Prenatal Hypoxia Affects Nicotine Consumption and Withdrawal in Adult Rats via Impairment of the Glutamate System in the Brain.

The role of damaging factors in the prenatal period as a basis for drug addiction in offspring is of great interest. In this study, we aim at deciphering the effects and possible mechanisms of prenatal severe hypoxia (PSH) on predisposition to nicotine addiction in adult rats. In PSH rats, we found an increasing tendency to nicotine consumption in the two-bottle choice test. After 2 weeks of chronic treatment with nicotine via osmotic minipump (9 mg/kg per day), we assessed the symptoms of withdrawal in the conditioned place aversion test after mecamylamine (an antagonist of nicotinic acetylcholine receptors, nAChR) treatment. We showed that the mecamylamine-precipitated withdrawal aversion was stronger in the PSH group than in the control group. This suggests that PSH acts as a predisposing factor for developing nicotine addiction in adulthood. PSH rats also demonstrated an increased level of phosphorylated DARPP-32 protein (known as the relay for dopamine and glutamate signaling) at 34 threonine (pThr34DARPP-32) in relation to its total amount in the nucleus accumbens of the striatum (NAc). Meanwhile, no changes in both the content of dopamine in the mesolimbic pathway and the first type of dopamine receptors (DAR1) in NAc were found. The increased rate of DARPP-32 phosphorylation in adult PSH rats might result from excessive glutamatergic stimulation of the dopaminergic (DA) neurons of the ventral tegmental area (VTA) caused by activation of presynaptic nAChR by nicotine. This hypothesis is supported by the observed increase in VGluT2-positive terminals to Nurr1-positive neuronal bodies in VTA in PSH animals. Thus, the altered glutamate signaling phenotype might play a significant role in the development of PSH-related nicotine addiction.