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Sardinian ethanol-preferring (sP), non-preferring (sNP), and Wistar rats show similar dopaminergic response to vanilla sugar consumption in nucleus accumbens shell (NAcS) and medial prefrontal cortex (mPFC), and similarly learn a vanilla sugar-sustained appetitive behavior. In this study we investigated whether in satiated sP, sNP, and Wistar rats vanilla sugar would also elicit a serotonergic response in NAcS and mPFC, and whether in these areas voluntary ethanol consumption would elicit dopaminergic and/or serotoninergic responses. In the NAcS, all rats showed similar serotonin increases in response to the two meals and similar development of rapid habituation. In the mPFC, Wistar and sNP rats showed similar serotonin increases after two vanilla sugar meals, while sP rats, which had low serotonin basal levels, did not show a serotonergic response. When presented with a 10% ethanol solution, Wistar and sP rats rapidly consumed it, while sNP rats did not. In the NAcS, Wistar and sP rats presented dopamine and serotonin increases in response to ethanol. However, while Wistar rats showed habituation in their response, sP rats did not. In the mPFC, ethanol induced similar dopamine increases in Wistar and sP rats; serotonin increases were observed only in Wistar rats. In conclusion, all three lines showed increased serotonin release in response to palatable food, but they profoundly differed in their response to ethanol. In fact, only Wistar and sP rats drank ethanol, Wistar rats showed a monoaminergic response similar to that obtained after palatable food, while sP rats did not develop habituation, suggesting that they perceived ethanol as a more relevant stimulus.

Sardinian ethanol-preferring (sP), non-preferring (sNP), and Wistar rats show similar dopaminergic response to vanilla sugar consumption in nucleus accumbens shell (NAcS) and medial prefrontal cortex (mPFC), and similarly learn a vanilla sugar-sustained appetitive behavior. In this study we investigated whether in satiated sP, sNP, and Wistar rats vanilla sugar would also elicit a serotonergic response in NAcS and mPFC, and whether in these areas voluntary ethanol consumption would elicit dopaminergic and/or serotoninergic responses. In the NAcS, all rats showed similar serotonin increases in response to the two meals and similar development of rapid habituation. In the mPFC, Wistar and sNP rats showed similar serotonin increases after two vanilla sugar meals, while sP rats, which had low serotonin basal levels, did not show a serotonergic response. When presented with a 10% ethanol solution, Wistar and sP rats rapidly consumed it, while sNP rats did not. In the NAcS, Wistar and sP rats presented dopamine and serotonin increases in response to ethanol. However, while Wistar rats showed habituation in their response, sP rats did not. In the mPFC, ethanol induced similar dopamine increases in Wistar and sP rats; serotonin increases were observed only in Wistar rats. In conclusion, all three lines showed increased serotonin release in response to palatable food, but they profoundly differed in their response to ethanol. In fact, only Wistar and sP rats drank ethanol, Wistar rats showed a monoaminergic response similar to that obtained after palatable food, while sP rats did not develop habituation, suggesting that they perceived ethanol as a more relevant stimulus.

Of the ionotropic glutamatergic receptors, the NMDA receptor is clearly implicated in the acute and chronic effects of ethanol; however, the role of the AMPA receptor in mediating the effects of ethanol in vivo is as yet unclear. Using mice deficient in the AMPA receptor subunit GluR1 (GluR1-/- mice), we investigated whether the AMPA receptor had a significant role in mediating the effects of ethanol. GluR1-/- mice showed greater locomotor activity in a novel environment, but by the fifth day of repeated testing their activity was the same as that of wild-type mice. In contrast to their enhanced locomotor activity, on an accelerating rotarod GluR1-/- mice performed consistently worse than wild-types. With regard to the effects of ethanol on motor responses, GluR1-/- mice did not differ significantly from wild-type mice in ethanol's sedative or incoordinating effects. However, the GluR1-/- mice were insensitive to the hypothermic effects of a hypnotic dose of ethanol in contrast to wild-types; this effect was dissociable from the hypnotic effects of ethanol. Further, tolerance to ethanol developed equally for GluR1-/- mice versus wild-type mice. In terms of alcohol drinking behavior, compared to wild-types, GluR1-/- mice differed neither in the acquisition of voluntary ethanol consumption nor in stress-induced ethanol drinking, nor in the expression of an alcohol deprivation effect (ADE) which is used as a model of relapse-like drinking behavior. In summary, although the loss of a hypothermic effect of ethanol in GluR1-/- mice indicates a critical role for the AMPA receptors in this effect, the GluR1 subunit of the AMPA receptor does not seem to play a critical role in the etiology of alcohol dependence. However, changes observed in activity patterns may be related to the putative role of AMPA receptors in attention deficit hyperactivity disorder.

