Behavioral sensitization to ethanol does not result in cross-sensitization to NMDA receptor antagonists
ABSTRACT Behavioral sensitization to the locomotor stimulant effects of ethanol may be related to neuroadaptations within glutamatergic systems. Previous research has suggested that the N-methyl-D: -aspartate (NMDA) subclass of glutamate receptors is critical for the development of ethanol sensitization. We hypothesized that sensitization to ethanol would be associated with changes in sensitivity to NMDA receptor ligands.
DBA/2J and heterogeneous stock (HS) mice were injected with ethanol or saline for 12 days and tested for their acute and sensitized responses to the locomotor effects of ethanol in automated activity monitors. After this treatment phase, mice were challenged with MK-801, ethanol, or ketamine, and locomotor activity was measured for 20 to 60 min. Other ethanol-sensitized and nonsensitized mice were assessed for sensitivity to the effects of NMDA after tail-vein infusions.
There was no evidence for cross-sensitization to MK-801 or ketamine, or altered sensitivity to NMDA in ethanol-sensitized animals, in any experiment. In one experiment, previously ethanol-treated HS mice developed tolerance to the locomotor stimulant effects of ketamine.
These results indicate that ethanol-induced behavioral sensitization is not associated with increased behavioral sensitivity to NMDA receptor antagonists or altered sensitivity to NMDA receptor agonists. To the extent that changes in sensitivity to these ligands reflect changes in NMDA receptors, these results are inconsistent with the hypothesis that ethanol sensitization is associated with alterations in NMDA receptor-mediated processes.
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ABSTRACT: Neuroadaptations supporting behavioral sensitization to abused drugs are suggested to underlie pathological, excessive motivation toward drugs and drug-associated stimuli. Drug-induced sensitization has also been linked to increased appetitive responses for non-drug, natural reinforcers. The present research investigated whether ethanol (EtOH)-induced neural changes, inferred from psychomotor sensitization, can modify consumption and intake dynamics for the natural reinforcer, sucrose. The effects of EtOH-induced sensitization in mice on the temporal structure of sucrose intake patterns were measured using a lickometer system. After sensitization, sucrose intake dynamics were measured for 1 hour daily for 7 days and indicated more rapid initial approach and consumption of sucrose in EtOH-sensitized groups; animals showed a shorter latency to the first intake bout and an increased number of sucrose bottle licks during the initial 15 minutes of the 1-hour sessions. This effect was associated with increased frequency and size of bouts. For the total 1-hour session, sucrose intake and bout dynamics were not different between groups, indicating a change in patterns of sucrose intake but not total consumption. When sensitization was prevented by the gamma-aminobutyric acid B receptor agonist, baclofen, the increased rate of approach and consumption of sucrose were also prevented. Thus, EtOH-induced sensitization, and not the mere exposure to EtOH, was associated with changes in sucrose intake patterns. These data are consistent with current literature suggesting an enhancing effect of drug-induced sensitization on motivational processes involved in reinforcement.Addiction Biology 07/2010; 15(3):324-35. DOI:10.1111/j.1369-1600.2010.00229.x · 5.93 Impact Factor
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ABSTRACT: Although disulfiram has been used in the treatment of alcoholism due to the unpleasant sensations its concomitant ingestion with ethanol provokes, some patients reported stimulant effects after its ingestion. This issue has not been addressed in studies with animals. In mice, the stimulant effect of ethanol has been associated with increased locomotor activity and behavioural sensitization. This study sought to analyze the influence of disulfiram on the development of behavioural sensitization to the stimulant effect of ethanol. Male Swiss mice pre-treated with vehicle or disulfiram (15 mg/kg) received saline or ethanol (2.0 g/kg) every other day, for 5 days. Forty-eight hours afterwards mice were challenged with Saline, and 48 h later they received Disulfiram, or Disulfiram+Ethanol or Ethanol. The co-administration of disulfiram (15 mg/kg) blocked the development of behavioural sensitization induced by ethanol (2.0 g/kg). Although the acute administration of disulfiram did not alter the locomotor activity, its acute administration-induced higher levels of locomotor activity in mice previously sensitized to ethanol than in controls which received saline. Our data suggest that besides the known psychological effects (fear of aversive effects) disulfiram efficacy on alcohol dependency treatment could also be due to its pharmacological interference in the brain neurotransmission.Behavioural brain research 11/2009; 207(2):441-6. DOI:10.1016/j.bbr.2009.10.032 · 3.39 Impact Factor
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ABSTRACT: Alcohol use disorders, like all drug addictions, involve a constellation of adaptive changes throughout the brain. Neural activity underlying changes in the rewarding properties of alcohol reflect changes in dopamine transmission in mesolimbic and nigrostriatal pathways and these effects are modulated by endogenous opioids such as β-Endorphin. In order to study the role of β-Endorphin in the development of locomotor sensitization to repeated EtOH exposure, we tested transgenic mice that vary in their capacity to synthesize this peptide as a result of constitutive modification of the Pomc gene. Our results indicate that mice deficient in β-Endorphin show attenuated locomotor activation following an acute injection of EtOH (2.0 g/kg) and, in contrast to wildtype mice, fail to demonstrate locomotor sensitization after 12 days of repeated EtOH injections. These data support the idea that β-Endorphin modulates the locomotor effects of EtOH and contributes to the neuroadaptive changes associated with chronic use.Frontiers in Molecular Neuroscience 08/2012; 5:87. DOI:10.3389/fnmol.2012.00087