The nicotinic antagonist mecamylamine preferentially inhibits cocaine vs. food self-administration in rats

Tobacco dependence is difficult to treat, with the vast majority of those who try to quit relapsing within the first year. Improvements in smoking cessation therapies may be achieved by improving current preclinical research methods. However, most experimental tests in animals use nicotine alone, ignoring the 8000 other constituents found in tobacco smoke. To improve on this model, we have used selfadministration to test the reinforcing properties of aqueous cigarette smoke extract (CSE) in rats, made by bubbling cigarette smoke through a saline solution. CSE is more potent than nicotine alone in both the acquisition and maintenance of self-administration, but did not exhibit higher progressive ratio responding. Mecamylamine and varenicline had similar potencies to block nicotine and CSE selfadministration, indicating the involvement of nicotinic receptors in CSE reinforcement. Following extinction of responding, reinstatement was triggered by exposing animals to a pharmacological stressor, yohimbine (2.5 mg/kg, i.p.), alone and in combination with cues. Animals that self-administered CSE were significantly more sensitive to stress-induced reinstatement than those that self-administered nicotine. Ligand binding autoradiography studies showed nicotine and CSE to have similar affinities for different nicotinic receptor types. CSE significantly reduced MAO-A and MAO-B activities in vitro, whereas nicotine did not. Although CSE inhibition of MAO-A activity in vitro was found to be partially irreversible, irreversible inhibition was not observed in vivo. These experiments show that CSE is an effective reinforcer acting via nicotinic receptors. Furthermore, it better models MAO inhibition and is more sensitive to stress-induced reinstatement than nicotine alone, which is a potent trigger for relapse in smokers.

Section: Discussionsupporting

confidence: 50%

Comparison of the Reinforcing Properties of Nicotine and Cigarette Smoke Extract in Rats

Costello

Reynaga

Mojica

et al. 2014

“…For instance, acetylcholinedepleting striatal lesions have been shown to disrupt appetitive, but spare aversive, learning (Kitabatake et al, 2003). Furthermore, both scopolamine (Sharf et al, 2006;Pratt and Kelley, 2004;Tikhonravov et al, 1997) and mecamylamine (Levin et al, 2000) tend to suppress foodreinforced lever pressing. Although such findings implicate both muscarinic and nicotinic receptors in instrumental performance, they provide little information about the nature of their contributions.…”

Section: Discussionmentioning

confidence: 99%

“…Drug doses and injection-to-test intervals are comparable to those used in previous studies (Anagnostaras et al, 1999;Levin et al, 2000;Mendez et al, 2012;Rodgers, 1979) and were selected to minimize nonspecific motor effects.…”

Section: Drugsmentioning

confidence: 99%

Differential Effects of Systemic Cholinergic Receptor Blockade on Pavlovian Incentive Motivation and Goal-Directed Action Selection

Ostlund¹,

Kosheleff²,

Maidment³

2013

Reward-seeking actions can be guided by external cues that signal reward availability. For instance, when confronted with a stimulus that signals sugar, rats will prefer an action that produces sugar over a second action that produces grain pellets. Action selection is also sensitive to changes in the incentive value of potential rewards. Thus, rats that have been prefed a large meal of sucrose will prefer a grain-seeking action to a sucrose-seeking action. The current study investigated the dependence of these different aspects of action selection on cholinergic transmission. Hungry rats were given differential training with two unique stimulus-outcome (S1-O1 and S2-O2) and action-outcome (A1-O1 and A2-O2) contingencies during separate training phases. Rats were then given a series of Pavlovian-toinstrumental transfer tests, an assay of cue-triggered responding. Before each test, rats were injected with scopolamine (0, 0.03, or 0.1 mg/kg, intraperitoneally), a muscarinic receptor antagonist, or mecamylamine (0, 0.75, or 2.25 mg/kg, intraperitoneally), a nicotinic receptor antagonist. Although the reward-paired cues were capable of biasing action selection when rats were tested off-drug, both anticholinergic treatments were effective in disrupting this effect. During a subsequent round of outcome devaluation testing-used to assess the sensitivity of action selection to a change in reward value-we found no effect of either scopolamine or mecamylamine. These results reveal that cholinergic signaling at both muscarinic and nicotinic receptors mediates action selection based on Pavlovian reward expectations, but is not critical for flexibly selecting actions using current reward values.

“…Levine et al (2011) recently observed that nicotine pretreatment increased cocaine locomotor sensitization and conditioned place preference (CPP) in mice. Similarly, the nonselective nicotinic antagonist mecamylamine decreased cocaine self-administration in rats (Levin et al, 2000;Blokhina et al, 2005) and reduced cue-induced cocaine craving in cocaine-dependent and cigarette smoking humans (Reid et al, 1998). In addition, dihydro-betaerythroidine (DHbE) (b2* nAChR antagonist), but not methyllycaconitine (a7* nAChR antagonist), microinjected into the VTA prevented cocaine locomotor sensitization (Champtiaux et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Differential Roles of α6β2* and α4β2* Neuronal Nicotinic Receptors in Nicotine- and Cocaine-Conditioned Reward in Mice

Sanjakdar

Maldoon

Marks

et al. 2014

Mesolimbic a6* nicotinic acetylcholine receptors (nAChRs) are thought to have an important role in nicotine behavioral effects. However, little is known about the role of the various a6*-nAChRs subtypes in the rewarding effects of nicotine. In this report, we investigated and compared the role of a6*-nAChRs subtypes and their neuro-anatomical locus in nicotine and cocaine reward-like effects in the conditioned place preference (CPP) paradigm, using pharmacological antagonism of a6b2* nAChRs and genetic deletion of the a6 or a4 subunits in mice. We found that a6 KO mice exhibited a rightward shift in the nicotine dose-response curve compared with WT littermates but that a4 KO failed to show nicotine preference, suggesting that a6a4b2*-nAChRs are involved. Furthermore, a6b2* nAChRs in nucleus accumbens were found to have an important role in nicotine-conditioned reward as the intra-accumbal injection of the selective a6b2* a-conotoxin MII [H9A; L15A], blocked nicotine CPP. In contrast to nicotine, a6 KO failed to condition to cocaine, but cocaine CPP in the a4 KO was preserved. Intriguingly, a-conotoxin MII [H9A; L15A], blocked cocaine conditioning in a4 KO mice, implicating a6b2* nAChRs in cocaine reward. Importantly, these effects did not generalize as a6 KO showed both a conditioned place aversion to lithium chloride as well as CPP to palatable food. Finally, dopamine uptake was not different between the a6 KO or WT mice. These data illustrate that the subjective rewarding effects of both nicotine and cocaine may be mediated by mesolimbic a6b2* nAChRs and that antagonists of these receptor subtypes may exhibit therapeutic potential.