Attenuation of Cocaine's Reinforcing and Discriminative Stimulus Effects via Muscarinic M₁ Acetylcholine Receptor Stimulation

Abstract

Muscarinic cholinergic receptors modulate dopaminergic function in brain pathways thought to mediate cocaine's abuse-related effects. Here, we sought to confirm and extend in the mouse species findings that nonselective muscarinic receptor antagonists can enhance cocaine's discriminative stimulus. More importantly, we tested the hypothesis that muscarinic receptor agonists with varied receptor subtype selectivity can blunt cocaine's discriminative stimulus and reinforcing effects; we hypothesized a critical role for the M 1 and/or M 4 receptor subtypes in this modulation. Mice were trained to discriminate cocaine from saline, or to self-administer intravenous cocaine chronically. The nonselective muscarinic antagonists scopolamine and methylscopolamine, the nonselective muscarinic agonists oxotremorine and pilocarpine, the M 1 /M 4 -preferring agonist xanomeline, the putative M 1 -selective agonist (4-hydroxy-2-butynyl)-1-trimethylammonium-3-chlorocarbanilate chloride (McN-A-343), and the novelwere tested as substitution and/or pretreatment to cocaine. Both muscarinic antagonists partially substituted for cocaine and enhanced its discriminative stimulus. Conversely, muscarinic agonists blunted cocaine discrimination and abolished cocaine self-administration with varying effects on food-maintained behavior. Specifically, increasing selectivity for the M 1 subtype (oxotremorine Ͻ xanomeline Ͻ TBPB) conferred lesser nonspecific rate-suppressing effects, with no rate suppression for TBPB. In mutant mice lacking M 1 and M 4 receptors, xanomeline failed to diminish cocaine discrimination while rate-decreasing effects were intact. Our data suggest that central M 1 receptor activation attenuates cocaine's abuse-related effects, whereas non-M 1 /M 4 receptors probably contribute to undesirable effects of muscarinic stimulation. These data provide the first demonstration of anticocaine effects of systemically applied, M 1 receptor agonists and suggest the possibility of a new approach to pharmacotherapy for cocaine addiction.Cocaine and other stimulant abuse is a considerable public health problem, for which no established pharmacotherapy is available. Mounting evidence suggests that cholinergic systems are implicated in abuse-related effects of cocaine and other abused drugs. The reinforcing effects of cocaine depend on dopamine systems that arise in the ventral tegmental area (VTA) and project to the nucleus accumbens (NAc; Roberts et al., 1980). Dopamine release in these pathways is regulated by cholinergic input through muscarinic receptors (Oakman et al., 1995;Blaha et al., 1996). In addition, muscarinic receptors within the striatum (including the NAc) colocalize with dopamine receptors and modulate neuronal responses to dopamine receptor activation. Specifically, M 4 and D 1 receptors exert directly opposing effects on cyclic AMP synthesis, whereas M 1 receptors oppose the effects of D 2 receptors (Di Chiara et al., 1994;Onali and Olianas, 2002). Systemic administration of muscarinic antagonists induces str...

Acetylcholine, Drug Reward and Substance Use Disorder Treatment: Intra- and Interindividual Striatal and Accumbal Neuron Ensemble Heterogeneity May Explain Apparent Discrepant Findings

“…on cue-or methamphetamine-induced reinstatement of responding for methamphetamine, an inhibitory effect that could be counteracted by systemic administration of the nicotinic blocker mecamylamine but not of the muscarinic blocker scopolamine [12]. Finally, the work of Grasing and colleagues is corroborated by Thomsen et al [13] who found that systemic M1-and/or M4-preferring muscarinic agonists flattened the cocaine i.v. FR1 selfadministration curve.…”

“…Similarly, in the experiments by Crespo et al [23], acquisition of an approach to food was not affected by unilateral intra-accumbens core blockade of nicotinic or muscarinic acetylcholine receptors, whereas an approach to drugs of abuse (cocaine, remifentanil, or morphine) was inhibited by local intra-accumbens muscarinic or nicotinic blockade [22], also arguing against a 'general memory-impairing' effect as the basis for the observed effects on drug reward. Interestingly, Thomsen et al [13] found that the more M1-and/or M4-preferring the antagonist was, the more selective its effect on the expression of responding for cocaine versus food under an FR1 schedule of reinforcement turned out to be.…”

Antipsychotic Drug-Like Effects of the Selective M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0152100

“…Interestingly, muscarinic agonist-induced reductions in accumbal and striatal DA release are absent in M 4 KO mice, suggesting that M 4 negatively regulates dopaminergic tone in these regions (Threlfell et al, 2010). M 4 KO mice also exhibit deficits in PPI and social interaction and enhanced dopamine D1 receptor-mediated effects on locomotor activity, which are recapitulated in D1-M 4 KO mice (Gomeza et al, 1999;Jeon et al, 2010;Koshimizu et al, 2012;Thomsen et al, 2010). Importantly, the APD-like effects of xanomeline are also abolished in both M 4 KO and D1-M 4 KO mice (Woolley et al, 2009;Dencker et al, 2011).…”

Effects of dopamine D1-like and D2-like antagonists on cocaine discrimination in muscarinic receptor knockout mice

“…Selective stimulation of M 1 or M 4 receptors attenuates cocaine’s discriminative stimulus (S D ) effects and reinforcing effects in rats and mice (Thomsen et al 2010a, 2012, 2014; Dencker et al 2012). Tests using the M 1 /M 4 -preferring agonist xanomeline in knockout mice lacking M 1 receptors (M 1 −/− ), M 4 receptors (M 4 −/− ), or both receptors, indicated that both subtypes are involved in blocking the S D effects of cocaine, while other receptors, likely M 3 , appear to mediate side effects observed with non-selective ligands (Thomsen et al 2010a, 2012).…”

“…Tests using the M 1 /M 4 -preferring agonist xanomeline in knockout mice lacking M 1 receptors (M 1 −/− ), M 4 receptors (M 4 −/− ), or both receptors, indicated that both subtypes are involved in blocking the S D effects of cocaine, while other receptors, likely M 3 , appear to mediate side effects observed with non-selective ligands (Thomsen et al 2010a, 2012). The mechanisms and neural pathways mediating these effects are still poorly understood, but likely involve striatal muscarinic receptors, based on brain region-specific injections using non-selective ligands or cholinergic neuron toxins (Hikida et al 2001; Smith et al 2004; Mark et al 2006).…”