GLUCOCORTICOID-DEPENDENT MECHANISMS OF NICOTINE ADDICTION PREDISPOSITION FOLLOWING PRENATAL HYPOXIC EXPOSURE

The role of prenatal hypoxia in disrupting limbic system development and predisposing offspring to drug addiction is known, but the specific mechanisms remain unclear. This study aimed to differentiate the role of hypoxia and glucocorticoid stress during pregnancy in the development of a predisposition to nicotine addiction in offspring. Two models were used: prenatal intrauterine ischemia (PII) and prenatal severe hypoxia (PSH). The study was performed on embryos, neonates, and adult rats that had experienced PSH or PII. We assessed the effects of PSH and PII on HIF1α expression, HIF1α-dependent metabolism, acetylcholine metabolism, acetylcholine receptor expression in the brain, and glucocorticoid system activity. Behavioral tests assessed nicotine addiction susceptibility and withdrawal severity in adulthood.
Both PSH and PII induced stable HIF1α-dependent metabolic changes in the brain but did not affect acetylcholine metabolism. However, PSH (but not PII) in adulthood causes a decrease in glucocorticoid receptor expression and glucocorticoid-dependent transcription, including α7 subunit nicotinic acetylcholine receptors (α7nAChR) in cells of the prefrontal cortex and hippocampus and their terminals to the nucleus accumbens, without altering dopaminergic innervation, which is accompanied by a predisposition to nicotine addiction. The results of this study suggest that the maternal glucocorticoid stress response to hypoxia causes a predisposition to nicotine addiction in offspring in adulthood due to impaired glucocorticoid receptor expression in the hippocampus and prefrontal cortex, resulting in a decrease in α7nAChR expression, which disrupts glutamatergic innervation of the nucleus accumbens.