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Effects of muscarinic receptor antagonists on cocaine discrimination in wild-type mice and in muscarinic receptor M1, M2, and M4 receptor knockout mice

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@article{31e86b77d41042e48b4450f5f4c2a418,
title = "Effects of muscarinic receptor antagonists on cocaine discrimination in wild-type mice and in muscarinic receptor M1, M2, and M4 receptor knockout mice",
abstract = "Muscarinic M1/M4 receptor 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 10mg/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.",
keywords = "Journal Article",
author = "Lauren Joseph and Morgane Thomsen",
note = "Copyright {\circledC} 2017 Elsevier B.V. All rights reserved.",
year = "2017",
month = "6",
day = "30",
doi = "10.1016/j.bbr.2017.04.023",
language = "English",
volume = "329",
pages = "75--83",
journal = "Behavioural Brain Research",
issn = "0166-4328",
publisher = "Elsevier BV",

}

RIS

TY - JOUR

T1 - Effects of muscarinic receptor antagonists on cocaine discrimination in wild-type mice and in muscarinic receptor M1, M2, and M4 receptor knockout mice

AU - Joseph, Lauren

AU - Thomsen, Morgane

N1 - Copyright © 2017 Elsevier B.V. All rights reserved.

PY - 2017/6/30

Y1 - 2017/6/30

N2 - Muscarinic M1/M4 receptor 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 10mg/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.

AB - Muscarinic M1/M4 receptor 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 10mg/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.

KW - Journal Article

U2 - 10.1016/j.bbr.2017.04.023

DO - 10.1016/j.bbr.2017.04.023

M3 - Journal article

VL - 329

SP - 75

EP - 83

JO - Behavioural Brain Research

JF - Behavioural Brain Research

SN - 0166-4328

ER -

ID: 52616185