Nicotine Stimulation on Extracellular Glutamate Levels in the Nucleus Accumbens of Ethanol-withdrawn Rats In Vivo

Abstract

Nicotine can release glutamate in the limbic system. Presynaptic activation of glutamate receptors might be relevant for the subsequent firing of excitatory postsynaptic potentials. This might be relevant in early ethanol withdrawal. The effects and differences of nicotine stimulation on glutamate response measured by microdialysis in the nucleus accumbens (NAC) between ethanol-withdrawn rats (EW group) and ethanol-naïve rats (control group) were investigated. Rats were ethanol-intoxicated according to a binge-drinking model: recurrent cycle of 4 days of intoxication (EW group) or 5% sucrose (control group), followed by a 3-day recovery. This was followed by a 2-day intoxication period and subsequent abstinence. After the last oral intake, microdialysis was performed in the left NAC for a 16-hour withdrawal period. At the end of the withdrawal period, a rated withdrawal score (RWS) was documented. Then, nicotine was given subcutaneously at a dose of 0.5 mg/kg and amino acid levels determined by microdialysis were followed for an additional 3 hours. The RWS was not correlated to the last amount of ethanol received, but was correlated to the total amount of ethanol administered during the pretreatment period: the basal values of extracellular glutamate were found to be decreased in the EW group before withdrawal. Cessation of ethanol significantly increased glutamate levels with a peak between 4 and 10 hours after the last oral intake. Sixteen hours after ethanol withdrawal, the same level as in the control group was achieved. Nicotine significantly increased glutamate levels in the NAC of the EW group but not in ethanol-naïve rats. This study showed that withdrawal of ethanol was associated with an increase in extracellular glutamate levels. Systemic administration of nicotine in vivo produced an increase in extracellular levels of glutamate in the core region of the NAC during ethanol withdrawal. This might be a relevant pathomechanism for increased craving either for alcohol or for nicotine after ethanol withdrawal.