Prenatal nicotine exposure and development of nicotinic and fast amino acid-mediated neurotransmission in the control of breathing

Abstract

There is mounting evidence that neonatal animals exposed to nicotine in the prenatal period exhibit a variety of anatomic and functional abnormalities that adversely affect their respiratory and cardiovascular control systems, but how nicotine causes these developmental alterations is unknown. The principle that guides our work is that PNE impairs the ability of nicotinic acetylcholine receptors (nAChRs) to modulate the pre-synaptic release of both inhibitory (particularly GABA) and excitatory (glutamate) neurotransmitters, leading to marked alterations in the density and/or function of receptors on the (post-synaptic) membrane of respiratory neurons. Such changes could lead to impaired ventilatory responses to sensory afferent stimulation, and altered breathing patterns, including central apneic events. In this brief review we summarize the work that lead to the development of this hypothesis, and introduce some new data that support and extend it.

Figure 1

This figure, taken from our recent study (Luo et al., 2007), shows that microinjection of glycine or muscimol into the preBotzinger complex causes transient apnea. Panel A shows representative recordings from saline-exposed and nicotine-exposed neonates, and demonstrates that the duration of the transient, drug-induced apnea is longer in the nicotine-exposed animals. Panel B provides average values for apnea duration induced with either drug, in saline-exposed and nicotine-exposed neonates. As discussed in the text, these effects of drug injection must be due to actions on GABAA receptors located on the post-synaptic membrane of neurons that control respiratory motor output.

Figure 2

Recordings from the C4 ventral nerve root (C4 VR) in a saline-exposed and a nicotine-exposed brainstem-spinal cord preparation from 2–3 day-old neonatal rat pups. Nicotine (0.5 uM nicotine bitartrate, equivalent to 175 nM free nicotine) was applied to the brainstem chamber of a split-bath configuration, leading to a sharp increase in C4 ventral nerve burst frequency in the saline-exposed, but not the nicotine-exposed, neonate. The increase in frequency with nicotine could be fully reversed with dihydro-b-erythroidine hydrobromide, which is an antagonist of the α4β2 receptor subtype, suggesting that this nAChR subtype is largely responsible for modulating respiratory frequency in this preparation. See text for details.

Figure 3

Schematic diagram summarizing putative physiologic and anatomic changes that occur secondary to the influence of prenatal nicotine exposure on inhibitory synaptic transmission in brainstem respiratory neurons. Prenatal nicotine exposure results in an up-regulation of nicotinic acetylcholine receptors that are located presynaptically on both GABAergic and glutamatergic neurons. However, the nicotinic receptors are subsequently desensitized leading to a diminution of GABA and glutamate release. The reduction in GABA and glutamate release leads to an up-regulation of GABAA and glutamate receptors (probably both NMDA and AMPA subtypes) on the postsynaptic neuron. As a result, any endogenous stressor associated with an increase in GABA or glutamate release (e.g., hypoxia) would be associated with an exaggerated post-synaptic response (see text for detailed explanation). This model is an adaptation and extension of a similar one published by Luo et al. (Luo et al., 2007).