Of the ionotropic glutamatergic receptors, the NMDA receptor is clearly implicated in the acute and chronic effects of ethanol; however, the role of the AMPA receptor in mediating the effects of ethanol in vivo is as yet unclear. Using mice deficient in the AMPA receptor subunit GluR1 (GluR1-/- mice), we investigated whether the AMPA receptor had a significant role in mediating the effects of ethanol. GluR1-/- mice showed greater locomotor activity in a novel environment, but by the fifth day of repeated testing their activity was the same as that of wild-type mice. In contrast to their enhanced locomotor activity, on an accelerating rotarod GluR1-/- mice performed consistently worse than wild-types. With regard to the effects of ethanol on motor responses, GluR1-/- mice did not differ significantly from wild-type mice in ethanol's sedative or incoordinating effects. However, the GluR1-/- mice were insensitive to the hypothermic effects of a hypnotic dose of ethanol in contrast to wild-types; this effect was dissociable from the hypnotic effects of ethanol. Further, tolerance to ethanol developed equally for GluR1-/- mice versus wild-type mice. In terms of alcohol drinking behavior, compared to wild-types, GluR1-/- mice differed neither in the acquisition of voluntary ethanol consumption nor in stress-induced ethanol drinking, nor in the expression of an alcohol deprivation effect (ADE) which is used as a model of relapse-like drinking behavior. In summary, although the loss of a hypothermic effect of ethanol in GluR1-/- mice indicates a critical role for the AMPA receptors in this effect, the GluR1 subunit of the AMPA receptor does not seem to play a critical role in the etiology of alcohol dependence. However, changes observed in activity patterns may be related to the putative role of AMPA receptors in attention deficit hyperactivity disorder.

We compared the modulation of GABA (gamma-aminobutyric acid)-activated currents by benzodiazepines in recombinant GABAA receptors containing either one of two alpha subunits, alpha 1 or alpha 6. Lüddens et al. (Nature, 346 (1990) 648-651) have previously demonstrated that the alpha 6 subunit is part of a cerebellar receptor subtype which selectively binds Ro15-4513, an antagonist of alcohol-induced motor ataxia. Here we report that the imidazobenzodiazepine Ro15-4513 (ethyl 8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-(1,5-a) (1,4)benzodiazepine-3-carboxylate) reduced GABA-activated currents in recombinant alpha 6 beta 2 gamma 2 and alpha 1 beta 2 gamma 2 receptors, thus acting consistently as an inverse agonist. Moreover, another well characterized negative modulator, DMCM (methyl-4-ethyl-6,7-dimethoxy-beta-carboline-3-carboxylate), also reduces GABA activated-currents in both receptors. In contrast, flunitrazepam (FNZM), a benzodiazepine agonist, increases GABA-activated currents in alpha 1 beta 2 gamma 2 receptors, but not in alpha 6 beta 2 gamma 2 receptors. This study lends further support to the hypothesis that the binding sites of full and partial inverse agonists are different.

We compared the modulation of GABA (gamma-aminobutyric acid)-activated currents by benzodiazepines in recombinant GABAA receptors containing either one of two alpha subunits, alpha 1 or alpha 6. Lüddens et al. (Nature, 346 (1990) 648-651) have previously demonstrated that the alpha 6 subunit is part of a cerebellar receptor subtype which selectively binds Ro15-4513, an antagonist of alcohol-induced motor ataxia. Here we report that the imidazobenzodiazepine Ro15-4513 (ethyl 8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-(1,5-a) (1,4)benzodiazepine-3-carboxylate) reduced GABA-activated currents in recombinant alpha 6 beta 2 gamma 2 and alpha 1 beta 2 gamma 2 receptors, thus acting consistently as an inverse agonist. Moreover, another well characterized negative modulator, DMCM (methyl-4-ethyl-6,7-dimethoxy-beta-carboline-3-carboxylate), also reduces GABA activated-currents in both receptors. In contrast, flunitrazepam (FNZM), a benzodiazepine agonist, increases GABA-activated currents in alpha 1 beta 2 gamma 2 receptors, but not in alpha 6 beta 2 gamma 2 receptors. This study lends further support to the hypothesis that the binding sites of full and partial inverse agonists are different.

Maximal L-glutamate/glycine-evoked currents were inhibited by ethanol in Xenopus laevis oocytes expressing recombinant heteromeric NMDA receptors consisting of NR1-NR2A, NR1-NR2B, and NR1-NR2C subunit combinations. Concentration-dependent inhibition was observed at ethanol concentrations of > or = 50 mM both in Ca(2+)-containing and Ca(2+)-deficient, Ba(2+)-containing Mg(2+)-free media. The NR1-NR2C channels were slightly less sensitive to ethanol inhibition than the other heteromeric channels in Ca(2+)-deficient, Ba(2+)-containing medium. The inhibition was unaffected by the clamping-voltage and by a mutation [NR1-NR2A(N595Q)] that prevents the Mg(2+)-blockade of the channels, indicating that the mechanism of action of ethanol differs from that of Mg2+. The results are consistent with the hypothesis that the NMDA receptor subtypes can mediate many behavioural actions of ethanol.

Maximal L-glutamate/glycine-evoked currents were inhibited by ethanol in Xenopus laevis oocytes expressing recombinant heteromeric NMDA receptors consisting of NR1-NR2A, NR1-NR2B, and NR1-NR2C subunit combinations. Concentration-dependent inhibition was observed at ethanol concentrations of > or = 50 mM both in Ca(2+)-containing and Ca(2+)-deficient, Ba(2+)-containing Mg(2+)-free media. The NR1-NR2C channels were slightly less sensitive to ethanol inhibition than the other heteromeric channels in Ca(2+)-deficient, Ba(2+)-containing medium. The inhibition was unaffected by the clamping-voltage and by a mutation [NR1-NR2A(N595Q)] that prevents the Mg(2+)-blockade of the channels, indicating that the mechanism of action of ethanol differs from that of Mg2+. The results are consistent with the hypothesis that the NMDA receptor subtypes can mediate many behavioural actions of ethanol.