Neuronal nicotinic receptor ligands modulate chronic nicotine-induced ethanol consumption in C57BL/6J mice

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Abstract

Alcohol and nicotine are commonly abused drugs in humans and evidence suggests that neuronal nicotinic acetylcholine receptors (nAChRs) in the midbrain dopamine system are common targets for the neurobehavioral interactions between alcohol (ethanol) and nicotine. The present study examined the efficacy of nAChR ligands with different pharmacological profiles such as cytisine, lobeline and dihydro-β-erythroidine (DHβE) to modulate chronic nicotine-induced increase in ethanol intake by C57BL/6J mice, using a two-bottle choice procedure. After establishment of baseline ethanol preference (10%, v/v), animals received daily subcutaneous injections of saline, nicotine (0.4 mg/kg) or different doses of cytisine, lobeline or DHβE 15 min prior to nicotine, for 10 days. Ethanol and water were presented immediately after the last (saline or nicotine) injection and fluid levels were monitored for post 1 h and 2 h treatment. Compared to control, nicotine injection significantly increased mean ethanol intake over 10 days, at both post 1 h and 2 h. Pretreatment with cytisine (0.5, 1.5 or 3.0 mg/kg) or lobeline (4.0 or 10.0 mg/kg) significantly reduced nicotine-induced increase in ethanol intake post 1 h and 2 h, without affecting water consumption. DHβE (0.5 or 2.0 mg/kg) failed to suppress nicotine-induced ethanol intake across 2 h post injection. These results indicate that nAChR-mediated signaling is critical in regulating nicotine-induced ethanol drinking behaviors.

Highlights

► Chronic nicotine treatment increased free-choice ethanol intake in mice. ► Cytisine pretreatment attenuated nicotine-induced ethanol intake and preference. ► Lobeline pretreatment reduced nicotine-induced ethanol consumption and preference. ► DHβE pretreatment did not suppress nicotine-induced ethanol intake or preference. ► Nicotinic receptors are critical in regulating nicotine-induced ethanol intake.

Introduction

Alcohol use disorders (AUDs) including addiction have a detrimental impact on public health across the globe. Evidence indicates that alcohol and nicotine are frequently co-abused and there is a strong positive association between AUDs and nicotine addiction (Falk et al., 2006, Rose et al., 2004). Preclinical studies also indicate that nicotine treatment significantly increases operant or free-choice alcohol (ethanol) self-administration (Blomqvist et al., 1996, Lê et al., 2003) and reinstates ethanol seeking behavior in rodents (Hauser et al., 2011, Lê et al., 2010). Further, co-administration of ethanol and nicotine produced an additive effect on accumbal dopamine release (Ericson et al., 2009, Tizabi et al., 2007). Therefore, it is believed that the midbrain dopamine system is a convergent site of action for reinforcing effects of ethanol and nicotine (Koob and Volkow, 2010, Larsson and Engel, 2004, Söderpalm et al., 2009).

Evidence suggests a critical role for the neuronal nicotinic acetylcholine receptors (nAChRs) as potential targets for the reinforcing actions of ethanol (Chatterjee and Bartlett, 2010, Larsson and Engel, 2004, Rahman, 2011). Previous studies indicate the ability of nAChR ligands to modulate various ethanol drinking behaviors (Chatterjee et al., 2011, Hendrickson et al., 2009, Larsson et al., 2002). The nAChRs are ligand-gated ion channels which are extensively distributed in midbrain dopaminergic neurons (Klink et al., 2001, Livingstone and Wonnacott, 2009). These receptors are composed of pentameric assemblies of α (2–10) and β (2–4) subunits, resulting in diverse subtypes with distinct functional properties (Gotti et al., 2006, Rahman et al., 2008). Also, it is reported that nAChRs are primarily involved in behaviors related to nicotine addiction (Picciotto et al., 1998, Picciotto et al., 2008). Therefore, nAChRs could have an important role in mediating the correlation between AUDs and nicotine addiction (Chatterjee and Bartlett, 2010).

