Effects of muscarinic receptor antagonists on cocaine discrimination in wild-type mice and in muscarinic receptor M 1 , M 2 , and M 4 receptor knockout mice

Abstract

Muscarinic M1/M4 stimulation can reduce abuse-related effects of cocaine and may represent avenues for treating cocaine addiction. Muscarinic antagonists can mimic and enhance effects of cocaine, including discriminative stimulus (SD) effects, but the receptor subtypes mediating those effects are not known. A better understanding of the complex cocaine/muscarinic interactions is needed to evaluate and develop potential muscarinic-based medications. Here, knockout mice lacking M1, M2, or M4 receptors (M1-/-, M2-/-, M4-/-), as well as control wild-type mice and outbred Swiss-Webster mice, were trained to discriminate 10 mg/kg cocaine from saline. Muscarinic receptor antagonists with no subtype selectivity (scopolamine), or preferential affinity at the M1, M2, or M4 subtype (telenzepine, trihexyphenidyl; methoctramine, AQ-RA 741; tropicamide) were tested alone and in combination with cocaine. In intact animals, antagonists with high affinity at M1/M4 receptors partially substituted for cocaine and increased the SD effect of cocaine, while M2-preferring antagonists did not substitute, and reduced the SD effect of cocaine. The cocaine-like effects of scopolamine were absent in M1-/- mice. The cocaine SD attenuating effects of methoctramine were absent in M2-/- mice and almost absent in M1-/- mice. The findings indicate that the cocaine-like SD effects of muscarinic antagonists are primarily mediated through M1 receptors, with a minor contribution of M4 receptors. The data also support our previous findings that stimulation of M1 receptors and M4 receptors can each attenuate the SD effect of cocaine, and show that this can also be achieved by blocking M2 autoreceptors, likely via increased acetylcholine release.

G protein-coupled receptor heteromers are key players in substance use disorder

“…Co-immunoprecipitation from rat cortical membrane of GABA B2 subunit together with the muscarinic M 2 receptor confirmed in vivo proximity (Boyer et al, 2009) and suggested that the heteromer may play a role in drug addiction by modulating the endogenous acetylcholine tone at presynaptic level. A possible outcome would be a contribution of these heteromers to the discriminative stimulus properties of cocaine (Joseph and Thomsen, 2017).…”

Inhibition of basal and amphetamine-stimulated extracellular signal-regulated kinase (ERK) phosphorylation in the rat forebrain by muscarinic acetylcholine M4 receptors

“…This agent was also 4–10 times more potent than the widely used M1 antagonist pirenzepine (Eltze et al, 1985). Thus, telenzepine is being frequently used to clarify the functional role of M1 receptors in vivo (Tanda et al, 2007; Ztaou et al, 2016; Joseph and Thomsen, 2017). Indeed, an i.p.…”

“…We first evaluated the role of striatal M1 and M4 receptors. A systemically active antagonist with moderate subtype selectivity for M1 receptors, telenzepine (Doods et al, 1987; Tanda et al, 2007; Ztaou et al, 2016; Joseph and Thomsen, 2017), or M4 receptors, tropicamide (Lazareno et al, 1990; Ztaou et al, 2016), was injected to adult rats. Their effects on ERK phosphorylation were examined in the two subdivisions of the striatum, the caudate putamen (CPu) and nucleus accumbens (NAc).…”

Severe Hypoglycemia–Induced Fatal Cardiac Arrhythmias Are Mediated by the Parasympathetic Nervous System in Rats

“…At 1 week after surgery, all rats underwent a severe hypoglycemic clamp as described above. [18,19]; n 5 13).…”