Opposite effects of ethanol and ketamine in the elevated plus-maze test in Wistar rats undergoing a chronic oral voluntary consumption procedure.

The anxiolytic effects of ethanol (EtOH) have been involved in the vulnerability to EtOH drinking in humans. However, the role of the anxiolytic effects of EtOH during a chronic ingestion of the drug has not been extensively addressed, either in humans or in animal models. Since it was first shown that EtOH interacts with the N-methyl-d-aspartate (NMDA) receptor, a growing body of evidence demonstrating the involvement of this receptor in a wide range of EtOH effects has been reported. The present study aimed to investigate the ability of a voluntary consumption of EtOH to exert its putative anxiolytic-like activity in non-selected male Wistar rats held under a voluntary chronic oral consumption procedure using the elevated plus-maze (EPM) test. The effects of EtOH were compared with those of the noncompetitive NMDA receptor antagonist ketamine (KET), and with a mixture of both drugs. Rats were provided with 1-h limited access to one of the following sweetened (10% w/v glucose) solutions: (i) control; (ii) EtOH (ethanol, 10% v/v); (iii) KET (ketamine HCl, 0.28 mg/ml); or (iv) mixed (EtOH 10% v/v plus ketamine HCl 0.28 mg/ml) for 35 consecutive days. At the end of this period, and immediately after the last 1-h access to the respective solution, animals were independently tested in either EPM or open field tests. Previously, rats were tested on the inclined screen test during 15 consecutive days. The opposite effects were observed with EtOH and KET consumption in the EPM test, with EtOH decreasing and KET increasing the percentage of time spent in the open arms of the EPM, which was shown to be independent of any locomotor impairment, whereas consumption of the mixed solution did not significantly affect any test. Since the EtOH did not exhibit anxiolytic-like effects after its chronic oral consumption, it might be hypothesized that the anxiolytic activity of the EtOH is not critically involved in the maintenance of a voluntary EtOH consumption in non-selected rats. On the other hand, the lack of effects from mixed solution consumption suggests that EtOH and KET may interact in such a way that their effects are neutralized.

Evidence for a crucial modulating role of the sodium channel in the QTc prolongation related to antipsychotics.

Blockade of the cardiac hERG channel is recognized as the main mechanism underlying the QT prolongation induced by many classes of drugs, including antipsychotics. However, antipsychotics interact with a variety of other pharmacological targets that could also modulate cardiac function. The present study aims to identify those key factors involved in the QT prolongation induced by antipsychotics. The interactions of 28 antipsychotics were measured on a variety of pharmacological targets. Binding affinity (K(i)), functional channel blockade (IC50), and the corresponding ratios to total and free plasma drug concentration were compared with the corrected QT changes (QTc) associated with the therapeutic use of these drugs by multivariable linear regression analysis to determine the best predictors of QTc. Besides confirming hERG as the primary predictor of QTc, all analyses consistently show the concomitant involvement of Na(V)1.5 channel as modulating factor of the QTc related to hERG blockade. In particular, the hERG/Na(V)1.5 ratio explains the 57% of the overall QTc variability associated with antipsychotics. Since it is known that inhibition of late I Na could offset the dysfunctional effects of hERG blockade, we hypothesize the inhibition of late I(Na) as a crucial compensatory mechanism of the QTc associated with antipsychotics and hence an important factor to consider concomitantly with hERG blockade to appraise the arrhythmogenic risk of these drugs more accurately.