Prenatal nicotine is associated with reduced AMPA and NMDA receptor-mediated rises in calcium within the laterodorsal tegmentum: a pontine nucleus involved in addiction processes

Abstract

Despite huge efforts from public sectors to educate society as to the deleterious physiological consequences of smoking while pregnant, 12-25% of all babies worldwide are born to mothers who smoked during their pregnancies. Chief among the negative legacies bestowed to the exposed individual is an enhanced proclivity postnatally to addict to drugs of abuse, which suggests that the drug exposure during gestation changed the developing brain in such a way that biased it towards addiction. Glutamate signalling has been shown to be altered by prenatal nicotine exposure (PNE) and glutamate is the major excitatory neurotransmitter within the laterodorsal tegmental nucleus (LDT), which is a brainstem region importantly involved in responding to motivational stimuli and critical in development of drug addiction-associated behaviours, however, it is unknown whether PNE alters glutamate signalling within this nucleus. Accordingly, we used calcium imaging, to evaluate AMPA and NMDA receptor-mediated calcium responses in LDT brain slices from control and PNE mice. We also investigated whether the positive AMPA receptor modulator cyclothiazide (CYZ) had differential actions on calcium in the LDT following PNE. Our data indicated that PNE significantly decreased AMPA receptor-mediated calcium responses, and altered the neuronal calcium response to consecutive NMDA applications within the LDT. Furthermore, CYZ strongly potentiated AMPA-induced responses, however, this action was significantly reduced in the LDT of PNE mice when compared with enhancements in responses in control LDT cells. Immunohistochemical processing confirmed that calcium imaging recordings were obtained from the LDT nucleus as determined by presence of cholinergic neurons. Our results contribute to the body of evidence suggesting that neurobiological changes are induced if gestation is accompanied by nicotine exposure. We conclude that in light of the role played by the LDT in motivated behaviour, the cellular changes in the LDT induced by exposures to nicotine prenatally, when combined with alterations in other reward-related regions, could contribute to the increased susceptibility to smoking observed in the offspring.

Calcium rises induced by AMPA and nicotine receptors in the ventral tegmental area show differences in mouse brain slices prenatally exposed to nicotine

“…One concern with the oral method of nicotine delivery is the potential for indirect effects on the developing fetal brain due to changes in maternal drinking habits. As has been seen in other studies with this method (Pauly et al, ; Alkam et al, 2013a, 2013b), in our laboratory, we have noted that pregnant mice do consume less water when nicotine is included (McNair and Kohlmier, ), which could cause potential changes in the developing fetus due to inadequate hydration. However, body weight at birth and weight gain in the postnatal days of the PNE offspring are similar to those in the control group in our experience, as has been reported in some studies (Alkam et al, ), but these findings are in contrast to reports of lower weight gains seen in others (Paz et al, ; Zhu et al, ; Alkam et al, ).…”

“…Therefore, the reduced calcium response to AMPA in PNE males seen could be due to subunit alterations within the VTA promotive of reduced calcium permeability or perhaps to reductions in agonist binding of the AMPAR, which are not mutually exclusive possibilities. Furthermore, reductions in AMPAR‐mediated calcium rises could be due to other PNE‐altered mechanisms involved secondarily in rises in postsynaptic calcium (McNair and Kohlmier, ). Nevertheless, at this time, we do not know whether differences in rises are mediated by changes in subunits in the AMPAR, or whether alterations induced in other mediators of the response are involved.…”

“…In addition, although reductions in cellular excitability in the VTA have been reported following PNE, as well as inhibition of release of DA to target structures (Alkam et al, 2013a, 2013b), other studies have found enhanced DA neural activity, suggestive of heightened excitability in PNE rodent offspring (Zhang et al, ). We have shown that cholinergic signaling in a brain stem cholinergic group which provides excitatory glutamatergic and the majority of cholinergic input to the VTA is altered by PNE, suggesting a role for this alteration in behavioral outcomes associated with PNE (Christensen et al, ; McNair and Kohlmier, ). In our continuing goal of elucidating neural changes associated with early life exposure to nicotine, we wished to test our hypothesis that AMPAR‐ and nAChR‐based excitability is altered in the VTA in PNE animals, reflected as alterations in AMPAR and nAChR‐stimulated rises in intracellular calcium.…”

Plasticity in the Brainstem: Prenatal and Postnatal Experience Can Alter Laterodorsal Tegmental (LDT) Structure and Function

“…Consistent with this, in unpublished observations, we noted that while PNE LDT neurons displayed higher inward currents upon AMPA application in the absence of TTX, a significantly smaller percentage of neurons fired action potentials following AMPAR activation in the PNE group relative to the number of cells in which AMPA induced action potential firing in control. A lower functionality of VGCC in these neurons upon depolarization reconciles findings from earlier work from our group, in which application of AMPA was associated with reduced intracellular calcium rises in PNE LDT neurons, despite enhanced postsynaptic AMPAR-induced current amplitudes (McNair and Kohlmeier, 2015;Polli and Kohlmeier, 2018). In the earlier study, the AMPA-induced depolarization in PNE LDT neurons was likely associated with a reduced VGCC functioning, resulting in an overall lower intracellular calcium rise.…”

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

“…Given its connectivity, changes induced by PNE in the LDT could influence behaviors regulated by mesolimbic, mesocortical, and thalamic pathways. PNE-associated LDT functional changes have been demonstrated for nAChRs, glutamatergic receptors, voltage-operated calcium channels (VOCCs), and neuronal membrane properties (Christensen, Nielsen, & Kohlmeier, 2015;McNair & Kohlmeier, 2015;. Changes in excitability were shown to be age-dependent, which would be layered upon ontologically-appropriate developmental shifts in cellular distribution (Ninomiya, Kayama, & Koyama, 2005).…”