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

• Published in: Psychopharmacologia Vol. 222; no. 4; pp. 565 - 577
• Main Authors: Sørensen, Gunnar, Jensen, Morten, Weikop, Pia, Dencker, Ditte, Christiansen, Søren H., Loland, Claus Juul, Bengtsen, Cecilie Hee, Petersen, Jørgen Holm, Fink-Jensen, Anders, Wörtwein, Gitta, Woldbye, David P. D.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.08.2012; Springer; Springer Nature B.V
• Subjects: Addictive behaviors; Adult and adolescent clinical studies; Analysis; Animals; Animals, Outbred Strains; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; c-Fos protein; Cocaine; Cocaine - administration & dosage; Cocaine - antagonists & inhibitors; Cocaine - pharmacology; Cocaine-Related Disorders - drug therapy; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Cyclohexanes - pharmacology; Cyclohexanes - therapeutic use; Data processing; Disease Models, Animal; Dopamine; Dopamine - metabolism; Dopamine Plasma Membrane Transport Proteins - metabolism; Dopamine transporter; Dose-Response Relationship, Drug; Drug abuse; Drug addiction; Drug development; Drug Interactions; Drug self-administration; Female; Hyperactivity; Hyperkinesis - chemically induced; Hyperkinesis - drug therapy; Immunocytochemistry; Immunoreactivity; Male; Medical sciences; Mice; Mice, Knockout; Microdialysis; Neostriatum; Neurobiology; Neurons; Neuropeptide Y; Neuropharmacology; Neurosciences; Nucleus accumbens; Nucleus Accumbens - drug effects; Nucleus Accumbens - metabolism; Original Investigation; Peptides; Pharmacology. Drug treatments; Pharmacology/Toxicology; Psychiatry; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychopharmacology; Receptors, Neuropeptide Y - antagonists & inhibitors; Receptors, Neuropeptide Y - genetics; Reinforcement (Psychology); Rodents; Self Administration; Ventral tegmentum; Xanthenes - pharmacology; Xanthenes - therapeutic use; Denmark; Neuropeptide Y; Reinforcement; Drug abuse; Cocaine; Microdialysis; Behaviour; Drug addiction; CNS stimulant; Psychotropic; Peptide hormone; Rodentia; Substance abuse; Y5 neuropeptide Y receptor; Ester; Vertebrata; Mammalia; Mouse; Animal; Drug of abuse; Behavior
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-012-2651-y

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.