Neuropeptide Y Y5 receptor antagonism attenuates cocaine-induced effects in mice

被引:27
|
作者
Sorensen, Gunnar [3 ,5 ]
Jensen, Morten [2 ,4 ]
Weikop, Pia [3 ]
Dencker, Ditte [3 ]
Christiansen, Soren H. [1 ,2 ]
Loland, Claus Juul [5 ]
Bengtsen, Cecilie Hee [3 ]
Petersen, Jorgen Holm [6 ]
Fink-Jensen, Anders [3 ]
Wortwein, Gitta [3 ]
Woldbye, David P. D. [1 ,2 ]
机构
[1] Univ Copenhagen, Dept Neurosci & Pharmacol, Prot Lab, DK-2200 Copenhagen, Denmark
[2] Univ Copenhagen, Dept Neurosci & Pharmacol, Lab Neuropsychiat, DK-2200 Copenhagen, Denmark
[3] Univ Copenhagen, Psychiat Ctr Copenhagen, Lab Neuropsychiat, DK-2200 Copenhagen, Denmark
[4] Univ Copenhagen, Dept Neurosci & Pharmacol, Mol Pharmacol Lab, DK-2200 Copenhagen, Denmark
[5] Univ Copenhagen, Dept Neurosci & Pharmacol, Mol Neuropharmacol Lab, DK-2200 Copenhagen, Denmark
[6] Univ Copenhagen, Dept Biostat, DK-2200 Copenhagen, Denmark
关键词
Neuropeptide Y; Cocaine; Reinforcement; Drug abuse; Microdialysis; Behaviour; MUSCARINIC ACETYLCHOLINE-RECEPTORS; RAT NUCLEUS-ACCUMBENS; BRAIN; DOPAMINE; ADDICTION; STRIATUM; IMMUNOREACTIVITY; OVEREXPRESSION; PARAMETERS; SEIZURES;
D O I
10.1007/s00213-012-2651-y
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Several studies suggest a role for neuropeptide Y (NPY) in addiction to drugs of abuse, including cocaine. However, the NPY receptors mediating addiction-related effects remain to be determined. To explore the potential role of Y5 NPY receptors in cocaine-induced behavioural effects. The Y5 antagonist L-152,804 and Y5-knockout (Y5-KO) mice were tested in two models of cocaine addiction-related behaviour: acute self-administration and cocaine-induced hyperactivity. We also studied effects of Y5 receptor antagonism on cocaine-induced c-fos expression and extracellular dopamine with microdialysis as well as dopamine transporter-mediated uptake of dopamine in vitro. Immunocytochemistry was used to determine whether dopamine neurons express Y5-like immunoreactivity. In self-administration, L-152,804 prominently decreased nose-poking for the peak dose of cocaine and shifted the dose-response curve for cocaine downward. Y5-KO mice also showed modestly attenuated self-administration. Cocaine-induced hyperactivity was attenuated by L-152,804 and in Y5-KO mice. Cocaine failed to increase c-fos expression in the nucleus accumbens and striatum of L-152,804-treated mice, indicating that the Y5 antagonist could act by influencing neural activity in these regions. Accordingly, the cocaine-induced increase in accumbal extracellular dopamine was attenuated by L-152,804 and in Y5-KO mice, suggesting that Y5 antagonism influences cocaine-induced behaviour by regulating dopamine. Consistent with this concept, dopamine neurons in the ventral tegmental area appeared to contain Y5 receptors. In contrast, neither L-152,804 nor NPY influenced dopamine transporter-mediated dopamine uptake. The present data indicate that Y5 antagonism may attenuate cocaine-induced behavioural effects, suggesting that Y5 receptors could be a potential therapeutic target in cocaine addiction.
引用
收藏
页码:565 / 577
页数:13
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