Inhibition of both alpha7* and beta2* nicotinic acetylcholine receptors is necessary to prevent development of sensitization to cocaine-elicited increases in extracellular dopamine levels in the ventral striatum.
BACKGROUND
Several studies have suggested that nicotine treatment can modulate the behavioral and neurochemical responses to other psychostimulants, such as cocaine.


OBJECTIVE
The current study examined the hypothesis that nicotinic acetylcholine receptor (nAChR) blockade influences the ability of cocaine to elicit increases in extracellular dopamine levels.


METHODS
Pharmacological studies using nicotinic antagonists as well as genetic inactivation of beta2* nAChRs were used to determine the effect of nAChR blockade on dopamine levels in ventral striatum elicited by acute or repeated administrations of cocaine in mice.


RESULTS
Administration of mecamylamine (a general nicotinic antagonist that is not highly selective for individual nAChR subtypes) or co-administration of methyllycaconitine (a more selective antagonist of alpha7* nAChRs) with dihydro-beta-erythroidine (a more selective antagonist of beta2* nAChRs and other heteromeric nAChR subtypes) prevented sensitization of cocaine-elicited increases in extracellular DA levels in the ventral striatum in wild-type mice. In contrast, neither of the more specific antagonists alone was effective in preventing sensitization. Finally, methyllycaconitine administration prevents sensitization in beta2-/- mice but not in beta2+/+ or wild-type mice.


CONCLUSIONS
These data indicate that inhibition of both alpha7* and beta2* nAChRs is necessary to prevent development of sensitization of cocaine-elicited increases in extracellular dopamine levels in the ventral striatum of mice.
Zanetti
Lara
L
Department of Biomedical Sciences, Section of Physiology University of Modena and Reggio Emilia, via Campi 287, 41100 Modena, Italy.
de Kerchove D'Exaerde
Alban
A
Zanardi
Alessio
A
Changeux
Jean-Pierre
JP
Picciotto
Marina R
MR
Zoli
Michele
M
D000157:Aconitine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D045604:Extracellular Fluid / Q000187:drug effects*; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects*; D064569:alpha7 Nicotinic Acetylcholine Receptor
D000157:Aconitine; D000697:Central Nervous System Stimulants; D003042:Cocaine; D004298:Dopamine; D008464:Mecamylamine; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C579166:Chrna7 protein, mouse; C054634:methyllycaconitine