MK-801 Potentiates Ethanol’s Effects on Locomotor Activity in Mice

doi:10.1016/S0091-3057(97)00389-4

Pharmacology Biochemistry and Behavior

Volume 59, Issue 1, January 1998, Pages 135-143

https://doi.org/10.1016/S0091-3057(97)00389-4 Get rights and content

Abstract

FAST vs. SLOW selected mouse lines and C57BL/6J (B6) vs. DBA/2J (D2) inbred strains differ in their sensitivities to ethanol’s locomotor stimulant effects, and provide two unique sets of genetic animal models to study neurophysiological substrates of this behavior. To determine whether NMDA receptor function mediates sensitivity to ethanol’s stimulant effects, we assessed the effects of the noncompetitive NMDA antagonist, MK-801, on locomotor activity of naive and ethanol-treated FAST, SLOW, B6, and D2 mice. MK-801 (0.01–0.5 mg/kg, IP) had biphasic effects in all genotypes, with stimulation at moderate doses and decreased activation at the highest dose. FAST mice were more activated by MK-801 than SLOW mice, suggesting that selection differentially altered NMDA receptor function between the lines. B6 and D2 mice did not differ in locomotor responses following MK-801 administration. Stimulant doses of MK-801 decreased or blocked ethanol-stimulated locomotor activity in FAST and D2 mice, and potentiated the locomotor depressant actions of ethanol in SLOW and B6 mice. Potentiation of ethanol’s activating properties was observed in one treatment group in D2 mice. These data suggest that NMDA receptors modulate ethanol’s stimulant properties, by a more significant involvement in expression of ethanol’s locomotor depressant properties.

Section snippets

Animals

FAST and SLOW mice were bred at the Portland VA Medical Center (Portland, OR). Selective breeding of these lines has been thoroughly described 8, 38, 46. Briefly, replicate sets of FAST and SLOW mice were contemporaneously derived from comparable, but genetically independent, populations of HS/Ibg mice (Boulder, CO), resulting in FAST-1 and SLOW-1, FAST-2 and SLOW-2 lines. Selection was based upon the difference in locomotor activity assessed on two consecutive test days: after saline injection

Age and Body Weight

Analysis of body weight and age for each experiment revealed slight but significant differences between genotypes in some cases. When they occurred, significant differences ranged from 1.1 to 2.0 g in body weight, and 7 to 8 days in age. Age and body weight were well matched across treatment groups in all cases, and we could find no evidence for systematic effects of these small differences on locomotor responses in these studies.

FAST and SLOW mice

There was a significant main effect of replicate on total

Discussion

In these experiments, we used two sets of genetic animal models, FAST and SLOW selected lines and B6 and D2 inbred strains, to assess the role of the NMDA-type glutamate receptor in mediating differences in sensitivity to EtOH’s locomotor stimulant effects, and in modulating locomotor responses to EtOH. MK-801 administration produced a biphasic dose effect profile in all genotypes, with locomotor activation at lower doses and decreased activation at the highest dose tested. These results are

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In contrast to the anxio-selective changes produced by stress, however, AP5 produced a profile more consistent with generalized locomotor hyperactivity or behavioral disinhibition – significantly increasing the total distance as well as the distance traveled in both the (aversive) light and (safe) dark compartments of the apparatus. Potent disinhibitory/locomotor hyperactivity effects of systemically administered NMDAR antagonists in mice are well known (e.g., Chen and Holmes, 2009; Karlsson et al., 2008; Shen and Phillips, 1998), and the current data show that these drugs can have a similar effect when locally delivered in the BLA. Unfortunately however, the non-specific behavioral profile produced by AP5 largely prevented meaningful interpretation of the potential modulatory effect of the drug on stress-induced anxiety-related behavior.
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ArticlesMK-801 Potentiates Ethanol’s Effects on Locomotor Activity in Mice

Abstract

Section snippets

Animals

Age and Body Weight

FAST and SLOW mice

Discussion

Prog. Brain Res.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Pharmacol. Biochem. Behav.

Neuropharmacology

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Brain Res.

Pharmacol. Biochem. Behav.

Neuroscience

Trends Pharmacol. Sci.

Alcohol

Eur. J. Pharmacol.

FEBS Lett.

Biol. Psychiatry

Int. Rev. Neurobiol.

Biobehav. Rev.

Brain Res.

Pharmacol. Biochem. Behav.

Alcohol

Antagonism by alpha methyltyrosine of the ethanol-induced stimulation and euphoria in man

Clin. Pharmacol. Ther.

Ethanol inhibition of recombinant heteromeric NMDA channels in the presence and absence of modulators

J. Neurochem.

Biphasic effects of ethanol on open-field activitySensitivity and tolerance in C57BL/6N and DBA/2N mice

J. Comp. Physiol. Psychol.

Estimation of genetic correlationInterpretation of experiments using selectively bred and inbred animals

Alcohol. Clin. Exp. Res.

Effects of ethanol, chlordiazepoxide, and MK-801 on performance in the elevated plus-maze and on locomotor activity

Alcohol. Clin. Exp. Res.

Effect of volatile general anesthetics and n-alcohols on glutamate-stimulated increases in calcium ion flux in hippocampal membrane vesicles

Pharmacology

Articles
MK-801 Potentiates Ethanol’s Effects on Locomotor Activity in Mice