Cytisine and lobeline are known nAChR ligands with distinct pharmacological profiles and have shown partial efficacy for smoking cessation (Dwoskin and Crooks, 2002, Tutka and Zatoński, 2006). Cytisine is a high affinity partial agonist at α4β2* (* indicates the inclusion of other subunits) nAChRs and a full agonist at β4*- and α7-specific nAChRs (Papke and Heinemann, 1994); while lobeline is a non-selective nAChR antagonist at β2* containing nAChRs (Dwoskin and Crooks, 2002) and was found to displace [3H] nicotine from its binding sites with high affinity (Damaj et al., 1997, Miller et al., 2000). Both, cytisine and lobeline were found to inhibit nicotine-evoked accumbal dopamine release (Benwell and Balfour, 1998, Coe et al., 2005) and ethanol-induced increase in midbrain dopamine content (Sajja et al., 2010). In addition, lobeline was shown to attenuate the neurobehavioral effects of psychostimulants (Harrod et al., 2001) and is presently under phase II trials for methamphetamine dependence (National Institute on Drug Abuse). Previous studies indicate that cytisine and lobeline modulate voluntary ethanol drinking behaviors in HAD-2 rats (Bell et al., 2009) and mice (Farook et al., 2009, Hendrickson et al., 2009). Recently, we have demonstrated that these nAChR ligands selectively reduce the acquisition of ethanol preference and binge-like excess ethanol drinking-in-the-dark (Sajja and Rahman, 2011).

However, the effects of cytisine or lobeline on nicotine and ethanol interactions have not been investigated thus far. Given the evidence that nicotine abuse strongly correlates with ethanol drinking and both ligands reduce the neurobehavioral responses to nicotine or ethanol alone, we therefore examined the effects of cytisine and lobeline on nicotine–ethanol interactions in a co-addiction model using C57BL/6J mice. Specifically, the current study examined whether pretreatment with repeated daily injections of cytisine or lobeline attenuates chronic systemic nicotine-induced increase in ethanol drinking in mice. To further pharmacologically characterize the specific subunit containing nAChRs involved in such neurobehavioral interactions, we examined the effects of dihydro-β-erythroidine (DHβE), a selective antagonist at α4β2 nAChRs (Larsson and Engel, 2004).

Section snippets

Animals

Male C57BL/6J mice (5–6 weeks old) were purchased from The Jackson Laboratory (Bar Harbor, ME). This inbred mouse strain was used for its innate high ethanol preference (Sajja and Rahman, 2011). Animals were acclimated to the procedure room in clear plastic cages (4/cage) for at least 1 week prior to testing. After acclimation, mice were transferred to individual standard home cages and had access to food and water ad libitum, unless noted. Standard temperature and humidity conditions were

Effects of cytisine on nicotine-induced ethanol consumption and tap water

As shown in Fig. 2A and B, one way ANOVA indicated an overall significant main effect of treatment on ethanol consumption post 1 h [F(5, 34) = 7.3, p < 0.001] and post 2 h [F(5, 32) = 6.8, p < 0.001] respectively. Further analysis with Tukey's post-hoc test revealed that chronic nicotine (0.4 mg/kg, s.c.) treatment for 10 days significantly increased mean ethanol consumption, compared to control at post 1 h (178.8% of control, p < 0.05) and post 2 h (165% of control, p < 0.05). Pretreatment with different doses

Discussion

The important findings from the present study are that chronic and concomitant nicotine treatment selectively increased mean ethanol drinking in mice. Pretreatment with known nAChR ligands such as cytisine or lobeline, with different mechanisms of action, significantly suppressed nicotine-induced increase in ethanol drinking and preference in mice. In contrast, pretreatment with DHβE, at all doses used in this study, failed to reduce nicotine-induced increase in ethanol consumption.

Conclusions

In summary, the present study indicates the likely involvement of nAChR-mediated signaling in nicotine and ethanol neurobehavioral interactions, leading to their co-addiction. Cytisine and lobeline significantly suppressed nicotine-induced increase in ethanol consumption and preference in a partial co-addiction model. Thus, data from the present study implicate the potential role of nAChR-mediated signaling in nicotine-induced ethanol drinking behaviors.

Acknowledgments

The authors would like to thank Dr. William Corrigall of University of Minnesota for comments. The authors also thank Matthew Spinar and Trent Harris for providing technical assistance during this study. This study was supported in part by the American Foundation for Pharmaceutical Education and American Association of Colleges of Pharmacy NIP Research Grant (SR); South Dakota Governor's 2010 Research Initiative and SDSU RS/SF Grants (SR).

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