Reduced Cocaine Self-Administration in Muscarinic M₅Acetylcholine Receptor-Deficient Mice

Abstract

The reinforcing effects of cocaine have been related to increased extracellular concentrations of dopamine in the ventral striatum. Several studies suggest that M 5 muscarinic receptors facilitate striatal dopamine release. We tested the hypothesis that the reinforcing effects of cocaine are decreased in M 5 receptor-deficient mice using chronic intravenous cocaine self-administration in extensively backcrossed mice. We also assessed whether operant performance generally, rather than cocaine self-administration specifically, was altered in the mutant mice. To this end, we evaluated both food-maintained operant behavior and cocaine self-administration under a fixed ratio 1 and a progressive ratio (PR) schedule of reinforcement. We also evaluated acquisition of self-administration in experimentally naive mice using several doses of cocaine. M 5 receptor deletion decreased self-administration of low to moderate doses of cocaine under a PR schedule of reinforcement and diminished acquisition of self-administration of a low dose in experimentally naive mice. We found no differences between genotypes in food-maintained behavior. The present study extends our previous findings using backcrossed mice and covering various experimental conditions. Our results indicate that M 5 receptor deletion diminished the reinforcing effects of low doses of cocaine and identified specific conditions under which this may be observed.

The Role of Acetylcholine in Cocaine Addiction

“…In FR models, animals increase their rate of self-administration as the unit dose of a drug is decreased (to compensate for decreases in the unit dose) and reduce responding as the unit dose is increased (Arnold and Roberts, 1997;Koob, 2000). Progressive ratio schedules are used to evaluate the reinforcing efficacy of a selfadministered drug by increasing the response requirements for each successive reinforcement and determining the (Ikemoto and Wise, 2002;Redgrave and Horrell, 1976) Rewarding effect of cocaine mediated through M 5 receptors (Fink-Jensen et al, 2003;Thomsen et al, 2005;Yeomans and Baptista, 1997;Yeomans et al, 2001) Striatum Striatal ACh increase associated with reward, possibly satiation (Imperato et al, 1993a, b;Mark et al, 1992;Pratt and Kelley, 2004;Zocchi and Pert, 1994).…”

“…M 5 receptor-deficient (M 5 À/À ) rats lack sustained NAc DA release following electrical stimulation of VTA cholinergic input (Forster et al, 2002), and striatal DA release induced by oxotremorine is significantly reduced in these M 5 receptor-knockout mice (Zhang et al, 2002). The absence of M 5 receptors on the VTA likely accounts for the lower rate of cocaine self-administration in M 5 À/À rodents (Fink-Jensen et al, 2003; Thomsen et al, 2005). Although a 4-6 b 2 and a 4-5 b 2 nAChRs have been identified on VTA DANs (Klink et al, 2001), VTA mACh receptors appear to play a more prominent role in maintaining reward relative to nAChRs.…”

“…Treatment trials of rivastigmine in the treatment of cocaine addiction are ongoing. The relevance of the M 5 receptor in cocaine reinforcement (Fink-Jensen et al, 2003;Thomsen et al, 2005) suggests that targeting this muscarinic subtype may be of particular importance.…”

A Differential Role for the Adenosine A2A Receptor in Opiate Reinforcement vs Opiate-Seeking Behavior

“…This reflects the motivation of an animal to self-administer a given drug and may therefore provide more accurate data pertaining to the reinforcing efficacy of that drug (Arnold and Roberts, 1997). The PR protocol utilized was modified from Thomsen et al, 2005, with 0.1 mg/kg morphine delivered per infusion. The breakpoint was defined as the last completed ratio, after which a period of 60 min ensued where no reinforcer was earned.…”

Altered Neural Cholinergic Receptor Systems in Cocaine-Addicted Subjects

“…Of equal interest, however, is the impact of the mACh receptor on cocaine-induced reward and administration. The rewarding effects of cocaine are mediated by M 5 receptors in the ventral tegmentum (Fink-Jensen et al, 2003;Thomsen et al, 2005;Yeomans et al, 2001) and M 5 -deficient rats show an attenuation of cocaine-induced conditioned place preference (Fink-Jensen et al, 2003). Several investigators have observed alterations in striatal mACh receptors after chronic cocaine administration (Lipton et al, 1995;Macedo et al, 2004).…”