Bivalent effects of MK-801 on ethanol-induced sensitization do not parallel its effects on ethanol-induced tolerance (original) (raw)
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MK-801 Blocks the Development of Behavioral Sensitization to Ethanol
Alcoholism: Clinical and Experimental Research, 2000
Background: Studies have indicatcd that MK-801 (a noncompetitive N-methyl-o-aspartate receptor antagonist) participates in the long-term neural changcs rcsponsible for sensitization to stimulant drugs. It is known that repeated administration of low doses of ethanol sensitizes animals to its stimulant effect. In this work we investigated whether MK-801 alters the development of behavioral sensitization to ethanol.
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.
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.
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.
PRIOR EXPOSURE TO MK-801 SENSITIZES RATS TO ETHANOL-INDUCED CONDITIONED TASTE AVERSION
Alcohol and Alcoholism, 1998
Pretreatment with an uncompetitive NMDA receptor antagonist, dizocilpine [( + )MK-801; six daily injections of 0.1 or 0.2 mg/kg, i.p.] significantly enhanced subsequent 1.5 g/kg ethanol-induced conditioned taste aversion (CTA). In a control experiment, dizocilpine (0.05-0.2 mg/kg) produced only a marginal CTA. Thus, pre-exposure to low, non-aversive doses of MK-801 may sensitize rats to the aversive stimulus effects of ethanol.
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.
NMDA Receptor Antagonism and the Ethanol Intoxication Signal
Annals of The New York Academy of Sciences, 2003
Abstract: This paper reviews clinical evidence suggesting that antagonism of the N-methyl-d-aspartate subtype of glutamate receptors by ethanol may convey an important component of the ethanol intoxication signal, that is, subjective and objective responses associated with the consumption of a large amount of ethanol. It will then review recent evidence that two phenotypes associated with increased risk for heavy alcohol consumption, recovering ethanol-dependent patients, and healthy individuals with a family history of alcohol dependence, exhibit reduced sensitivity to the dysphoric consequences of administration of the NMDA receptor antagonist, ketamine. Each of these groups displays reduced sensitivity to a potentially important response that might normally trigger the cessation of ethanol consumption. These data raise the possibility that alterations in NMDA receptor function that reduce the response to the NMDA antagonist component of ethanol may increase the risk for heavy drinking. This hypothesis is consistent with growing evidence that NMDA receptor antagonists may play a role in the treatment of alcoholism by suppressing alcohol withdrawal, reducing the development or expression of alcohol tolerance, or preventing or reversing the sensitiziation to ethanol effects.
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 sensitivity of NMDA receptors
Neurochemistry International, 2002
NMDA receptors are ionotropic glutamate receptors assembled of subunits of the NR1 and of the NR2 family (NR2A-NR2D). The subunit diversity largely affects the pharmacological properties of NMDA receptors and, hence, gives rise to receptor heterogeneity. As an overall result of studies on recombinant and native NMDA receptors, ethanol inhibits the function of receptors containing the subunits NR2A and/or NR2B to a greater extent than those containing NR2C or NR2D. For example, in rat cultured mesencephalic neurons, NR2C expression was developmentally increased, whereas expression of NR2A and NR2B was decreased. These changes coincided with a developmental loss of sensitivity of NMDA responses to ethanol and ifenprodil, a non-competitive NMDA receptor antagonist that shows selectivity for NR2B-containing receptors. Also in rat locus coeruleus neurons, the low ethanol sensitivity of somatic NMDA receptors could be explained by a prominent expression of NR2C. The inhibitory site of action for ethanol on the NMDA receptor is not yet known. Patch-clamp studies suggest a target site exposed to or only accessible from the extracellular environment. Apparently, amino acid residue Phe 639 , located in the TM3 domain of NR1, plays a crucial role in the inhibition of NMDA receptor function by ethanol. Since this phenylalanine site is common to all NMDA and non-NMDA receptor (AMPA/kainate receptor) subunits, this observation is consistent with accumulating evidence for a similar ethanol sensitivity of a variety of NMDA and non-NMDA receptors, but it cannot explain the differences in ethanol sensitivity observed with different NR2 subunits.