Nicotinic acetylcholine receptors in the mesolimbic pathway: primary role of ventral tegmental area alpha6beta2* receptors in mediating systemic nicotine effects on dopamine release, locomotion, and reinforcement.
alpha6* nicotinic acetylcholine receptors (nAChRs) are highly and selectively expressed by mesostriatal dopamine (DA) neurons. These neurons are thought to mediate several behavioral effects of nicotine, including locomotion, habit learning, and reinforcement. Yet the functional role of alpha6* nAChRs in midbrain DA neurons is mostly unknown. The aim of this study was to determine the composition and in vivo functional role of alpha6* nAChR in mesolimbic DA neurons of male rats. Immunoprecipitation and immunopurification techniques coupled with cell-specific lesions showed that the composition of alpha6* nAChR in the mesostriatal system is heterogeneous, with (non-alpha4)alpha6beta2* being predominant in the mesolimbic pathway and alpha4alpha6beta2* in the nigrostriatal pathway. We verified whether alpha6* receptors mediate the systemic effects of nicotine on the mesolimbic DA pathway by perfusing the selective antagonists alpha-conotoxin MII (CntxMII) (alpha3/alpha6beta2* selective) or alpha-conotoxin PIA (CntxPIA) (alpha6beta2* selective) into ventral tegmental area (VTA). The intra-VTA perfusion of CntxMII or CntxPIA markedly decreased systemic nicotine-elicited DA release in the nucleus accumbens and habituated locomotion; the intra-VTA perfusion of CntxMII also decreased the rate of nicotine infusion in the maintenance phase of nicotine, but not of food, self-administration. Overall, the results of these experiments show that the alpha6beta2* nAChRs expressed in the VTA are necessary for the effects of systemic nicotine on DA neuron activity and DA-dependent behaviors such as locomotion and reinforcement, and suggest that alpha6beta2*-selective compounds capable of crossing the blood-brain barrier may affect the addictive properties of nicotine and therefore be useful in the treatment of tobacco dependence.
Gotti
Cecilia
C
Department of Medical Pharmacology, Consiglio Nazionale delle Ricerche, Institute of Neuroscience, Cellular and Molecular Pharmacology Center, University of Milan, 20129 Milan, Italy.
Guiducci
Stefania
S
Tedesco
Vincenzo
V
Corbioli
Silvia
S
Zanetti
Lara
L
Moretti
Milena
M
Zanardi
Alessio
A
Rimondini
Roberto
R
Mugnaini
Manolo
M
Clementi
Francesco
F
Chiamulera
Christian
C
Zoli
Michele
M
D000818:Animals; D020916:Conotoxins / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009434:Neural Pathways / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009538:Nicotine / Q000008:administration & dosage / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012054:Reinforcement, Psychology; D012646:Self Administration; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000502:physiology*
D020916:Conotoxins; D004298:Dopamine; D009538:Nicotine; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; C559463:alpha6beta2 nicotinic acetylcholine receptor; C104518:nicotinic receptor alpha6
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