Does Prenatal Nicotine Exposure Sensitize the Brain to Nicotine-Induced Neurotoxicity in Adolescence?

Abstract

Offspring of women who smoke during pregnancy are themselves more likely to take up smoking in adolescence. We evaluated neurotoxicant effects of prenatal and adolescent nicotine exposure in developing rats to evaluate whether these contribute to a biological basis for this relationship. Rats were given nicotine or vehicle throughout pregnancy and the offspring then again received nicotine or vehicle during adolescence (postnatal days PN30-47.5); this regimen reproduces the plasma nicotine levels found in smokers. Indices of neural cell number (DNA concentration and content), cell size (protein/DNA ratio), and cell membrane surface area (membrane/total protein) were then evaluated in brain regions during adolescent nicotine administration (PN45) and up to 1 month post-treatment. By itself, prenatal nicotine administration produced cellular alterations that persisted into adolescence, characterized by net cell losses in the midbrain and to a lesser extent, in the cerebral cortex, with corresponding elevations in the membrane/total protein ratio. The hippocampus showed a unique response, with increased DNA content and regional enlargement. Adolescent nicotine treatment alone had similar, albeit smaller effects, but also showed sex-dependence, with effects on protein biomarkers preferential to females. When animals exposed to nicotine prenatally were then given nicotine in adolescence, the net outcome was worsened, largely representing summation of the two individual effects. Our results indicate that prenatal nicotine exposure alters parameters of cell development lasting into adolescence, where the effects add to those elicited directly by adolescent nicotine; neurotoxicant actions may thus contribute to the association between maternal smoking and subsequent smoking in the offspring.

Visuospatial Memory Deficits Emerging During Nicotine Withdrawal in Adolescents with Prenatal Exposure to Active Maternal Smoking

“…The hippocampus is unique among brain regions in retaining the capacity to generate new neurons into adolescence (McEwen, 1999(McEwen, , 2001, and has been shown to exhibit synaptic sprouting and reinnnervation in response to lesioning throughout the juvenile period Lynch, 1983, 1984). Hippocampal changes pursuant to gestational exposure to nicotine thus likely reflect adaptive rearrangement of neuronal populations and synapses (Abreu-Villaca et al, 2004a), and are magnified when followed by adolescent nicotine administration (Abreu-Villaca et al, 2004a). The present findings suggest that, in human adolescents, changes in hippocampal architecture associated with combined prenatal and adolescent exposure to active tobacco smoking produce alterations in hippocampal function during nicotine withdrawal and concomitant deficits in visuospatial memory.…”

“…Prenatal nicotine exposure increases hippocampal size, DNA content, and neuronal packing density (Roy et al, 2002;Abreu-Villaca et al, 2004a). The hippocampus is unique among brain regions in retaining the capacity to generate new neurons into adolescence (McEwen, 1999(McEwen, , 2001, and has been shown to exhibit synaptic sprouting and reinnnervation in response to lesioning throughout the juvenile period Lynch, 1983, 1984).…”

“…More females than males participated in this preliminary study. Preclinical work has suggested that the combined effects of prenatal and adolescent exposure to nicotine on protein biomarkers may be more marked in female rodents (Abreu-Villaca et al, 2004a), while the combined effects of prenatal and adolescent exposure on some markers of cholinergic tone may be more pronounced in male rodents (Abreu-Villaca et al, 2004b). Recent clinical work has suggested that the effects of adolescent tobacco smoking on cognitive performance may be more pronounced in males (Jacobsen et al, 2005).…”

“…Adolescence is also a period of continued brain development, with ongoing neuroproliferation, apoptosis, synaptic rearrangement, and maturation of central cholinergic systems (Bayer, 1983;Bayer et al, 1982;Huttenlocher, 1990;Matthews et al, 1974;Nadler et al, 1974;Zahalka et al, 1993). Rodent models developed to investigate the effects of prenatal nicotine exposure on response to nicotine administration during adolescence have shown that prenatal nicotine exposure reduces the upregulation of nAChRs induced by adolescent nicotine exposure, produces cholinergic hypoactivity during nicotine withdrawal in adolescence (Abreu-Villaca et al, 2004b), and magnifies the effects of adolescent nicotine exposure on indices of cell number, size, and surface area (Abreu-Villaca et al, 2004a).…”

Prenatal Nicotine Exposure Impairs the Proliferation of Neuronal Progenitors, Leading to Fewer Glutamatergic Neurons in the Medial Prefrontal Cortex

“…Nicotine can act as either a pro-apoptotic or anti-apoptotic agent, depending on the target cells investigated, the concentration used and the period of time it is applied (Dwyer et al, 2008;Zeidler et al, 2007). For example, the apoptotic effects of nicotine have been observed both in vivo and in vitro in the developing brain (Abreu-Villaca et al, 2004;Qiao et al, 2003). Continuous exposure to nicotine has been reported to have little effect on cell survival in neural progenitors in vitro (Takarada et al, 2012).…”