The Neuropeptide Y System: a Role in Alcohol Withdrawal Kindling

Abstract

Repeated episodes of alcohol withdrawal during long-term alcohol abuse results in a progressive and irreversible intensification of the withdrawal reaction, a concept known as alcohol withdrawal kindling. This paradigm is a model for a severe withdrawal reaction, delirium tremens and seizures, and also for the cognitive and emotional impairments, that can lead to further alcohol craving and addiction.

The alcohol withdrawal reaction is associated with neuronal hyperexcitability. The neurotransmitter neuropeptide Y (NPY) plays an important role in regulating neuronal excitability, via its receptors Y1, Y2, and Y5. It has been demonstrated that neuroadaptational changes occur in the NPY-system after chronic alcohol intoxication and withdrawal.

In the present study the NPY system was investigated in the rat brain after alcohol withdrawal kindling using a well-validated model of alcohol dependence. Kindling was induced by multiple episodes of two days of intoxication separated by five days of withdrawal. During the alcohol intoxication phase repeated intragastric infusions of a 20% ethanol solution was administrated. The NPY-system was examined during several phases of the withdrawal reaction, measuring gene expression of NPY and its receptors in hippocampal and cortical areas using in situ hybridization.

The results show that alcohol withdrawal kindling induces complex plastic changes in the NPY system, with decreased and increased gene expression occurring in a time- and region-specific manner. These changes may play an important role in mediating changes in neuronal excitability during kindling, leading to physical and convulsive withdrawal symptoms and relapse to alcohol addiction.