MK-801 Blocks the Development of Behavioral Sensitization to Ethanol (original) (raw)
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Alcohol, 1999
BIENKOWSKI, P., E. KOROS, W. KOSTOWSKI AND W. DANYSZ. Effects of N-methyl-D -aspartate receptor antagonists on reinforced and nonreinforced responding for ethanol in rats. ALCOHOL 18 (2/3) [131][132][133][134][135][136][137] 1999.-Results of several recent studies indicate that the discriminative stimulus effects of ethanol are related, at least partially, to ethanol-induced decrease in the N-Methyl-D -aspartate (NMDA) receptor function. The role of NMDA receptors in ethanol reinforcement remains still unclear. The aim of the present study was to evaluate the effects of two novel NMDA receptor antagonists in rats lever pressing for 8% ethanol in the oral self-administration procedure. In addition, the effects of the drugs on intensity of nonreinforced responding for ethanol (i.e., "experimental craving") were examined in the extinction procedure. To assess selectivity of the drugs' actions the same range of doses was tested in rats lever pressing for water (control experiments). A low-affinity, uncompetitive NMDA receptor antagonist, MRZ 2/579 (2.5-7.5 mg/kg) selectively and dose-dependently decreased ethanol self-administration. This compound exerted also selective effects on nonreinforced responding for ethanol with lower dose (2.5 mg/kg) increasing and higher dose (5 mg/kg) suppressing operant behavior in the extinction procedure. MRZ 2/579 (5 mg/kg) did not alter open field activity when given in combination with either saline or ethanol (0.5-1 g/kg). In contrast, a glycine B site antagonist, MRZ 2/576 (2.5-7.5 mg/kg) did not produce any selective effects on either reinforced or nonreinforced lever pressing for ethanol. The present results suggest that MRZ 2/579 may selectively suppress both ethanol self-administration and experimental ethanol craving. © 1999 Elsevier Science Inc. All rights reserved.
Behavioral Neuroscience, 2003
The relationship between the effects of the N-methyl-D-aspartate (NMDA) antagonist MK-801 on acute responses to ethanol and its ability to block ethanol sensitization and tolerance was examined in DBA/2J mice. Cross-sensitization between these drugs was also studied. Repeated administration of 0.1 mg/kg MK-801 with ethanol potentiated, whereas 0.25 mg/kg attenuated, sensitization to ethanol's locomotor stimulant effects; rearing was similarly affected. There was evidence for cross-sensitization between ethanol and 0.25 mg/kg MK-801. MK-801 potentiated ethanol's ataxic effects in the grid test, but had no effect on tolerance to this effect. MK-801's effects on ethanol sensitization appeared to be related to its own behavioral effects, rather than NMDA receptor blockade per se. Further, these studies demonstrate dissociation between ethanol sensitization and tolerance.
NMDA-receptor antagonists block the development of rapid tolerance to ethanol in mice
Addiction Biology, 1998
Several studies have emphasized the role of learning in the development of rapid and chronic tolerances. Recently, it was shown that the NMDA antagonists MK-801(dizocilpine) and ketamine block the development of tolerance to ethanol in rats submitted to tilt-plane apparatus. The present study examines the generality of this inhibition using mice submitted to the rota-rod test. Mice were tested in the rota-rod apparatus at 5, 10 and 15 minutes after intraperitoneal ethanol injections. The first experiment evaluated the time course of acute effects of different doses of ethanol (1.0-2.25 g/kg) in the rota-rod test. In the second experiment, the most effective dose of ethanol to produce rapid tolerance (RT) was determined. Mice were injected on day 1 with ethanol or saline and tested on the rota-rod. After 24 hours, all groups were injected with the same doses of ethanol and tested. The third experiment investigated whether ketamine (1.0-5.0 mg/kg) injected before ethanol on day 1 influenced the development of RT to ethanol. The last experiment compared the actions of the (+) and (-)MK-801 isomers (0.015-0.060 mg/kg) on RT to ethanol. Maximum motor impairment was obtained 5 minutes after ethanol injections. Pretreatment of animals with ketamine (2.5 and 5 mg/kg) or with (+)MK-801 (0.030 and 0.060 mg/kg) significantly blocked the development of RT. The (-)MK-801 isomer did not affect RT, suggesting that the blockade by MK-801 is stereospecific. These results confirm and extend previous studies showing that NMDA receptor antagonists block RT to the motor impairment produced by ethanol in other animals tested in different models.
