期刊
NEUROPSYCHOPHARMACOLOGY
卷 45, 期 12, 页码 1994-2002出版社
SPRINGERNATURE
DOI: 10.1038/s41386-020-0684-1
关键词
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资金
- National Institutes of Health National Institute on Drug Abuse (NIH-NIDA) [DA027825]
- Independent Research Fund Denmark [8020-00110B]
- Mental health services in the Capital Region of Denmark
- Research Foundation Mental Health Services in the Capital Region of Denmark
- Ivan Nielsen Foundation
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-1 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 M-1 receptor stimulation reinforce our interest in this target as potential treatment of cocaine addiction. M-1 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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