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Effects of muscarinic M1 receptor stimulation on reinforcing and neurochemical effects of cocaine in rats

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Abstract

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 M1 receptor-selective agonist VU0364572 in adult male rats that self-administer cocaine in a cocaine vs. food 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 4 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 marked decreases in cocaine-induced dopamine and glutamate outflow 4 weeks after VU0364572 treatment, without significant changes in dopamine uptake function. These lasting and marked effects of M1 receptor stimulation reinforce our interest in this target as potential treatment of cocaine addiction. M1 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.

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Fig. 1: Experimental timelines.
Fig. 2: Cocaine self-administration behavior was markedly reduced 4 weeks after acute VU0364572 (1 mg/kg) administration.
Fig. 3: Behavior was gradually reallocated from cocaine taking towards the food reinforcer.
Fig. 4: VU0364572 treatment four weeks before testing prevented cocaine-induced increases in extracellular mPFC dopamine and NAc glutamate in cocaine-experienced rats.
Fig. 5: VU0364572 treatment had no effect on dopamine uptake in cocaine-naïve rats, and produced only a non-significant trend of decreased uptake in cocaine-experienced rats.

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Acknowledgements

We thank professors P. Jeffery Conn and Craig W. Lindsley (Vanderbilt University) for the gift of VU0364572 for these studies. We thank Christopher Adam, Benoît Niclou, Kevin Stoll (behavior), and Saiy Kiasari, Dr. Gitta Wörtwein, Anne-Marie Paulsen (microdialysis) for technical assistance. This research was supported by National Institutes of Health National Institute on Drug Abuse (NIH-NIDA) grant DA027825 (MT), Independent Research Fund Denmark grant 8020-00110B (MT), the Mental health services in the Capital Region of Denmark (Anders Fink-Jensen) and Research Foundation Mental Health Services in the Capital Region of Denmark (MT), and the Ivan Nielsen Foundation (MT). Sponsors had no role in study design, data interpretation, or the decision to publish.

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MT conceptualized the studies. MT, PW, and KLJ designed the experiments, analyzed the data, and interpreted the data. PW conducted the microdialysis studies, KLJ conducted the dopamine uptake experiments. MT directed the self-administration experiments. MT wrote the manuscript with assistance from KLJ and PW.

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Correspondence to Morgane Thomsen.

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Weikop, P., Jensen, K.L. & Thomsen, M. Effects of muscarinic M1 receptor stimulation on reinforcing and neurochemical effects of cocaine in rats. Neuropsychopharmacol. 45, 1994–2002 (2020). https://doi.org/10.1038/s41386-020-0684-1

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