Perinatal alcohol exposure leads to prolonged upregulation of hypothalamic GABA A 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, GABA A receptor subunit mRNA levels and alpha4 and delta 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 GABA A receptor agonist, gaboxadol (5 mg/kg s.c.). In the PF region, mRNA and protein levels for the alpha4 and delta subunits were significantly higher and beta3 and gamma2 subunit mRNAs were also increased in the AE group. In the VLPO region, only the delta 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 GABA A 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.
Volgin
Denys V
DV
Department of Animal Biology, 209E/VET, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104, USA. dvolgin@vet.upenn.edu
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects*; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology*; D018755:GABA Agonists / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects*; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*
D002492:Central Nervous System Depressants; D018755:GABA Agonists; D007555:Isoxazoles; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D000431:Ethanol; C015542:gaboxadol