Chronic administration of ethanol (2 g/kg, p.o.) on days 1-6 and its withdrawal produced an anxiogenic reaction in mice as assessed in the mirrored-chamber test. Daily administration of quercetin (25 or 50 mg/kg, p.o.) prior to ethanol for 6 days prevented withdrawal-induced anxiety in mice. However, acute administration of a single dose of quercetin (50 mg/kg) to animals withdrawn from ethanol, i.e., on day 7, did not prevent withdrawal-induced anxiety. Ethanol withdrawal also induced a significant increase in the locomotor activity of mice indicating an anxiogenic response. Daily administration of quercetin (25 or 50 mg/kg, p.o.) prior to ethanol for 6 days prevented withdrawal-induced increased locomotor activity. Ethanol withdrawal also sensitized the convulsogenic reaction to pentylenetetrazole (PTZ). A non-convulsive dose (40-60 mg/kg) of PTZ produced full-blown convulsions and increased mortality in ethanol-withdrawn mice. Both acute and chronic administration of quercetin (25 or 50 mg/kg, p.o.) produced a significant protection against ethanol withdrawal-induced reduction in PTZ threshold in mice. The result suggests the protective effect of this safe drug, quercetin, in the management of ethanol withdrawal reactions.
In an earlier study, we reported the ability of quercetin to reverse the development of morphine tolerance and dependence in mice. In the present study we have attempted to explore the possible involvement of nitric oxide (NO) system in quercetin reversal of morphine tolerance and dependence in mice. Co-administration of L-N(G)-nitro arginine methyl ester (L-NAME) or quercetin with morphine during the induction phase (days 1-9) delayed the development of tolerance to the antinociceptive action of morphine and also reversed naloxone precipitated withdrawal jumps. L-Arginine administration during the induction phase enhanced the development of tolerance to the antinociceptive effect of morphine but had no effect on the naloxone-precipitated withdrawal jumps. During the expression phase (day 10) acute administration of quercetin or L-NAME reversed, whereas L-arginine facilitated naloxone- precipitated withdrawal jumps in morphine-tolerant mice, but none of these drugs affected the nociceptive threshold in morphine-tolerant mice. Further, co-administration of quercetin or L-NAME with L-arginine during the induction phase antagonized the latter effects on the development of morphine tolerance. Also, prior administration of quercetin or L-NAME reversed the L-arginine potentiation of nalaxone-precipitated withdrawal jumps in morphine-tolerant mice. The results of the present study suggest that quercetin reversal of morphine tolerance and dependence may involve its ability to suppress nitric oxide synthase (NOS) activity.
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