Title : Attenuation of cocaine ’ s reinforcing and discriminative stimulus effects via muscarinic M 1 acetylcholine receptor stimulation
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چکیده
Muscarinic cholinergic receptors modulate dopaminergic function in brain pathways thought to mediate cocaine’s abuse-related effects. Here we sought to confirm and extend in the mouse species findings that nonselective muscarinic receptor antagonists can enhance cocaine’s discriminative stimulus. More importantly, we tested the hypothesis that muscarinic receptor agonists with varied receptor subtype selectivity can blunt cocaine’s discriminative stimulus and reinforcing effects; we hypothesized a critical role for the M1 and/or M4 receptor subtypes in this modulation. Mice were trained to discriminate cocaine from saline, or to self-administer intravenous cocaine chronically. The non-selective muscarinic antagonists scopolamine and methylscopolamine, the non-selective muscarinic agonists oxotremorine and pilocarpine, the M1/M4-preferring agonist xanomeline, the putative M1-selective agonist McN-A-343, and the novel M1-selective agonist TBPB were tested as substitution and/or pretreatment to cocaine. Both muscarinic antagonists partially substituted for cocaine and enhanced its discriminative stimulus. Conversely, muscarinic agonists blunted cocaine discrimination and abolished cocaine self-administration with varying effects on food-maintained behavior. Specifically, increasing selectivity for the M1 subtype (oxotremorine < xanomeline < TBPB) conferred lesser nonspecific rate-suppressing effects, with no rate suppression for TBPB. In mutant mice lacking M1 and M4 receptors, xanomeline failed to diminish cocaine discrimination while rate-decreasing effects were intact. Our data suggest that central M1 receptor activation attenuates cocaine’s abuse-related effects, while non-M1/M4 receptors likely contribute to undesirable effects of muscarinic stimulation. These data provide the first demonstration of anti-cocaine effects of systemically applied, M1 receptor agonists and suggest the possibility of a new approach to pharmacotherapy for cocaine addiction. This article has not been copyedited and formatted. The final version may differ from this version. JPET Fast Forward. Published on December 8, 2009 as DOI: 10.1124/jpet.109.162057 at A PE T Jornals on A ril 5, 2017 jpet.asjournals.org D ow nladed from
منابع مشابه
Attenuation of cocaine's reinforcing and discriminative stimulus effects via muscarinic M1 acetylcholine receptor stimulation.
Muscarinic cholinergic receptors modulate dopaminergic function in brain pathways thought to mediate cocaine's abuse-related effects. Here, we sought to confirm and extend in the mouse species findings that nonselective muscarinic receptor antagonists can enhance cocaine's discriminative stimulus. More importantly, we tested the hypothesis that muscarinic receptor agonists with varied receptor ...
متن کاملTitle : Attenuation of cocaine ’ s reinforcing and discriminative stimulus
Muscarinic cholinergic receptors modulate dopaminergic function in brain pathways thought to mediate cocaine’s abuse-related effects. Here we sought to confirm and extend in the mouse species findings that nonselective muscarinic receptor antagonists can enhance cocaine’s discriminative stimulus. More importantly, we tested the hypothesis that muscarinic receptor agonists with varied receptor s...
متن کاملMicrosoft Word - 39700264-file00
Muscarinic cholinergic receptors modulate dopaminergic function in brain pathways thought to mediate cocaine’s abuse-related effects. Here we sought to confirm and extend in the mouse species findings that nonselective muscarinic receptor antagonists can enhance cocaine’s discriminative stimulus. More importantly, we tested the hypothesis that muscarinic receptor agonists with varied receptor s...
متن کاملJPET Fast
Muscarinic cholinergic receptors modulate dopaminergic function in brain pathways thought to mediate cocaine’s abuse-related effects. Here we sought to confirm and extend in the mouse species findings that nonselective muscarinic receptor antagonists can enhance cocaine’s discriminative stimulus. More importantly, we tested the hypothesis that muscarinic receptor agonists with varied receptor s...
متن کاملReduced cocaine self-administration in muscarinic M5 acetylcholine receptor-deficient mice.
The reinforcing effects of cocaine have been related to increased extracellular concentrations of dopamine in the ventral striatum. Several studies suggest that M5 muscarinic receptors facilitate striatal dopamine release. We tested the hypothesis that the reinforcing effects of cocaine are decreased in M5 receptor-deficient mice using chronic intravenous cocaine self-administration in extensiv...
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تاریخ انتشار 2009