Sex-specific alterations in GABA receptor-mediated responses in laterodorsal tegmentum are associated with prenatal exposure to nicotine

Smoking during pregnancy is associated with deleterious physiological and cognitive effects on the offspring, which are likely due to nicotine-induced alteration in the development of neurotransmitter systems. Prenatal nicotine exposure (PNE) in rodents is associated with changes in behaviors controlled in part by the pontine laterodorsal tegmentum (LDT), and LDT excitatory signaling is altered in a sex and age-dependent manner by PNE. As effects on GABAergic LDT signaling are unknown, we used calcium imaging to evaluate GABA(A) receptor- (GABA(A)R as well as GABA(A)-R-rho) and GABA(B) receptor (GABA(B)R)-mediated calcium responses in LDT brain slices from female and male PNE mice in two different age groups. Overall, in older PNE females, changes in calcium induced by stimulation of GABA(A)R and GABA(B)R, including GABA(A)-R-rho were shifted toward calcium rises. In both young and old males, PNE was associated with alterations in calcium mediated by all three receptors; however, the GABA(A)R was the most affected. These results show for the first time that PNE is associated with alterations in GABAergic transmission in the LDT in a sex- and age-dependent manner, and these data are the first to show PNE-associated alterations in functionality of GABA receptors in any nucleus. PNE-associated alterations in LDT GABAergic transmission within the LDT would be expected to alter output to target regions and could play a role in LDT-implicated, negative behavioral outcomes following gestational exposure to smoking. Accordingly, our data provide further supportive evidence of the importance of eliminating the consumption of nicotine during pregnancy.