Antidepressant drugs and ethanol: Behavioral and pharmacokinetic interactions in mice

Abstract

The interactions between ethanol and antidepressant drugs (both tricyclics and newer non-tricyclics) were studied in mice. The ability of these drugs to enhance the sedative effects of ethanol at two different doses (3.2 and 4.0 g/kg) was measured. The percentage of mice losing the righting-reflex was used for the lower dose, and the duration of ethanol-induced sleep was used at the higher dose. The relative order of potency was amitriptyline greater than or equal to imipramine > maprotiline = mianserin > desipramine greater than or equal to chlorimipramine > iprindole greater than or equal to alaproclate > norzimelidine greater than or equal to zimelidine. Amitriptyline (60 mg/kg) caused death in all mice when combined with 4.0 g/kg ethanol. Clinically established antidepressants which enhanced ethanol sedation only at doses considerably above therapeutic levels were zimelidine and iprindole. The relative potency of the antidepressants to enhance ethanol sedation is correlated with their inherent sedative properties which are in turn related to their ability to block central 5-HT, alpha-NA, muscarinic and H1-receptors. Amitriptyline (20 mg/kg) was found to increase ethanol plasma levels to 202, 167 and 132% of control values at 30, 60 and 90 min after ethanol administration, respectively. Desipramine, mianserin and alaproclate also increased ethanol plasma levels initially, but to a lesser extent. These findings suggest that in addition to their sedative effect, several antidepressants, particularly amitriptyline, are likely to interact with ethanol by increasing its concentration in plasma.

Desipramine potentiation of the acute depressant effects of ethanol: Modulation by α2-adrenoreceptors and stress

“…A recent study found that desipramine or another NET blocker, nisoxetine, increased the depressant effects of acute ethanol injection, as assayed by the duration of ethanol-induced sleep time in inbred long sleep (ILS) and inbred short sleep (ISS) mice (Haughey et al, 2005) (see also Cott and Ogren, 1980). Present data replicate these findings in the C57BL/6J mouse strain: pre-treatment with DMI markedly potentiated sleep time in a dose-dependent manner.…”

“…Howerton et al, 1982). Moreover, treatment with the NET blockers desipramine or nisoxetine potentiates the depressant effects of ethanol, and these effects were found to be greater in ILS than ISS mice (Cott and Ogren, 1980;Haughey et al, 2005). One possible interpretation of these data is that NET deficiency promotes ethanol's depressant effects.…”

Acute kinetic and dynamic interactions of zimelidine with ethanol

“…When the equations were fitted relating NZ concentrations to AUC, the mean C parameter (rate of demethylation of Z to NZ) was reduced by 46% after E (F,,, = 7.73; P = 0.04), while the mean ^b parameter (rate of disappearance of NZ) was reduced after E by 18% (F,,, = 4.69; P = 0.08). An alternate analysis that fits P and ^b to each subject's data for each of the 2 days separately and for the 2 days combined supports Volume 36 Number 5 Zimelidine interactions with ethanol 657 Z potentiated the deleterious effects of E on recall memory, postural stability on one foot, and manual tracking ( Fig. 3).…”

“…This provides further evidence against such an explanation for the Zinduced reductions in E intake.lS E induced inconsistent self-ratings of sedation and consistent ones of intoxication, the former of which was diminished by Z in some subjects. Despite these ratings, however, there was objective evidence that the combination of Z and E can in-Volume 36 Number 5 duce more psychomotor impairment than when either is taken alone. The magnitude of the potentiation of E effect by Z for manual tracking and postural stability was about equal in magnitude to the E effect itself; in none of these cases did Z have an effect in the absence of E. The absence in previous reportsL such an interaction can be attributed to differences in design sensitivity.…”

Mianserin, but not Ondansetron, reduces the locomotor stimulating effect of ethanol in preweanling rats

“…The BECs were measured only in response to this Mianserin dose only because it was the only treatment that attenuated the ethanol effect without affecting locomotor activity in water controls. In previous studies it was found that Mianserin can increase ethanol plasma levels in mice (Cott & Ogren, 1980). Procedures were similar to those described for the locomotor activity test.…”