title: Varenicline attenuates nicotine-enhanced brain-stimulation reward by activation of alpha4beta2 nicotinic receptors in rats.
abstract: Varenicline, a partial alpha4beta2 and full alpha7 nicotinic receptor agonist, has been shown to inhibit nicotine self-administration and nicotine-induced increases in extracellular dopamine in the nucleus accumbens. In the present study, we investigated whether varenicline inhibits nicotine-enhanced electrical brain-stimulation reward (BSR), and if so, which receptor subtypes are involved. Systemic administration of nicotine (0.25-1.0 mg/kg, i.p.) or varenicline (0.03-3 mg/kg, i.p.) produced biphasic effects, with low doses producing enhancement (e.g., decreased BSR threshold), and high doses inhibiting BSR. Pretreatment with low dose (0.03-1.0 mg/kg) varenicline dose-dependently attenuated nicotine (0.25 or 0.5 mg/kg)-enhanced BSR. The BSR-enhancing effect produced by varenicline was blocked by mecamylamine (a high affinity nicotinic receptor antagonist) or dihydro-beta-erythroidine (a relatively selective nicotinic alpha4-containing receptor antagonist), but not methyllycaconitine (a selective alpha7 receptor antagonist), suggesting an effect mediated by activation of alpha4beta2 receptors. This suggestion is supported by findings that the alpha4beta2 receptor agonist SIB-1765F produced a dose-dependent enhancement of BSR, while pretreatment with SIB-1765F attenuated nicotine (0.5 mg/kg)-enhanced BSR. In contrast, the selective alpha7 receptor agonist ARR-17779, altered neither BSR itself nor nicotine-enhanced BSR, at any dose tested. These findings suggest that: 1) varenicline inhibits nicotine-enhanced BSR, supporting its use as a smoking cessation aid; and 2) varenicline-enhanced BSR by itself and varenicline's anti-nicotine effects are mediated by activation of alpha4beta2, but not alpha7, receptors.
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Krista
authors.initials: K
authors.lastname: Spiller
authors.forename: Zheng-Xiong
authors.initials: ZX
authors.lastname: Xi
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.forename: Charles R
authors.initials: CR
authors.lastname: Ashby
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Callahan
authors.forename: Ashok
authors.initials: A
authors.lastname: Tehim
authors.forename: Eliot L
authors.initials: EL
authors.lastname: Gardner
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D008297:Male; D008474:Medial Forebrain Bundle / Q000187:drug effects / Q000502:physiology; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012201:Reward; D000068580:Varenicline
chemical_list: D001552:Benzazepines; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011810:Quinoxalines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D009538:Nicotine; D000068580:Varenicline