Parametric analysis of the development and expression of ethanol-induced behavioral sensitization in female Swiss mice: effects of dose, injection schedule, and test context

Didone, Vincent; Quoilin, Caroline; Tirelli, Ezio; Quertemont, Étienne

doi:10.1007/s00213-008-1266-9

Cited by 36 publications

(60 citation statements)

References 38 publications

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“…Thus it would appear that antagonism of the NMDAR abolishes contextual conditioning. In mice, the development of behavioural sensitisation to ethanol, an indirect NMDAR antagonist, was also reported to be independent of environmental context (Didone et al, 2008) as has been observed with the direct NMDAR antagonists MK-801 (present study) and PCP (Clark et al, 2002, Xu andDomino, 1994b). Overall, the absence of environmental contextual modulation on MK-801 sensitisation reported in this study is congruent with the literature.…”

Section: Experiments 22: Effect Of Environmental Context On Mk-801-insupporting

confidence: 92%

“…It is postulated that the enhancing effect of environmental context on drug-induced behavioural sensitisation is due in part to a learning and memory process dependent on activation of NMDARs (Battisti et al, 2000, Battisti et al, 1999. Therefore it is not surprising that drugs that antagonize NMDARs such as PCP and ethanol (Lovinger et al, 1989b), are also not modulated by environmental context , Xu and Domino, 1994, Didone et al, 2008. Our study is the first to provide evidence that sensitisation to MK-801 is not modulated by environmental context.…”

Section: Mk-801 Sensitisation and Stress Signallingmentioning

confidence: 58%

“…Behavioural sensitisation to PCP, which acts as an antagonist at NMDARs and agonist at σ-receptors, was previously found to be independent of environmental context (Clark et al, 2002, Xu andDomino, 1994b). Additionally, behavioural sensitisation to ethanol, which acts indirectly as an NMDAR antagonist, was recently reported to be independent of environmental context (Didone et al, 2008). Therefore I sought to test the hypothesis that behavioural sensitisation to a drug that antagonizes NMDARs, such as MK-801, may not be affected by environmental context.…”

Section: Aims and Outlinementioning

confidence: 95%

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Neural mechanisms of MK-801 induced sensitisation

Lefevre¹

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Behavioural sensitisation describes the progressive and enduring augmentation of a drug-induced response that develops with repeated exposure. Sensitisation is a putative mechanism in the pathophysiology of drug addiction and neuropsychiatric disorders such as schizophrenia. In rodents, drug-induced behavioural sensitisation has been described for several different drug classes. The neural mechanisms underpinning behavioural sensitisation to most drugs of abuse share similarities, such as NMDA receptor (NMDAR) activation, although not all use the same mechanism of action.The NMDAR antagonist MK-801 can inhibit sensitisation to other drugs of abuse. However, MK-801 also produces behavioural sensitisation to its own hyperlocomotor inducing effects, suggesting that MK-801 sensitisation has a distinctive mechanism of action.The overall aim of my thesis was to investigate the neural mechanisms of behavioural sensitisation to MK-801 in rats. First, I established the effect of drug dose, environmental context, length of withdrawal period and rat strain on the ability of repeated intermittent MK-801 administration to induce behavioural sensitisation. MK-801-induced sensitisation was shown to be dependent on the dose of MK-801, length of withdrawal period and the rat strain. Sensitisation however was not modulated by the environmental context in which MK-801 administration occurred.In the established sensitisation paradigm, a functional and molecular analysis of the nucleus accumbens of rats sensitised to MK-801 was undertaken. Ex vivo slice electrophysiology revealed a decrease in the excitatory synaptic strength in the nucleus accumbens of rats sensitised to MK-801. An LC-MS/MS proteomics approach demonstrated that proteins altered by MK-801 sensitisationwere predominately related to functions including calcium signalling and mitochondrial dysfunction.I also probed the role of corticosterone signalling using a pharmacological and physiological approach. Pharmacological antagonism of the glucocorticoid receptor with RU486 was found to facilitate behavioural sensitisation to MK-801, potentially through its augmenting effect on MK-801 induced corticosterone levels. Following on from this experiment, I showed that pharmacological antagonism of the stress-related kappa opioid receptor with nor-Binaltorphimine did not have the same effect as RU486. Lastly, I also used LY354740, a pharmacological agonist of the metabotropic glutamate receptors, as a preliminary investigation into the role of glutamatergic transmission. Stimulation of these receptors however was without effect on MK-801 sensitisation.ii Using a range of approaches I have elucidated some of the neural mechanisms and adaptations associated with behavioural sensitisation to MK-801. These results predominately show that sensitisation to MK-801 differs from the mechanism of sensitisation to other drugs of abuse. This model could prove useful for studying the role of NMDARs in the pathophysiology of drug addiction and schizophrenia.iii

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Section: Experiments 22: Effect Of Environmental Context On Mk-801-insupporting

confidence: 92%

Section: Mk-801 Sensitisation and Stress Signallingmentioning

confidence: 58%

Section: Aims and Outlinementioning

confidence: 95%

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Neural mechanisms of MK-801 induced sensitisation

