Prenatal nicotine alters development of the laterodorsal tegmentum: Possible role for attention-deficit/hyperactivity disorder and drug dependence

Abstract

As we cycle between the states of wakefulness and sleep, a bilateral cholinergic nucleus in the pontine brain stem, the laterodorsal tegmentum (LDT), plays a critical role in controlling salience processing, attention, behavioral arousal, and electrophysiological signatures of the sub- and microstates of sleep. Disorders involving abnormal alterations in behavioral and motivated states, such as drug dependence, likely involve dysfunctions in LDT signaling. In addition, as the LDT exhibits connectivity with the thalamus and mesocortical circuits, as well as receives direct, excitatory input from the prefrontal cortex, a role for the LDT in cognitive symptoms characterizing attention-deficit/hyperactivity disorder (ADHD) including impulsivity, inflexibility, and dysfunctions of attention is suggested. Prenatal nicotine exposure (PNE) is associated with a higher risk for later life development of drug dependence and ADHD, suggesting alteration in development of brain regions involved in these behaviors. PNE has been shown to alter glutamate and cholinergic signaling within the LDT. As glutamate and acetylcholine are major excitatory mediators, these alterations would likely alter excitatory output to target regions in limbic motivational circuits and to thalamic and cortical networks mediating executive control. Further, PNE alters neuronal development and transmission within prefrontal cortex and limbic areas that send input to the LDT, which would compound effects of differential processing within the PNE LDT. When taken together, alterations in signaling in the LDT are likely to play a role in negative behavioral outcomes seen in PNE individuals, including a heightened risk of drug dependence and ADHD behaviors.

Keywords: Prenatal nicotine exposure, Pregnancy outcome, Addiction risk, Laterodorsal tegmentum, Arousal, Attention

Core Tip: Offspring of women who used nicotine-containing products while pregnant exhibit risk factors for later-life development of cognitive deficits, including attention deficit/hyperactivity disorder and drug dependence. This suggests that circuits that play a role in cognition are being altered by nicotine. The laterodorsal tegmental nucleus of the pons plays a role in attention, motivation, and other cognitive-related processes, and nicotine during gestation has been shown in animal studies to alter functioning of this nucleus. In this review, we discuss the human and animal literature that indicate that alterations in functioning of the laterodorsal tegmental nucleus could arise following prenatal nicotine exposure, and that these alterations could play a role in the negative risks associated with early-life nicotine exposure.