title: Age-related changes in functional postsynaptic nicotinic acetylcholine receptor subunits in neurons of the laterodorsal tegmental nucleus, a nucleus important in drug addiction.
abstract: The earlier an individual initiates cigarette smoking, the higher the likelihood of development of dependency to nicotine, the addictive ingredient in cigarettes. One possible mechanism underlying this higher addiction liability is an ontogenetically differential cellular response induced by nicotine in neurons mediating the reinforcing or euphoric effects of this drug, which could arise from age-related differences in the composition of nicotinic acetylcholine receptor (nAChR) subunits. In the current study, we examined whether the subunit composition of nAChRs differed between neurons within the laterodorsal tegmentum (LDT), a nucleus importantly involved in drug addiction associated behaviours, across two periods of ontogeny in which nicotine-mediated excitatory responses were shown to depend on age. To this end, whole-cell patch-clamp recordings in mouse brain slices from identified LDT neurons, in combination with nAChR subunit-specific receptor antagonists, were conducted. Comparison of the contribution of different nAChR subunits to acetylcholine (ACh)-induced inward currents indicated that the contributions of the β2 and/or β4 and α7 nAChR subunits alter across age. Taken together, we conclude that across a limited ontogenetic period, there is plasticity in the subunit composition of nAChRs in LDT neurons. In addition, our data indicate, for the first time, functional presence of α6 nAChR subunits in LDT neurons within the age ranges studied. Changes in subunit composition of nAChRs across ontogeny could contribute to the age-related differential excitability induced by nicotine. Differences in the subunit composition of nAChRs within the LDT would be expected to contribute to ontogenetic-dependent outflow from the LDT to target regions, which include reward-related circuitry.
authors.affiliation: Department of Drug design and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Denmark.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Christensen
authors.affiliation: Department of Drug design and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Denmark.
authors.forename: Kristi A
authors.initials: KA
authors.lastname: Kohlmeier
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000375:Aging / Q000502:physiology*; D000818:Animals; D066298:In Vitro Techniques; D008464:Mecamylamine / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009419:Nerve Tissue Proteins / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011978:Receptors, Nicotinic / Q000187:drug effects*; D055366:Synaptic Potentials / Q000187:drug effects; D013681:Tegmentum Mesencephali / Q000187:drug effects
chemical_list: D000109:Acetylcholine; D008464:Mecamylamine; D009419:Nerve Tissue Proteins; D009538:Nicotine; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; C486720:Chrnb4 protein, mouse; C104518:nicotinic receptor alpha6
keywords: Electrophysiology; LDT; REM sleep; mouse