Tolerance to ethanol sedation and withdrawal hyper-excitability is mediated via neuropeptide Y Y1 and Y5 receptors

Aims: Neuropeptide Y (NPY) is widely distributed throughout the brain and has been implicated in some of the actions of ethanol. The aim of the present study was to characterize the subtypes of NPY receptors in ethanol induced sedation, tolerance and withdrawal hyper-excitability. Main methods: The loss of righting reflex paradigm was used to record the sleep duration in mice. Key findings: The acute administration of ethanol (3-4 g per kg, i.p., 20%v/v) resulted in marked sedation. While prolonged ethanol consumption led to the development of tolerance, the mice showed hyperexcitability following ethanol withdrawal. Prior acute intracerebroventricular (i.c.v.) injection of NPY (5-20 ng per mouse) or NPY Y1 and Y5 receptors agonist [Leu(31), Pro(34)]-NPY (0.02-0.2 ng per mouse) potentiated ethanol induced sedation. On the other hand, administration of selective NPY Y1 receptor antagonist BIBP3226 (5 ng per mouse, i.c.v.) inhibited ethanol induced sedation. Chronic concomitant treatment of NPY (20 ng per mouse, i.c.v.) or [Leu(31), Pro(34)]-NPY (0.2 ng per mouse, i.c.v.) to ethanol-fed groups prevented the development of tolerance and attenuated withdrawal hyper-excitability. Moreover, acute treatment of NPY (5 ng per mouse, i.c.v.) or [Leu(31), Pro(34)]-NPY (0.02 ng per mouse, i.c.v.) reversed the peak ethanol withdrawal hyper-excitability. Significance: The results underscore a role for NPY Y1 and Y5 receptors in the ethanol induced sedation, tolerance and withdrawal hyper-excitability. We suggest that modulation of NPY Y1 and Y5 receptors may be a strategy to address the ethanol withdrawal conditions. (C) 2009 Elsevier Inc. All rights reserved.