Neuropeptide Y Y5 Receptor Antagonism Attenuates Cocaine-Induced Effects in Mice

Gunnar Sørensen, Morten Jensen, Pia Weikop, Ditte Dencker, Søren H Christiansen, Claus Juul Loland, Cecilie Hee Bengtsen, Jørgen Holm Petersen, Anders Fink-Jensen, Gitta Wörtwein, David P D Woldbye

Psychopharmacology (Berl). 2012 Aug;222(4):565-77.

PMID: 22367168

Abstract:

Rationale:




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.













Objectives:




To explore the potential role of Y5 NPY receptors in cocaine-induced behavioural effects.













Methods:




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.













Results:




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.













Conclusions:




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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP6508436	L-152,804		6508-43-6	Price