The International Journal of Neuropsychopharmacology, 2010
Repeated ethanol administration may induce behavioural sensitization, defined as a progressive potentiation of locomotor stimulant effects. This process is associated with neuroadaptations in the mesolimbic pathway and the nucleus accumbens. The aim of the present study was to analyse dopamine D 1 receptor (D 1 R) participation in locomotor response to an agonist and an antagonist of the D 1 R in mice with different levels of sensitization to ethanol. In three separate experiments, mice received administrations of 2.2 g/kg ethanol or saline every other day for 10 d. According to their locomotor response on the last day, ethanol-treated animals were classified into two groups : sensitized or non-sensitized. After the treatment, mice were challenged with 4 or 8 mg/kg SKF-38393 (i.p.), a D 1 R agonist (expt 1) ; or with 0.01 or 0.1 mg/kg SCH-23390 (i.p.), a D 1 R antagonist, followed by 2.2 g/kg ethanol (i.p.) administration (expt 2). In expt 3, mice were challenged with intra-accumbens (intra-NAc) SKF-38393 (1 mg/side, in 0.2 ml), and with intra-NAc SCH-23390 (3 mg/side, in 0.2 ml) followed by 2.2 g/kg ethanol (i.p.). Although the i.p. administration of SKF-38393 did not affect the locomotion of mice, the intra-NAc administration of SKF-38393 significantly increased the locomotor activity in sensitized mice, suggesting that sensitized mice present functionally hyperresponsive D 1 Rs in the NAc. Both i.p. and intra-NAc administration of SCH-23390 blocked the expression of ethanol sensitization, suggesting that the activation of NAc D 1 Rs seems to be essential for the expression of ethanol sensitization.
Ethanol-induced sensitization depends preferentially on D1 rather than D2 dopamine receptors
Pharmacology Biochemistry and Behavior, 2011
Behavioral sensitization, defined as a progressive increase in the locomotor stimulant effects elicited by repeated exposure to drugs of abuse, has been used as an animal model for drug craving in humans. The mesoaccumbens dopaminergic system has been proposed to be critically involved in this phenomenon; however, few studies have been designed to systematically investigate the effects of dopaminergic antagonists on development and expression of behavioral sensitization to ethanol in Swiss mice. We first tested the effects of D 1 antagonist SCH-23390 (0-0.03 mg/kg) or D 2 antagonist Sulpiride (0-30 mg/kg) on the locomotor responses to an acute injection of ethanol (2.0 g/kg). Results showed that all tested doses of the antagonists were effective in blocking ethanol's stimulant effects. In another set of experiments, mice were pretreated intraperitoneally with SCH-23390 (0.01 mg/kg) or Sulpiride (10 mg/kg) 30 min before saline or ethanol injection, for 21 days. Locomotor activity was measured weekly for 20 min. Four days following this pretreatment, all mice were challenged with ethanol. Both antagonists attenuated the development of ethanol sensitization, but only SCH-23390 blocked the expression of ethanol sensitization according to this protocol. When we tested a single dose (30 min before tests) of either antagonist in mice treated chronically with ethanol, both antagonists attenuated ethanol-induced effects. The present findings demonstrate that the concomitant administration of ethanol with D 1 but not D 2 antagonist prevented the expression of ethanol sensitization, suggesting that the neuroadaptations underlying ethanol behavioral sensitization depend preferentially on D 1 receptor actions.
Blockade of chronic tolerance to ethanol by the NMDA antagonist, (+)-MK-801
European Journal of Pharmacology, 1993
Previous studies indicated that learning and memory play important roles in the development of tolerance to ethanol. (+)-MK-801 has been shown to impair learning and might thus also block the development of tolerance to ethanol. To test this possibility, rats were trained to criterion on the moving belt, a complex motor coordination test. Acute i.p. injection of (+)-MK-801 (a non-competitive NMDA channel blocker) produced dose-related impairment on this test. A dose of 0.1 mg/kg, that had negligible effect by itself, potentiated the acute effects of ethanol. In a chronic experiment with different animals, half of the rats received (+)-MK-801 or saline daily, followed 30 min later by ethanol (1.8 g/kg i.p.) and three practice runs on the belt, and 1 h later a second dose of (+)-MK-801 or saline. The other half received the same drugs but ethanol followed the practice. ( +)-MK-801 blocked the functional tolerance to ethanol in both groups when the pre-ethanol dose was 0.25 mg/kg, but not when it was 0.1 mg/kg. Tolerance to the effects of (+)-MK-801 itself did not occur over 2 weeks of treatment. These results suggest that NMDA receptors are involved in development of chronic tolerance to ethanol as shown previously with rapid tolerance.
