Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors.
Worldwide, 100 million people are expected to die this century from the consequences of nicotine addiction, but nicotine is also known to enhance cognitive performance. Identifying the molecular mechanisms involved in nicotine reinforcement and cognition is a priority and requires the development of new in vivo experimental paradigms. The ventral tegmental area (VTA) of the midbrain is thought to mediate the reinforcement properties of many drugs of abuse. Here we specifically re-expressed the beta2-subunit of the nicotinic acetylcholine receptor (nAChR) by stereotaxically injecting a lentiviral vector into the VTA of mice carrying beta2-subunit deletions. We demonstrate the efficient re-expression of electrophysiologically responsive, ligand-binding nicotinic acetylcholine receptors in dopamine-containing neurons of the VTA, together with the recovery of nicotine-elicited dopamine release and nicotine self-administration. We also quantified exploratory behaviours of the mice, and showed that beta2-subunit re-expression restored slow exploratory behaviour (a measure of cognitive function) to wild-type levels, but did not affect fast navigation behaviour. We thus demonstrate the sufficient role of the VTA in both nicotine reinforcement and endogenous cholinergic regulation of cognitive functions.
Maskos
U
U
Unité Récepteurs et Cognition, CNRS URA 2182, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris Cedex 15, France.
Molles
B E
BE
Pons
S
S
Besson
M
M
Guiard
B P
BP
Guilloux
J-P
JP
Evrard
A
A
Cazala
P
P
Cormier
A
A
Mameli-Engvall
M
M
Dufour
N
N
Cloëz-Tayarani
I
I
Bemelmans
A-P
AP
Mallet
J
J
Gardier
A M
AM
David
V
V
Faure
P
P
Granon
S
S
Changeux
J-P
JP
D000818:Animals; D003071:Cognition / Q000187:drug effects / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D015870:Gene Expression; D008124:Locomotion / Q000502:physiology; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009538:Nicotine / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D018343:Receptors, Adrenergic, beta-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects / Q000502:physiology
D018343:Receptors, Adrenergic, beta-2; D011978:Receptors, Nicotinic; D009538:Nicotine; D009020:Morphine; D004298:Dopamine