Perinatal alcohol exposure leads to prolonged upregulation of hypothalamic GABAA receptors and increases behavioral sensitivity to gaboxadol

Prenatal alcohol exposure (AE) is associated with lasting abnormalities of sleep and motor development, but the underlying mechanisms are unknown. We hypothesized that AE alters development of GABAergic signaling in the hypothalamic regions important for the control of sleep and motor activity. Alcohol (5.25 g/(kg day)) was administered intragastrically to male rats on postnatal days (PD) 4–9, a period of brain development equivalent to the human third trimester (AE group). Control pups were sham-intubated (S group). Motor activity was monitored on PD27 and 28. On PD29 and 30, GABAA receptor subunit mRNA levels and α4 and δ subunit proteins were quantified by RT-PCR and immunoblotting, respectively, in the wake- and motor activity-promoting perifornical (PF) region of the posterior hypothalamus and the sleep-promoting ventrolateral preoptic (VLPO) region of the anterior hypothalamus. Then, in 47–52-day-old rats, motor activity was quantified following administration of GABAA receptor agonist, gaboxadol (5 mg/kg s.c.). In the PF region, mRNA and protein levels for the α4 and δ subunits were significantly higher and β3 and γ2 subunit mRNAs were also increased in the AE group. In the VLPO region, only the δ subunit mRNA was increased. Spontaneous motor activity was lower and suppressed more by gaboxadol in the AE than S group, and the latency to a transient total loss of activity after gaboxadol was shorter in the AE group. Thus, perinatal AE leads to GABAA receptor overexpression in the vigilance- and motor activity-promoting hypothalamic PF region, with the neurochemical and functional outcomes lasting long beyond the period of the insult.