Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas.
A single nicotine exposure increases dopamine levels in the mesolimbic reward system for hours, but nicotine concentrations experienced by smokers desensitize nAChRs on dopamine neurons in seconds to minutes. Here, we show that persistent modulation of both GABAergic and glutamatergic synaptic transmission by nicotine can contribute to the sustained increase in dopamine neuron excitability. Nicotine enhances GABAergic transmission transiently, which is followed by a persistent depression of these inhibitory inputs due to nAChR desensitization. Simultaneously, nicotine enhances glutamatergic transmission through nAChRs that desensitize less than those on GABA neurons. The net effect is a shift toward excitation of the dopamine reward system. These results suggest that spatial and temporal differences in nicotinic receptor activity on both excitatory and inhibitory neurons in reward areas coordinate to reinforce nicotine self-administration.
Mansvelder
Huibert D
HD
Department of Anesthesia, University of Chicago, Chicago, IL 60637, USA.
Keath
J Russel
JR
McGehee
Daniel S
DS
D000110:Acetylcholinesterase / Q000378:metabolism; D000200:Action Potentials / Q000502:physiology; D000293:Adolescent; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D018680:Cholinergic Antagonists / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005731:Ganglionic Stimulants / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007306:Insecticides / Q000494:pharmacology; D051379:Mice; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009474:Neurons / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology*; D009946:Organothiophosphorus Compounds / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism; D012201:Reward; D012907:Smoking; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D017557:Ventral Tegmental Area / Q000166:cytology / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018680:Cholinergic Antagonists; D002800:Cholinesterase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D005731:Ganglionic Stimulants; D007306:Insecticides; D018727:Muscarinic Antagonists; D009946:Organothiophosphorus Compounds; D011810:Quinoxalines; D011978:Receptors, Nicotinic; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C056723:FG 9041; D009538:Nicotine; D001285:Atropine; C014655:methamidophos; D000110:Acetylcholinesterase; D004298:Dopamine