Alterations in NMDAR-mediated signaling within the laterodorsal tegmental nucleus are associated with prenatal nicotine exposure

Neuropharmacology. 2019 Nov 1;158:107744. doi: 10.1016/j.neuropharm.2019.107744. Epub 2019 Aug 19.


Cigarette smoking during pregnancy has been clinically associated with a variety of poorbehavioral outcomes for the exposed individuals, including higher risks for drug abuse and development of attention/deficit-hyperactive disorder (ADHD). Experimental studies support the hypothesis that nicotine might contribute to these risks, since prenatal nicotine exposure (PNE) in rodents was associated with greater addiction liability, hyperactivity, social impairments and a wide range of emotional and cognitive deficits. Alterations of glutamate signaling within brain regions involved in behavioral circuits could contribute to these outcomes. The pontine laterodorsal tegmental nucleus (LDT) exerts cholinergic modulation within the ventral tegmental area, nucleus accumbens, and cortical-projecting thalamic centers and PNE-associated alterations in LDT glutamate signaling could impact cholinergic output to these LDT targets. We have previously demonstrated that PNE alters AMPA-mediated signaling within LDT neurons, and in the present investigation, we focused on changes of NMDA receptors (NMDARs) and presence of silent synapses as an indicator of metaplastic processes in LDT cells associated with PNE treatment. PNE was associated with a decreased functional presence of GluN2B NMDAR subunits in synapses of large, putatively cholinergic neurons, whereas an increased function of this subunit was detected in small, likely GABAergic cells. In addition, PNE was associated with functional alterations of extrasynaptic NMDARs in putative cholinergic neurons, suggestive of an increased presence of GluN3A-containing NMDARs. An increased number of silent synapses was exclusively seen in the small cells. When taken together, we hypothesize that NMDA-mediated signaling changes within LDT neurons following PNE treatment would result in reductions of excitatory cholinergic modulatory tone in target brain regions, which would be expected to contribute to the behavioral deficits found among these individuals.

Keywords: Laterodorsal tegmental nucleus; Memantine; NMDA receptor; Prenatal nicotine exposure; Silent synapses; Synaptic/extrasynaptic NMDA receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cholinergic Neurons / drug effects*
  • Cholinergic Neurons / metabolism
  • Cigarette Smoking / metabolism
  • Female
  • GABAergic Neurons / drug effects*
  • GABAergic Neurons / metabolism
  • Mice
  • Nicotine / pharmacology*
  • Nicotinic Agonists / pharmacology*
  • Patch-Clamp Techniques
  • Pedunculopontine Tegmental Nucleus / cytology
  • Pedunculopontine Tegmental Nucleus / drug effects*
  • Pedunculopontine Tegmental Nucleus / metabolism
  • Pregnancy
  • Prenatal Exposure Delayed Effects / metabolism
  • Receptors, N-Methyl-D-Aspartate / drug effects*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Signal Transduction
  • Synapses / drug effects
  • Synapses / metabolism


  • GluN3A protein, mouse
  • NR2B NMDA receptor
  • Nicotinic Agonists
  • Receptors, N-Methyl-D-Aspartate
  • Nicotine