Effect of NMDA antagonists on rapid and chronic tolerance to ethanol: Importance of intoxicated practice

https://doi.org/10.1016/0091-3057(94)90343-3Get rights and content

Abstract

Recent studies from our laboratory have shown that NMDA antagonists ((+)MK-801 and ketamine) inhibit the development of both rapid and chronic tolerance to the motor-impairing (moving belt test) and hypothermic effects of ethanol. The present experiments were designed to determine a) the generality of this inhibition, by using a different test of motor function, the tilt-plane test, and b) the possible importance of the experimental paradigm (i.e., with and without intoxicated practice), for the effect of the NMDA antagonist on ethanol tolerance. Daily administration of ethanol 3.3 g/kg for 5 days produced the same degree of tolerance on this test, whether it was given as a single dose of 3.3 g/kg before the daily training session or as divided doses of 2.3 g/kg before and 1 g/kg immediately after the session. The inhibitory effect of a single dose of (+)MK-801 (0.25 mg/kg IP) on rapid tolerance did not lost longer than 1 day. Therefore, daily administration of the NMDA antagonists was necessary to block development of chronic tolerance. Daily injection of (+)MK-801 (0.25 mg/kg IP) failed to block chronic tolerance, but inclusion of a second dose of (+)MK-801 daily, and progressive increase of this second dose during the chronic treatment period did block chronic tolerance. Unlike (+)MK-801, ketamine does not have motor-impairing effects of its own, and does not potentiate those of ethanol; it was, therefore, used in the remaining experiments. Groups of rats received ethanol (3.3 g/kg) or saline, either before a daily practice session on the tilt-plane or after it. Tolerance to the ethanol effect developed on both regimens, but more rapidly in the animals receiving ethanol before the practice sessions. Ketamine inhibited the development of tolerance in the before group, but had no effect on the tolerance development in the after group. These results suggest that ketamine will block only practice-learned tolerance and not tolerance acquired purely by pharmacological exposure, and posttrial administration of ketamine was ineffective in blocking tolerance. These experiments provide further evidence consistent with the hypothesis that NMDA antagonists block tolerance development through inhibition of learning.

References (36)

  • J.M. Khanna et al.

    NMDA antagonist inhibits rapid tolerance to ethanol

    Brain Res. Bull.

    (1991)
  • R.L. McLamb et al.

    MK-801 impedes the acquisition of a spatial memory task in rats

    Pharmacol. Biochem. Behav.

    (1990)
  • D.L. Walker et al.

    Effects of the novel NMDA antagonist, NPC 12626, on long term potentiation, learning and memory

    Brain Res.

    (1991)
  • P.H. Wu et al.

    Blockade of chronic tolerance to ethanol by the NMDA antagonist, (+) MK-801

    Eur. J. Pharmacol.

    (1993)
  • A. Arvola et al.

    A test for level of alcohol intoxication in the rat

    J. Stud. Alcohol.

    (1958)
  • P.M. Beart et al.

    Chronic administration of MK-801 and the NMDA receptor: Further evidence for reduced sensitivity of the primary acceptor site from studies with the cortical wedge preparation

    J. Pharm. Pharmacol.

    (1990)
  • C.S. Chen

    A study of the alcohol-tolerance effect and an introduction of a new behavioral technique

    Psychopharmacologia

    (1968)
  • C.S. Chen

    A further note on studies of acquired behavioral tolerance to alcohol

    Psychopharmacologia

    (1972)
  • Cited by (38)

    • Effects of NMDA antagonists on the development and expression of tolerance to diazepam-induced motor impairment in mice

      2016, Pharmacology Biochemistry and Behavior
      Citation Excerpt :

      Ketamine is known to attenuate the development of rapidly learned and unlearned tolerance to chlordiazepoxide-induced motor impairment, measured by the tilt-plane test (Khanna et al., 1997). Furthermore, Wu et al. (1993)) and Khanna et al. (1991, 1992a, b, 1993b, 1994) showed the capacity of ketamine and MK-801 to inhibit the development of acute, rapid and chronic tolerance to motor incoordination produced by ethanol. Surprisingly enough, on their first attempt of evaluation of the above-mentioned connections, Khanna et al. (1992c)) observed no effect of ketamine on the development of rapid tolerance to chlordiazepoxide.

    • Chronic ethanol tolerance as a result of free-choice drinking in alcohol-preferring rats of the WHP line

      2012, Pharmacological Reports
      Citation Excerpt :

      These studies implicated a range of endogenous factors in the development of tolerance. Neurotransmitters and receptor system like GABAA [9], NMDA [20, 45], serotonin [14], dopamine [47], cannabinoid CB1 [7], and corticotropin releasing factor (CRF) [43] have been reported to be involved in the development of tolerance to ethanol. Higher GABAergic activity in medial septal or dorsal striatum has also been reported [17, 19].

    • N-methyl-D-aspartate glutamate receptors and alcoholism: Reward, dependence, treatment, and vulnerability

      2003, Pharmacology and Therapeutics
      Citation Excerpt :

      The contribution of NMDA receptors to tolerance- and withdrawal-related neuroplasticity has received growing attention. For example, features of the development of drug tolerance involve learning or experience-dependent neuroplasticity, as might be modeled by long-term potentiation (LTP) or long-term depression (LTD) (Kalant, 1993; Khanna et al., 1994; Trujillo & Akil, 1995). Consistent with this view, NMDA receptor antagonist coadministration appears to attenuate components of ethanol tolerance, particularly the environment-dependent component of tolerance (Szabo et al., 1994), while NMDA receptor facilitation may potentiate the development of this type of tolerance (Khanna et al., 1993; Wu et al., 1993; Rafi-Tari et al., 1996).

    View all citing articles on Scopus
    View full text