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

Abstract

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 GABAA receptor‐ (GABAAR as well as GABAA‐ρR) and GABAB receptor (GABABR)‐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 GABAAR and GABABR, including GABAA‐ρR 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 GABAAR 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.

Stereological estimations and neurochemical characterization of neurons expressing GABAA and GABAB receptors in the rat pedunculopontine and laterodorsal tegmental nuclei

“…Besides, GABAC receptors, a homopentameric subclass of GABAARs consisting solely of rho subunits (ρ1-3; GABAA-ρR), have been demonstrated on cholinergic LDT neurons in mice (Eliasen et al 2020 ; Kohlmeier and Kristiansen 2010 ) despite their very limited distribution. Assuming that there is little difference between species regarding subunit composition of GABAARs (Gao et al 1995 ; Boyes and Bolam 2007 ), GABAC receptors might be present in the LDT in addition to GABAARs, or ρ subunits might be expressed instead of α1 in association with the γ subunit, as has been shown in some brainstem nuclei both in mice and rat (Frazao et al 2007 ; Milligan et al 2004 ).…”

In Vitro and In Vivo Evaluation of Pellotine: A Hypnotic Lophophora Alkaloid

“…Mice from this age group were utilized as maintaining cell viability, and Fura-2AM loading is challenging in older brain slices. Procedures used were similar to those previously reported and will only briefly be presented here . Mice were anesthetized with 100% isoflurane (ScanVet Animal Health A/S, Denmark), and the depth of the anesthesia was evaluated by the loss of the righting reflex as well as failure to respond to a paw pinch.…”

“…Procedures used were similar to those previously reported and will only briefly be presented here. 65 Mice were anesthetized with 100% isoflurane (ScanVet Animal Health A/S, Denmark), and the depth of the anesthesia was evaluated by the loss of the righting reflex as well as failure to respond to a paw pinch. Following deep anesthesia, the brain was removed and brain slices (250 μm) containing the dorsal raphe (n = 64), laterodorsal tegmental nucleus (n = 67), or the locus coeruleus (n = 87) were prepared using a vibratome (VT 1200S, Leica, Germany).…”