Aj. Grottick et al., Evidence that nicotinic alpha(7) receptors are not involved in the hyperlocomotor and rewarding effects of nicotine, J PHARM EXP, 294(3), 2000, pp. 1112-1119
Citations number
45
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Neuronal nicotinic receptors are comprised of combinations of alpha(2-8) an
d beta(2-4) subunits arranged to form a pentameric receptor. Currently, the
principal central nervous system (CNS) subtypes are believed to be alpha(4
)beta(2) and a homomeric alpha(7) receptor, although other combinations alm
ost certainly exist. The identity of the nicotinic receptor subtype(s) invo
lved in the rewarding effects of nicotine are unknown. In the present study
, using some recently described subtype selective nicotinic agonists and an
tagonists, we investigated the role of the alpha(7) nicotinic receptor in t
he mediation of nicotine-induced hyperactivity and self-administration in r
ats. The alpha(7) receptor agonists AR-R 17779 and DMAC failed to stimulate
locomotor activity in both nicotine-nontolerant and -sensitized rats. In c
ontrast, nicotine and the putative alpha(4)beta(2) subtype selective agonis
t SIB1765F increased activity in both experimental conditions. In nicotine-
sensitized rats, the high affinity (including the alpha(4)beta(2) subtype)
nicotinic antagonist dihydro-beta-erythroidine (DH beta E), but not the sel
ective alpha(7) antagonist methyllycaconitine (MLA), antagonized a nicotine
-induced hyperactivity. Similarly, DH beta E, but not MLA, pretreatment red
uced nicotine self-administration. Electrophysiology experiments using Xeno
pus oocytes expressing the human alpha(7) receptor confirmed AR-R 17779 and
DMAC to be potent agonists at this site, and further studies demonstrated
the ability of systemically administered AR-R 17779 to penetrate into the C
NS. Taken together, these results indicate a negligible role of alpha(7) re
ceptors in nicotine-induced hyperlocomotion and reward in the rat, and supp
ort the view for an involvement of a member from the high-affinity nicotini
c receptor subclass, possibly alpha(4)beta(2). Issues such as drug potency,
CNS penetration, and desensitization of the alpha(7) receptor are discusse
d.