Effects of Developmental Nicotine Exposure on Frontal Cortical GABA-to-Non-GABA Neuron Ratio and Novelty-Seeking Behavior

Abstract

Abstract Cigarette smoking during pregnancy is a major public health concern, resulting in detrimental health effects in the mother and her offspring. The adverse behavioral consequences for children include increased risk for attention deficit hyperactivity disorder, working memory deficits, epilepsy, novelty-seeking, and risk-taking behaviors. Some of these behavioral conditions are consistent with an imbalance in frontal cortical excitatory (glutamate) and inhibitory (GABA) neurotransmitter signaling. We used a GAD67-GFP knock-in mouse model to examine if developmental nicotine exposure alters frontal cortical GABA neuron numbers, GABA-to-non-GABA neuron ratio and behavioral phenotypes. Female mice were exposed to nicotine (100 or 200 μg/mL) in drinking water beginning 3 weeks prior to breeding and until 3 weeks postpartum. Male and female offspring were examined beginning at 60 days of age. The nicotine exposure produced dose-dependent decreases in GABA-to-non-GABA neuron ratios in the prefrontal and medial prefrontal cortices without perturbing the intrinsic differences in cortical thickness and laminar distribution of GABA or non-GABA neurons between these regions. A significant increase in exploratory behavior and a shift toward “approach” in the approach–avoidance paradigm were also observed. Thus, developmental nicotine exposure shifts the cortical excitation–inhibition balance toward excitation and produces behavioral changes consistent with novelty-seeking behavior.