Varenicline attenuates nicotine-enhanced brain-stimulation reward by activation of α4β2 nicotinic receptors in rats

Abstract

Varenicline, a partial α4β2 and full α7 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-β-erythroidine (a relatively selective nicotinic α4-containing receptor antagonist), but not methyllycaconitine (a selective α7 receptor antagonist), suggesting an effect mediated by activation of α4β2 receptors. This suggestion is supported by findings that the α4β2 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 α7 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 α4β2, but not α7, receptors.

Introduction

Cigarette smoking is the primary cause of many preventable diseases, and much attention has focused on various therapies for smoking cessation. Currently, smoking cessation therapies include nicotine replacement products and the monoamine reuptake inhibitor bupropion. In addition, the U.S. Food and Drug Administration (FDA) has recently approved the nicotine receptor agonist varenicline and nicotine vaccines as newer medications for smoking cessation (Rollema et al., 2007b, Tutka, 2008, Xi et al., in press).

Nicotine is considered the major reinforcing component of cigarette tobacco for both humans and experimental animals (Goldberg et al., 1981, Watkins et al., 2000). Neuronal nicotinic acetylcholine (nAChR) receptors are either homomeric or heteromeric pentameric ion channels, consisting of different combinations of α2–α10 and β2–β4 subunits (Cooper et al., 1991, Le Novère et al., 2002). The non-neuronal subunits – α1, β1, γ, δ and ɛ – form peripheral nicotinic acetylcholine receptors at the neuromuscular junction (Le Novère et al., 2002). The predominant nAChRs are the α4β2-containing heteromers or α7-containing homomers (Couturier et al., 1990, Zoli et al., 1998), which modulate release of neurotransmitters such as dopamine (DA), glutamate or GABA (Zhu and Chiappinelli, 2002, Lambe et al., 2003, Cao et al., 2005).

Recent research has indicated that α4β2 receptors play a major role in mediating nicotine's action in the brain (Markou, 2008, Xi et al., in press). Repeated exposure to nicotine significantly increases nicotine binding to α4β2 receptors (Marks et al., 1992), and blockade of α4β2 nAChRs by dihydro-β-erythroidine (DHβE) inhibits nicotine self-administration (Watkins et al., 1999). Deletion of the β2 subunits significantly attenuates or abolishes nicotine self-administration, nicotine-induced taste aversion, nicotine discrimination, and nicotine-enhanced DA in the nucleus accumbens (NAc) (Picciotto et al., 1998, Grady et al., 2001, Shoaib et al., 2002). In contrast, animals lacking α7 subunits show normal acquisition of stimulus discrimination for nicotine (Stolerman et al., 2004).

Varenicline is a partial agonist at α4β2 and a full agonist at α7 nicotinic receptors (Foulds, 2006, Mihalak et al., 2006). Clinical trials indicate that varenicline is effective in decreasing relapse to smoking in humans (Zierler-Brown and Kyle, 2007, Tutka, 2008). Preclinical studies demonstrate that varenicline inhibits nicotine self-administration and nicotine-enhanced NAc DA (Rollema et al., 2007a). Varenicline partially substitutes for nicotine in self-administration testing in animals and partially generalizes to nicotine in the drug discrimination preclinical animal paradigm (Rollema et al., 2007a, Smith et al., 2007). Varenicline has also been reported to reduce ethanol, but not sucrose, self-administration, and decrease voluntary ethanol, but not water, consumption in rats (Steensland et al., 2007).

In addition to the self-administration and drug discrimination paradigms, electrical brain-stimulation reward (BSR) is another commonly used animal model to assess nicotine's action in the brain (Wise, 1996, Pak et al., 2006). In the present study, we first examined the effects of both varenicline and nicotine on BSR, and the effect of varenicline pretreatment on nicotine-enhanced BSR. To study the underlying receptor mechanisms, we further observed the effects of various high affinity nAChR agonists or antagonists with relative selectivity for α4β2 or α7 receptors on BSR and on varenicline- or nicotine-enhanced BSR.