Dose response Navitoclax Phase 2 relations have been shown (Fergusson, Horwood, & Lynskey, 1993; Slotkin, 2008). However, although numerous studies have documented associations between MSDP and offspring neurobehavioral deficits, there is a dearth of studies in humans that identify alterations in neural pathways (structures and function) that may underlie this relationship. Studies that specify alterations in neural structure and function from MSDP are critical in that they may elucidate neural pathways that may serve as targets for identification, intervention, and prevention efforts for offspring neurobehavioral deficits from MSDP. Such studies could also help to elucidate inconsistencies in the literature linking MSDP with long-term neurobehavioral deficits. We and others (Baler, Volkow, Fowler, & Benveniste, 2008; Cornelius & Day, 2009; Ernst et al.

, 2001) propose alterations in brain structure and function as key candidate mediators underlying links between MSDP and offspring neurobehavioral deficits in humans. In support of this hypothesis, disorders and deficits associated with exposure to MSDP in humans (e.g., ADHD, CD, SA, cognitive deficits) have been consistently linked to alterations in brain structure and function. In addition, a large body of research in animal models has revealed prenatal nicotine as a potent neuroteratogen, with evidence for disruption of key neurobiological pathways in offspring following prenatal exposure to nicotine (Slotkin, 1998, 2008; Slotkin, Pinkerton, Tate, & Seidler, 2006).

Identification of neural mediators may also help to (a) inform early prevention efforts with exposed offspring, (b) inform development of personalized treatment for exposed offspring with neurobehavioral deficits, and (c) lead to novel therapeutic targets for protecting exposed fetuses. The majority AV-951 of prior research investigating effects of MSDP on neural structure and function has been conducted using animal models. Results from animal studies demonstrate a robust association between prenatal nicotine exposure and upregulation of nicotinic acetylcholine receptors (nAChRs) across a wide array of brain regions as early as first trimester. Upregulation of nAChRs leads to inhibition of DNA synthesis and, ultimately, disruption of brain cell replication and differentiation (Slotkin, 1998). Prenatal nicotine has also been associated with dysregulation of cholinergic, catecholaminergic, serotonergic, and other neurotransmitter systems. Furthermore, unlike the majority of teratogens, effects of prenatal nicotine on offspring brain development have emerged even in the absence of effects on somatic growth, suggesting that nicotine specifically targets the fetal brain and central nervous system (CNS) (Slotkin, 1998).