Early chronic ethanol exposure in rats disturbs respiratory network activity and increases sensitivity to ethanol.
Chronic ethanol exposure during the fetal period alters spontaneous neuronal discharge, excitatory and inhibitory amino acid neurotransmission and neuronal sensitivity to ethanol in the adult brain. However, nothing is known about the effects of such exposure on the central respiratory rhythmic network, which is highly dependent on ethanol-sensitive amino acid neurotransmission. In 3- to 4-week-old rats, we investigated (1) the effects of chronic ethanol exposure (10% v/v as only source of fluid) during gestation and lactation on phrenic (Phr) and hypoglossal (XII) nerve activity using an in situ preparation and on spontaneous breathing at rest in unanaesthetized animals using plethysmography; (2) the sensitivity of the respiratory system to ethanol re-exposure in situ; and (3) the phrenic nerve response to muscimol, a GABA(A) receptor agonist, applied systemically in an in situ preparation. In control rats, ethanol (10-80 mm) induced a concentration-dependent decrease in the amplitude of both XII and Phr motor outflows. At 80 mm ethanol, the amplitude of the activity of the two nerves displayed a difference in sensitivity to ethanol and respiratory frequency increased as a result of shortening of postinspiratory duration period. After chronic ethanol exposure, respiratory frequency was significantly reduced by 43% in situ and by 23% in unanaesthetized animals, as a result of a selective increase in expiratory duration. During Phr burst, the ramp was steeper, revealing modification of inspiratory patterning. Interestingly that re-exposure to ethanol in situ elicited a dramatic inhibitory effect. At 80 mm, ethanol abolished rhythmic XII nerve outflow in all cases and Phr nerve outflow in only 50% of cases. Furthermore, administration of 50 microm muscimol abolished Phr nerve activity in all control rats, but only in 50% of ethanol-exposed animals. Our results demonstrate that chronic ethanol exposure at an early stage of brain development depresses breathing in juvenile rats, and sensitizes the respiratory network to re-exposure to ethanol, which does not seem to involve GABAergic neurotransmission.
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GRAP-JE 2462, Groupe de Recherche sur l'Alcool et les Pharmacodépendances, UFR de Pharmacie, 1, rue des Louvels, 80036 Amiens, France.
Naassila
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Daoust
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Pierrefiche
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D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004342:Drug Hypersensitivity / Q000503:physiopathology*; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology; D007002:Hypoglossal Nerve / Q000187:drug effects / Q000502:physiology; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D010791:Phrenic Nerve / Q000187:drug effects / Q000502:physiology; D010991:Plethysmography; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000187:drug effects / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology; D015656:Respiratory Mechanics / Q000187:drug effects*; D012137:Respiratory System / Q000187:drug effects / Q000294:innervation*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D002492:Central Nervous System Depressants; D018755:GABA Agonists; D018079:Receptors, GABA; D016194:Receptors, N-Methyl-D-Aspartate; D009118:Muscimol; D000431:Ethanol