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Several works have suggested a potential role for nitric oxide in alcohol-seeking behavior and we have recently shown that the specific blockade of the expression of the neuronal nitric oxide synthase (NOS1) decreases rat ethanol intake. Our previous results have also shown that chronic ethanol exposure has differential effect on the brain NOS activity depending on rat brain area. In the present study, we examine the effects of chronic administration of ethanol on the NOS1-mRNA levels measured with the competitive reverse transcriptase-polymerase chain reaction technique. Chronic administration of ethanol differentially regulated NOS1-mRNA levels depending on rat brain area. Chronic ethanol exposure had no effect on the NOS1-mRNA levels in frontal cortex, but decreased the NOS1-mRNA levels in hippocampus (P<0.01, 39% decrease) and induced a strong increase in striatum (P<0.01, 92% increase). These effects of ethanol were not affected by 7-nitro indazole (25 mg/kg, i.p. daily for 1 week) treatment. These data further support that NOS1 is regulated by chronic exposure to ethanol and that these effects are related to modifications of mRNA levels.

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 anin situpreparation and on spontaneous breathing at rest in unanaesthetized animals using plethysmography; (2) the sensitivity of the respiratory system to ethanol re‐exposurein situ; and (3) the phrenic nerve response to muscimol, a GABAAreceptor agonist, applied systemically in anin situpreparation. In control rats, ethanol (10–80 mm) induced a concentration‐dependent decrease in the amplitude of both XII and Phr motor outflows. At 80 mmethanol, 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 situand 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 ethanolin situelicited 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 µmmuscimol 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.

Little is known about the effects of alcohol exposure during pregnancy, which is responsible for fetal alcohol syndrome and the respiratory network functions, especially respiratory network plasticity (e.g., long-term facilitation) elicited after repeated short-lasting hypoxic episodes. The mechanism of induction of respiratory long-term facilitation involves 5-HT(2A/2C) receptors, which also participate in the response to hypoxia. Because fetal alcohol exposure is known to reduce serotonin centrally, and synaptic plasticity in the hippocampus, we hypothesized that alcohol exposure during gestation might impair respiratory long-term facilitation after hypoxic episodes.To analyze the effects of prenatal and postnatal alcohol exposure on respiratory long-term facilitation in 5- to 7-day-old rats.Respiratory frequency and amplitude were measured in vivo and in an in vitro rhythmic medullary slice before and after three hypoxia episodes or three applications of a 5-HT(2A/2C) receptor agonist in vitro. 5-HT(2A/2C) receptor mRNA was measured from the slice.Alcohol exposure impaired respiratory long-term facilitation and induced long-term depression of respiration in both in vivo and in vitro models. Alcohol altered 5-HT(2A/2C) mRNA expression, although 5-HT(2A/2C) agonist efficacy was not altered in increasing rhythmic activity in slices. However, a higher concentration of 5-HT(2A/2C) agonist was necessary to induce transient facilitation in slices from ethanol-exposed animals, suggesting disturbances in induction and maintenance mechanisms of respiratory long-term facilitation.Respiratory facilitation after repeated hypoxia was converted to long-term depression in rats treated with alcohol in utero. Alcohol exposure during pregnancy may therefore induce long-term maladaptive behavior of the respiratory system in neonates.

AbstractPropensity to drink alcohol and to initiate binge drinking behavior is driven by genetic factors. Recently, we proposed an original animal model useful in the study of voluntary binge‐like drinking (BD) in outbred Long–Evans rats by combining intermittent access to 20% ethanol in a two‐bottle choice (IA2BC) paradigm to 15‐min daily sessions of 20% ethanol operant self‐administration. We sought to compare three strains of outbred rats (Long–Evans, Sprague–Dawley, and Wistar) in our BD model. Because we found different propensity to BD between strains, we also sought to test interstrain differences using another procedure of two acute ethanol exposures known to alter long‐term depression of hippocampal synaptic plasticity. Our results demonstrate that in both IA2BC and operant procedures, the Long–Evans strain consumed the highest, Wistar the lowest amount of ethanol, and the Sprague–Dawley was intermediate. Long–Evans rats were also the fastest consuming with the shortest time to reach 50% of their maximum consumption in 15 min. When we tested the acute effects of ethanol, long‐term depression in hippocampus was abolished specifically in Long–Evans rats with no impact in the two other strains. Thus, our study reveals that the Long–Evans strain is the ideal strain in our recently developed animal model useful in the study of BD. In addition, with the other paradigm of forced acute ethanol exposure, the Long–Evans strain displayed an increase in sensitivity to the deleterious effect of BD on hippocampal synaptic plasticity. Further studies are needed in order to investigate why Long–Evans rats are more prone to BD.