Antagonism of the behavioral effects of ethanol by naltrexone in BALB/c, C57BL/6, and DBA/2 mice
Psychopharmacology, 1983
The effects of naltrexone on the increase in locomotor activity induced by a low dose (i.35 g/kg IP) of ethanol and on the duration of loss of righting reflex after a high dose (3.5 g/kg) of ethanol were studied in BALB/c, DBA/2, and C57BL/6 mice. Ethanol increased locomotor activity in DBA and BALB mice, but not in C57BL mice. Naltrexone, at a dose of 0.1 mg/kg, antagonized the ethanol-induced increase in locomotion similarly in DBA and BALB mice. The duration of loss of righting reflex was, however, differentially affected in all three strains by naltrexone. The BALB mice were the most sensitive strain (1 mg/kg naltrexone significantly counteracted ethanol hypnosis), the C57BL mice were intermediate (8 mg/kg naltrexone required to antagonize this effect of ethanol), and the DBA mice were least sensitive (no effect evident even at the highest dose of 8 mg/kg) to naltrexone. Thus, naltrexone could antagonize the behavioral effects of a low and high dose of ethanol, but the three strains, which differ in their behavioral response to ethanol, also were differentially sensitive to the effect of naltrexone in reversing ethanol-induced hypnosis and ethanol-induced changes in locomotor activity
Pharmacology Biochemistry and Behavior, 2010
Several evidences have indicated the involvement of neuronal nicotinic acetylcholine receptors (nAChR) in behavioral effects of drugs of abuse, including ethanol. nAChRs are implicated in ethanol-induced behaviors as well as neurochemical responses to ethanol. Recently, it is demonstrated that mecamylamine, a nAChR antagonist blocks cocaine-, d-amphetamine-, ephedrine-, nicotine-, and methylphenidate-induced psychomotor sensitization. However, no reports are available on its role in ethanol-induced psychomotor sensitization. Therefore, an attempt was made to evaluate its effect on ethanol-induced locomotor sensitization using a model previously described by us. The results revealed that acute administration of mecamylamine (1 and 2 mg/kg, i.p.) blocked the acute stimulant effect of ethanol (2.0 g/kg, i.p.). In addition, treatment with mecamylamine (0.5-2.0 mg/kg, i.p.), 30 min prior to the challenge dose of ethanol (2.0 g/kg, i.p.) dose dependently attenuated expression of sensitization to locomotor stimulant effect of ethanol. Moreover, administration of mecamylamine (1 and 2 mg/kg, i.p.) during development (prior to each ethanol injection on days 1, 4, 7, and 10) blocked acquisition as well as expression (day 15) of sensitization to locomotor stimulant effect of ethanol. Mecamylamine per se did not affect locomotor activity. Further, it also did not influence blood ethanol levels and rotarod performance in mice. These results support the hypothesis that neuroadaptive changes in nAChRs may participate in the development and the expression of ethanolinduced locomotor sensitization.
Alcoholism-clinical and Experimental Research, 1994
Several lines of research have suggested a link between the reward value of a drug and its ability to stimulate locomotion. One goal of the present study was to determine whether ethanol preferentially stimulates locomotor activity in lines of rat that show a preference for ethanol. A secondary goal was to determine the extent to which the benzodiazepine-like and NMDA antagonistic action of ethanol accounted for its effect on locomotor activity. To meet these goals, the effects of varying doses of ethanol (0.125-1.0 g/kg), MK-801 (0.1-0.3 mg/kg), and chlordiazepoxide (0.3-3 mg/kg) on locomotor activity were studied in several lines of rats that had been habituated to the testing procedure. The effect of low doses of ethanol on motor activity in the Alcohol-Preferring (P) and Fawn-Hooded rats, which show a strong ethanol preference, were similar to those of the alcohol-nonpreferring (NP), Flinders Sensitive Line, and Flinders Resistant Line rats. Only the Flinder Resistant Line rats showed a small, but significant increase in locomotor activity after the administration of ethanol. The highest dose of ethanol (1.0 g/kg) produced locomotor depression in all lines except the P and NP lines, which were not tested at this dose. These findings do not support a link between locomotor stimulation by ethanol and ethanol preference. In contrast, all lines exhibited locomotor stimulation after moderate (0.1-0.3 mg/kg) doses of MK-801, but did not exhibit increases in activity following any dose of chlordiazepoxide. These data indicate that the profiles of activity after MK-801 and chlordiazepoxide were distinct from that of ethanol in the various rat lines. Therefore, the effects of ethanol on locomotor activity cannot be accounted for by reference solely to its antagonist-like action at NMDA receptors and/or its agonist-like action at GABA/benzodiazepine receptors.