Nicotine and the adolescent brain

Abstract

Adolescence encompasses a sensitive developmental period of enhanced clinical vulnerability to nicotine, tobacco, and e-cigarettes. While there are sociocultural influences, data at preclinical and clinical levels indicate that this adolescent sensitivity has strong neurobiological underpinnings. Although definitions of adolescence vary, the hallmark of this period is a profound reorganization of brain regions necessary for mature cognitive and executive function, working memory, reward processing, emotional regulation, and motivated behavior. Regulating critical facets of brain maturation are nicotinic acetylcholine receptors (nAChRs). However, perturbations of cholinergic systems during this time with nicotine, via tobacco or e-cigarettes, have unique consequences on adolescent development. In this review, we highlight recent clinical and preclinical data examining the adolescent brain's distinct neurobiology and unique sensitivity to nicotine. First, we discuss what defines adolescence before reviewing normative structural and neurochemical alterations that persist until early adulthood, with an emphasis on dopaminergic systems. We review how acute exposure to nicotine impacts brain development and how drug responses differ from those seen in adults. Finally, we discuss the persistent alterations in neuronal signaling and cognitive function that result from chronic nicotine exposure, while highlighting a low dose, semi-chronic exposure paradigm that may better model adolescent tobacco use. We argue that nicotine exposure, increasingly occurring as a result of e-cigarette use, may induce epigenetic changes that sensitize the brain to other drugs and prime it for future substance abuse.

Figure 1. Adolescence is a developmental transition period with no clear hallmarks signaling its start or finish

Many define adolescence as equivalent to sexual maturation or puberty. However, maturation of neural systems extends beyond the period of sexual maturation, an effect seen in both humans (A) and rodents (B). Although puberty is an important component of adolescence, this transitional period is distinguished by the dramatic maturation and remodeling of the brain. Human age is defined by years, and rodent age is defined by postnatal days.

Figure 2. The immature adolescent brain undergoes substantial growth, reorganization, and pruning

At the start of adolescence, connectivity between the prefrontal cortex (PFC) and limbic regions is immature, as indicated by dashed lines. As adolescence proceeds, this connectivity markedly increases and completes development last. Similarly, dopaminergic projections from the ventral tegmental area (VTA) continue to develop into early adulthood and are strongly influenced by cholinergic projections from the laterodorsal tegmental nucleus (LDTg). The nucleus accumbens (NAc), on the other hand, develops earlier than associated prefrontal cortical regions, as indicated by solid lines, which may consequently lead to the characteristic expression of increased novelty-seeking and risk-taking behavior. Furthermore, with the immature projections from the basolateral amygdala (BLA) to the PFC, discrepant maturational timelines of cortical and subcortical regions leads to diminished executive control of reward and motivated behavior.

Figure 3. Microcircuitry of the prefrontal cortex (PFC) showing developmental differences in dopamine function

Adolescents (left) lack mature dopamine D₁–glutamate receptor interactions on prefrontal cortical pyramidal neurons, and acquisition of this element is vital for the development of cognitive and attentional processes. In addition, D₂ receptor-mediated GABAergic inhibitory control of prefrontal cortical activity is still immature, as indicated by the dashed lines, demonstrating that cognitive processing within the PFC and other limbic regions is profoundly different in adolescence than in adulthood (right).

Figure 4. Microcircuitry of the nucleus accumbens (NAc) showing developmental differences in dopamine function

Adolescents (left) lack mature accumbal D₁–NMDA receptor interactions and D₂–AMPA receptor interactions. In addition, GABAergic inhibitory control of medium spiny neuron activity in the NAc is still immature, as indicated by the dashed lines, illustrating that long term potentiation (LTP)/long term depression (LTD) within the NAc and associated limbic regions is profoundly different in adolescence from in adulthood (right).

Figure 5. Preclinical studies using rodent models indicate that nicotine produces age-specific behavioral responses

Adolescents exhibit greater behavioral sensitivity and susceptibility to other drugs of abuse after nicotine exposure. In contrast, adults display either opposite or no response to nicotine treatment.

Figure 6. Nicotine pretreatment alters dopamine-mediated behaviors, neuronal activation, and reward sensitivity in adolescent rats

We have found that brief, low-dose nicotine pretreatment during early adolescence enhances quinpirole-induced locomotion, an effect that is mediated by D₂ and 5-HT_1A receptors. Nicotine also enhances quinpirole-induced penile erection, an effect that is mediated by D₃ and CRF-1 receptors. Furthermore, nicotine pretreatment during adolescence sensitizes reward responses to drugs of abuse, enhancing the acquisition of cocaine, methamphetamine, and alcohol self-administration. Nicotine pretreatment also induces cocaine locomotor sensitization to low doses of cocaine. These effects are age-specific and are not present during late adolescence or adulthood.