Abstract
Neuronal nicotinic receptors are comprised of combinations of α2–9 and β2–4 subunits arranged to form a pentameric receptor. Currently, the principal central nervous system (CNS) subtypes are believed to be α4β2 and a homomeric α7 receptor, although other combinations almost certainly exist. The identity of the nicotinic receptor subtype(s) involved in the rewarding effects of nicotine are unknown. In the present study, using some recently described subtype selective nicotinic agonists and antagonists, we investigated the role of the α7 nicotinic receptor in the mediation of nicotine-induced hyperactivity and self-administration in rats. The α7 receptor agonists AR-R 17779 and DMAC failed to stimulate locomotor activity in both nicotine-nontolerant and -sensitized rats. In contrast, nicotine and the putative α4β2 subtype selective agonist SIB1765F increased activity in both experimental conditions. In nicotine-sensitized rats, the high affinity (including the α4β2 subtype) nicotinic antagonist dihydro-β-erythroidine (DHβE), but not the selective α7 antagonist methyllycaconitine (MLA), antagonized a nicotine-induced hyperactivity. Similarly, DHβE, but not MLA, pretreatment reduced nicotine self-administration. Electrophysiology experiments using Xenopus oocytes expressing the human α7 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 CNS. Taken together, these results indicate a negligible role of α7receptors in nicotine-induced hyperlocomotion and reward in the rat, and support the view for an involvement of a member from the high-affinity nicotinic receptor subclass, possibly α4β2. Issues such as drug potency, CNS penetration, and desensitization of the α7 receptor are discussed.
Footnotes
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Send reprint requests to: Dr. G. A. Higgins, PRBN-B, Bau 72/150, F. Hoffmann-La Roche Ltd., Basel, Switzerland. E-mail: guy_a.higgins{at}roche.com
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↵1 Funding for this work was provided by F. Hoffman-La Roche AG. We would like to thank Kathy Coen and Laurie Adamson for their contribution to the nicotine self-administration experiments and Eva Pflugfelder for assistance with the oocyte experiments.
- Abbreviations:
- ACh
- acetylcholine
- nAChR
- nicotinic acetylcholine receptor
- CNS
- central nervous system
- DA
- dopamine
- TO
- timeout
- PCR
- polymerase chain reaction
- VTA
- ventral tegmental area
- DMAC
- [4-[(1E,3E)-3-(5,6-dihydro-4H-[2,3′]bipyridinyl-3-ylidene)-propenyl]phenyl]dimethyl-amine
- DHβE
- dihydro-β-erythroidine
- MLA
- methyllycaconitine
- α-BGT
- α-bungarotoxin
- AR-R 17779
- (−)-spiro[1-azabicyclo[2.2.2]octane-3,5′-oxazolidin]-2′-one
- SIB-1765F
- 3-ethynyl-5-(1-methyl-2-pyrrolidinyl)pyridine
- Received February 18, 2000.
- Accepted May 8, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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