Lefevre¹

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“…injection of saline solution and were immediately placed into the center of the locomotor monitoring chamber. Locomotor activity was recorded for the next 5 min in the LE 8811 IR motor activity monitor (Bioseb, Vitrolles, France) to specifically capture the stimulant effects occurring during the ascending limb of the blood alcohol concentrations [42]. Mice were then divided into Saline-(n = 30) and EtOH-(n = 40) treated groups that were equated in terms of horizontal locomotion on day H. During 10 days (day 1 -day 10), mice received one daily i.p.…”

Section: Eibs Proceduresmentioning

confidence: 99%

Sensitization to the Stimulant Motor Effects of Ethanol Is Not Dependent On Tolerance to Ataxic or Sedative Properties of Ethanol in Female Mice

Legastelois¹

2015

J Alcohol Drug Depend

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Ethanol (EtOH)-induced behavioral sensitization (EIBS) is defined as an enhancement of locomotor activity following repeated EtOH exposure and is proposed to reflect an increase in EtOH "wanting". However, the reliability of the sensitization model in studying addiction is still a matter of debate. One major criticism is that the increase in locomotion occurring during sensitization may be a by-product of tolerance to the ataxic and/or sedative effects of EtOH.We investigated the relationship between EIBS amplitude and sensitivity to EtOH-induced ataxia and sedation after the development of tolerance to EtOH depressant effects in adult female DBA/2J mice. After receiving daily injection of saline or 2 g/kg EtOH during 10 consecutive days to induce EIBS, recovery from acute motor incoordination produced by ethanol (2 g/kg EtOH using rotarod) and from loss of righting reflex (4 g/kg EtOH) was measured.We showed that induction of EtOH sensitization after repeated administration of EtOH is associated with a more rapid recovery from acute motor incoordination and from sedation produced by ethanol when compared to the acute groups, suggesting the development of tolerance to the ataxic and sedative effects of EtOH. However, correlational analyses failed to detect any relationship between EIBS amplitude and the response to EtOH ataxic or sedative effects.Altogether, our results confirm and extend previous data showing a tolerance to the ataxic and sedative properties of EtOH after repeated exposure to EtOH and suggest that this tolerance is not related to the amplitude of EIBS.

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“…Locomotor activity, as a measure of spontaneous behavior, has been primarily assessed in behavioral sensitization studies (14,15). Additionally, behavioral sensitization has been established in rodents that have repeatedly been administered the same or incremental doses of a drug (16)(17)(18)(19). It has been demonstrated that behavioral sensitization may also be applied in a model of testing addictive behavior associated with drug seeking and relapse (12,20).…”

Section: Introductionmentioning

confidence: 99%

Huperzine A inhibits immediate addictive behavior but not behavioral sensitization following repeated morphine administration in rats

Sun

Tian

Cui

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Acetylcholinesterase inhibitors are regarded as promising therapeutic agents to treat addiction. The current study aimed to examine the effects of huperzine A, a cholinesterase inhibitor, on behavioral sensitization induced by repeated morphine administration and relapse induced by contextual conditioning. The present study also assessed whether the state-dependency hypothesis may explain the results. Adult rats were divided into four groups (n=8) and intraperitoneally injected with 0.2, 0.3 or 0.4 mg/kg huperzine A or saline (1 ml/kg, control), for 5 days. The effect of repeated huperzine A administration alone on locomotor activity was assessed. For the experiments that analyzed the development of morphine-induced sensitization, 40 rats were divided into five groups (n=8): Saline+Saline, Saline+Morphine, 0.2, 0.3 and 0.4 mg/kg huperzine A+Morphine. Following a withdrawal period of 7 days, all animals were administered saline or morphine, as appropriate. To test the state-dependency hypothesis, the rats in the Saline+Morphine group were injected with saline and morphine, while the other three groups were administered different doses of huperzine A and morphine. To examine the effect of huperzine A on the expression of morphine-induced sensitization, the rats in huperzine A+Morphine groups were injected with appropriate concentrations of huperzine A, and morphine. The current results indicated that the administration of huperzine A alone did not affect locomotor activity, while higher doses of huperzine A inhibited the addictive behavior induced by morphine at the development phase. Additionally, huperzine A administration during the expression phase of morphine sensitization did not inhibit the relapse induced by administration of saline.Furthermore, 0.4 mg/kg huperzine A inhibited the expression of morphine-induced behavioral sensitization. Therefore, the results of the current study do not support the state-dependency hypothesis.

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Parametric analysis of the development and expression of ethanol-induced behavioral sensitization in female Swiss mice: effects of dose, injection schedule, and test context

Abstract: Female Swiss mice develop a robust context-independent sensitization after repeated ethanol injections at all doses above 1.5 g/kg, including highly sedative doses such as 4 g/kg.

Cited by 36 publications

References 38 publications

Neural mechanisms of MK-801 induced sensitisation

Neural mechanisms of MK-801 induced sensitisation

Sensitization to the Stimulant Motor Effects of Ethanol Is Not Dependent On Tolerance to Ataxic or Sedative Properties of Ethanol in Female Mice

Huperzine A inhibits immediate addictive behavior but not behavioral sensitization following repeated morphine administration in rats

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