Role for M₅ muscarinic acetylcholine receptors in cocaine addiction

Abstract

Muscarinic cholinergic receptors of the M5 subtype are expressed by dopamine-containing neurons of the ventral tegmentum. These M5 receptors modulate the activity of midbrain dopaminergic neurons, which play an important role in mediating reinforcing properties of abused psychostimulants like cocaine. The potential role of M5 receptors in the reinforcing effects of cocaine was investigated using M5 receptor-deficient mice in a model of acute cocaine self-administration. The M5-deficient mice self-administered cocaine at a significantly lower rate than wild-type controls. In the conditioned place preference procedure, a classic test for evaluating the rewarding properties of drugs, M5-deficient mice spent significantly less time in the cocaine-paired compartment than control mice. Moreover, the severity of the cocaine withdrawal syndrome (withdrawal-associated anxiety measured in the elevated plus-maze) was significantly attenuated in mice lacking the M5 receptor. These results demonstrate that M5 receptors play an important role in mediating both cocaine-associated reinforcement and withdrawal.

The Role of Acetylcholine in Cocaine Addiction

“…Conversely, lesions of the pedunculopontine nucleus (a source of ACh to the VTA) inhibit the development of CPP to morphine and amphetamine (Bechara and van der Kooy, 1989;Olmstead and Franklin, 1993). M 5 À/À rodents also spend less time in a cocaine-paired compartment during a CPP procedure compared to wild-type rodents (Fink-Jensen et al, 2003). Consistent with the positive association of VTA ACh with reward, increasing both muscarinic and nicotinic cholinergic VTA activity appears to heighten CPP to drugs of abuse.…”

“…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).…”

“…Striatal ACh increase associated with cocaine acquisition Crespo et al, 2006;Mark et al, 1999) Striatal ACh alters cocaine-induced locomotor sensitization Hikida et al, 2001Hikida et al, , 2003 mACh receptors decrease after chronic cocaine (Lipton et al, 1995;Macedo et al, 2004;Wilson et al, 1994;Zeigler et al, 1991) Amygdala mAChR may facilitate acquisition of associative learning underlying context-dependent sensitization Itzhak and Martin, 2000) Explicit memory Hippocampus ACh involved in the encoding of new information (Hasselmo and Fehlau, 2001;Hasselmo et al, 2002) Hippocampal ACh increases following cocaine use (Imperato et al, 1993a(Imperato et al, , b, 1996Smith et al, 2004a, b) Conditioned learning VTA VTA ACh involved in conditioned learning (Bechara and van der Kooy, 1989;Museo and Wise, 1994;Olmstead and Franklin, 1993) M 5 -deficient rats decrease cocaine-induced CPP (Fink-Jensen et al, 2003) Striatum Striatal ACh involved in conditioned learning (Legault et al, 2006) NAc ACh inhibits cocaine-induced CPP (Hikida et al, 2001 ACh antagonist blocks induction of locomotor sensitization to cocaine-induced CPP (Itzhak and Martin, 2000) Amygdala Amygdalar ACh facilitates conditioned learning (McIntyre et al, 1998;Power et al, 2003) Amygdalar ACh alters cocaine-induced conditioned learning (See et al, 2003;Zeigler et al, 1991) Attention PFC Elevated ACh may focus attentional resources toward salient stimuli (Baxter and Chiba, 1999;Robbins, 2002;Sarter et al, 2003) Cocaine-addicted subjects show impaired attention (Horner et al, 1996;Jovanovski et al, 2005) Set shifting PFC ACh involved in set shifting (Ragozzino and Choi...…”

“…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.…”

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).…”