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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- "The present results are also in agreement with those of several laboratories that routinely use sensitization procedures in which ethanol is injected to mice in their home cages (Quadros et al., 2002; Meyer and Phillips, 2007). Together, these results indicate that the development and expression of a psychomotor sensitization to ethanol is not under the control of contextual cues and is probably because of contextindependent neuroadaptations. "
ABSTRACT: Repeated drug injections lead to sensitization of their stimulant effects in mice, a phenomenon sometimes referred to as drug psychomotor sensitization. Previous studies showed that sensitization to cocaine is context dependent as its expression is reduced in an environment that was not paired with cocaine administration. In contrast, the effects of the test context on ethanol sensitization remain unclear. In the present study, female OF1 mice were repeatedly injected with 1.5 g/kg ethanol to test for both the effects of context novelty/familiarity and association on ethanol sensitization. A first group of mice was extensively pre-exposed to the test context before ethanol sensitization and ethanol injections were paired with the test context (familiar and paired group). A second group was not pre-exposed to the test context, but ethanol injections were paired with the test context (nonfamiliar and paired group). Finally, a third group of mice was not pre-exposed to the test context and ethanol was repeatedly injected in the home cage (unpaired group). Control groups were similarly exposed to the test context, but were injected with saline. In a second experiment, cocaine was used as a positive control. The same behavioral procedure was used, except that mice were injected with 10 mg/kg cocaine instead of ethanol. The results show a differential involvement of the test context in the sensitization to ethanol and cocaine. Cocaine sensitization is strongly context dependent and is not expressed in the unpaired group. In contrast, the expression of ethanol sensitization is independent of the context in which it was administered, but is strongly affected by the relative novelty/familiarity of the environment. Extensive pre-exposure to the test context prevented the expression of ethanol sensitization. One possible explanation is that expression of ethanol sensitization requires an arousing environment.Behavioural pharmacology 07/2015; DOI:10.1097/FBP.0000000000000161 · 2.19 Impact Factor
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- "Ethyl alcohol (ethanol; EtOH) is one of the most widely used addictive drugs (Hines, et al., 2005), and significant relationships between alcoholism and eating disorders as well as sweet preference have been described (Krahn, et al., 2006; Sinha and O'Malley, 2000). Robust psychomotor sensitization to EtOH has been shown using multiple strains of mice (Broadbent, et al., 1999; Didone, et al., 2008; Masur and Boerngen, 1980; Meyer and Phillips, 2007; Lister, 1987; Pastor, et al., 2008; Phillips, et al., 1997), in rats using intracerebroventricular injections (Correa, et al., 2003) and, although rarely studied, also in humans (Newlin and Thomson, 1999). However, the behavioral relevance of EtOH-induced sensitization in the context of natural reinforcers has not been investigated. "
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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- "2.4.3. Treatment and challenge with ethanol, disulfiram or disulfiram + ethanol In order to evaluate the effect of disulfiram on the development and on the expression of sensitization to ethanol, we utilized protocols (for treatment and challenge test) based on previous studies   . The effects per se of disulfiram on locomotor activity and its influence on the development of sensitization to the stimulant effect of ethanol were evaluated in the " treatment " phase of the protocol (10-day treatment). "
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