Full-Gestational Exposure to Nicotine and Ethanol Results in Long-Term Dysregulation in the Ventral Tegmental Area

Nicotine is considered a gateway drug for other drugs of abuse. The majority of smokers that begin smoking in adolescence, continue into adulthood. Multiple factors have been linked with smoking initiation, including maternal smoking. Drug exposure during pregnancy has long been suspected to exert deleterious effects on the fetal brain. Concurrent use of smoking and drinking alcohol throughout pregnancy is an all too frequent occurrence in the human population especially in disadvantaged and younger women. The present study investigated the potential contributing factors for the enhanced nicotine self-administration as seen in offspring with gestational exposure to nicotine and ethanol (Nic+EtOH).* We focused on the mesocorticolimbic pathway, specifically the lambda-aminobutyric acid (GABA) and glutamate modulators of ventral tegmental area (VTA) dopamine (DA) neurons that project to the nucleus accumbens (NAcc). Our animal model of full gestational exposure to Nic+EtOH exposes the developing brain to both drugs throughout the entire 3 trimester human equivalent [i.e. gestational days (GD) 1-22 and postnatal days (PN) 2-12]. Using self-administration (SA), in vivo microdialysis, quantitative PCR, and western blot analysis, we investigated alterations in the VTA of offspring. We found that the enhancement of nicotine SA acquisition of offspring with gestational Nic+EtOH exposure is not due to changes in maternal-pup interactions. The offspring with gestational Nic+EtOH exposure have a dramatic change in neurotransmitter release in response to 30mug i.v. nicotine; that displays a 75% increase of NAcc DA and a 50% reduction of VTA GABA release. In comparison, pair-fed (PF) offspring show a 20% increase in NAcc DA and a 20% decrease in VTA GABA in response to nicotine. Nic+EtOH offspring also show sensitivity to n-methyl-d-aspartate (NMDA) in the VTA of offspring that results in a greater increase in NAcc DA and VTA glutamate release compared to the PF offspring. The enhanced acquisition of nicotine SA seen in Nic+EtOH offspring can be reduced to PF levels with disruption to the mesocorticolimbic pathway by infusion of either a GABA agonist or a NMDA receptor antagonist into the VTA. These results correlate with the epidemiologic data that suggests that children with gestational drug exposure are more likely to smoke. The alteration of the mesocorticolimbic pathway present in the offspring with gestational Nic+EtOH exposure is present in both adult and adolescent offspring, suggesting that the neurochemical changes are long-lasting.