Exposure to ethanol early in life can have long-lasting implications on brain function and drug of abuse response later in life. The present study investigated in rats, the long-term consequences of pre- and postnatal (early life) ethanol exposure on drug consumption/reward and the molecular targets potentially associated with these behavioral alterations. Since a relationship has been demonstrated between heightened drugs intake and susceptibility to drugs-induced locomotor activity/sensitization, anxiolysis, we tested these behavioral responses, depending on the drug, in control and early life ethanol-exposed animals. Our results show that progeny exposed to early life ethanol displayed increased consumption of ethanol solutions and increased sensitivity to cocaine rewarding effects assessed in the conditioned place preference test. Offspring exposed to ethanol were more sensitive to the anxiolytic effect of ethanol and the increased sensitivity could, at least in part, explain the alteration in the consumption of ethanol for its anxiolytic effects. In addition, the sensitivity to hypothermic effects of ethanol and ethanol metabolism were not altered by early life ethanol exposure. The sensitization to cocaine (20 mg/kg) and to amphetamine (1.2 mg/kg) was increased after early life ethanol exposure and, could partly explain, an increase in the rewarding properties of psychostimulants. Gene expression analysis revealed that expression of a large number of genes was altered in brain regions involved in the reinforcing effects of drugs of abuse. Dopaminergic receptors and transporter binding sites were also down-regulated in the striatum of ethanol-exposed offspring. Such long-term neurochemical alterations in transmitter systems and in the behavioral responses to ethanol and other drugs of abuse may confer an increased liability for addiction in exposed offspring.

AbstractEthanol (EtOH) induces cognitive impairment through modulation of synaptic plasticity notably in the hippocampus. The cellular mechanism(s) of these EtOH effects may range from synaptic signaling modulation to alterations of the epigenome. Previously, we reported that two binge‐like exposures to EtOH (3 g/kg, ip, 9 h apart) in adolescent rats abolished long‐term synaptic depression (LTD) in hippocampus slices, induced learning deficits, and increased N‐methyl‐d‐aspartate (NMDA) receptor signaling through its GluN2B subunit after 48 hours. Here, we tested the hypothesis of EtOH‐induced epigenetic alterations leading to modulation of GluN2B and GluN2A NMDA receptor subunits. Forty‐two days old rats were treated with EtOH or the histone deacetylase inhibitor (HDACi) sodium butyrate (NaB, 600 mg/kg, ip) injected alone or 30 minutes before EtOH. After 48 hours, learning was tested with novel object recognition while synaptic plasticity and the role of GluN2A and GluN2B subunits in NMDA‐fEPSP were measured in CA1 field of hippocampus slices. LTD and memory were impaired 48 hours after EtOH and NMDA‐fEPSP analysis unraveled changes in the GluN2A/GluN2B balance. These results were associated with an increase in histone deacetylase (HDAC) activity and HDAC2 mRNA and protein while Ac‐H4K12 labelling was decreased. EtOH increases expression of HDAC2 and mRNA level for GluN2B subunit (but not GluN2A), while HDAC2 modulates the promoter of the gene encoding GluN2B. Interestingly, NaB pretreatment prevented all the cellular and memory‐impairing effects of EtOH. In conclusion, the memory‐impairing effects of two binge‐like EtOH exposure involve NMDA receptor‐dependent LTD deficits due to a GluN2A/GluN2B imbalance resulting from changes in GluN2B expression induced by HDAC2.