotine at the circuit level [150]. Adult mice that were exposed to nicotine in adolescence show similar behavioral and electrophysiological responses to nicotine, suggesting that adolescent exposure arrests the development of dopaminergic circuitry.

Fig. 4. Summary of modifications in adult acetylcholine and dopaminergic systems induced by adolescent nicotine exposure.

Alterations in functional outputs in adulthood, such as receptor expression and function, have been noted for both ACh and DA circuits following nicotine in adolescence. Sex-specific changes are noted where that information is available.