Effects of muscarinic M₁receptor stimulation on reinforcing and neurochemical effects of cocaine in rats

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>Cocaine addiction is a chronic illness characterized by maladaptive drug-induced neuroplastic changes that confer lasting vulnerability to relapse. Over several weeks we observed the effects of the M<jats:sub>1</jats:sub> receptor-selective agonist VU0364572 in adult male rats that self-administer cocaine in a cocaine vs. natural reinforcer choice procedure. The drug showed unusual long-lasting effects, as rats gradually stopped self-administering cocaine, reallocating behavior towards the food reinforcer. The effect lasted as long as tested and at least four weeks. To begin to elucidate how VU0364572 modulates cocaine self-administration, we then examined its long-term effects using dual-probe in vivo dopamine and glutamate microdialysis in nucleus accumbens and medial prefrontal cortex, and ex vivo striatal dopamine reuptake. Microdialysis revealed dramatic decreases in cocaine-induced dopamine and glutamate outflow four weeks after VU0364572 treatment, without significant changes in dopamine uptake function. These lasting and dramatic effects of M<jats:sub>1</jats:sub> receptor stimulation reinforce our interest in this target as potential treatment of cocaine addiction. M<jats:sub>1</jats:sub> receptors are known to modulate medium spiny neuron responses to corticostriatal glutamatergic signaling acutely, and we hypothesize that VU0364572 may oppose the addiction-related effects of cocaine by causing lasting changes in this system.</jats:p>

Effects of acute and repeated administration of the selective M4 PAM VU0152099 on cocaine versus food choice in male rats

“…This result stands in contrast to our previously reported findings with M 1 partial agonist treatment, which produced delayed and long-lasting (weeks) suppression of cocaine choice in this assay. 21 Xanomeline exhibited a similar but much briefer 'post-treatment effect', 20 and rats treated with the AChEI tacrine or donepezil were found to decrease cocaine self-administration for several days after treatment ended. 3,5 Taken together with the results presented here, these findings suggest that the prolonged effects are attributable to action at M 1 receptors, but not to M 4 receptors.…”

“…20 Moreover, in the same assay protocol, acute administration of an allosteric M 1 receptor-selective partial agonist produced decreases in cocaine taking for several weeks after administration. 21 Postadministration, lasting effects were also seen in an extinction and reinstatement procedure in mice in which combined stimulation of M 1 and M 4 receptors facilitated extinction of cocaine seeking, by either xanomeline or a combination of the allosteric M 1 partial agonist VU0357017 and the M 4 PAM VU0152100, whereas neither VU0357017 nor VU0152100 alone had much effect. 22 On the other hand, M 4 PAMs alone, as acute dosing, can reduce cocaine selfadministration and diminish the discriminative stimulus effect of cocaine in mice.…”

M1 muscarinic receptor activation decreases alcohol consumption via a reduction in consummatory behavior

“…This result differs from recent findings using the M 1 agonist, VU0364572, which induced a prolonged reduction in cocaine choice over food for up to 4 weeks, accompanied by reductions in dopamine and glutamate outflow after administration. 28 The transient actions of PF-06767832 (PAM-agonist), compared with VU0364572 (bitopic agonist) may be driven by differences that exist between studies (e.g., rodent strain, drug class, and experimental paradigm). Indeed, experimental procedures employed would elicit differential cognitive requirements on the animals.…”

“…The role of M 1 mAChRs in fixed ratio alcohol self-administration Next, given the recent evidence that M 1 receptor enhancement reduces cocaine choice in male rats, 28 we assessed whether enhancing M 1 receptor activity reduced operant self-administration for alcohol in a separate cohort of rats (n = 16). Rats first underwent 9-12 24-h sessions of intermittent alcohol consumption in the home cage.…”

“…24 A recent study using a bitopic M 1 mAChR agonist, VU0364572, 27 showed acute systemic administration in rats reduced cocaine choice over food for a sustained period (up to 4 weeks). 28 However, whether this action is driven by cognitive or reward processes, generalizes across drug classes, or is mediated through positive allosteric modulation of ACh signaling is unknown. Another compound, PF-06767832, was developed as a selective M 1 compound, which shows both agonist and positive allosteric actions, classifying this compound as a PAM-agonist.…”