Behavioral sensitization to ethanol does not result in cross-sensitization to NMDA receptor antagonists

Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA.
Psychopharmacology (Impact Factor: 3.88). 12/2007; 195(1):103-15. DOI: 10.1007/s00213-007-0871-3
Source: PubMed


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. "
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    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 · 2.15 Impact Factor
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    • "For instance, both endorphins and endomorphins are highly efficacious agonists at μ receptors, and though these receptors appear to be unchanged in transgenic mice (Rubinstein et al., 1996), other opioids may also contribute. Moreover, evidence supports the involvement of various other neurotransmitters including amino acids (i.e., γ-aminobturic acid and glutamate) and monoamines, in this plasticity (Broadbent et al., 1995; Chester and Cunningham, 1999; Meyer and Phillips, 2007; Carrara-Nascimento et al., 2011). Repeated EtOH administration has also been linked to activation of the Hypothalamic Pituitary Adrenal (HPA) axis and shown to be dependent upon the neuroendocrine response to stress (Roberts et al., 1995; Pastor et al., 2008, 2012). "
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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 · 4.08 Impact Factor
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    • "Experiment 4: blood ethanol concentration (BEC) Separate experiments were conducted to determine BEC using identical procedures to those described in Experiments 2 and 3. Mice were sacrificed by cervical dislocation at 20 min after the last ethanol injection to assess possible effects of dopamine antagonists on the pharmacokinetics of ethanol. The 20-min time point was chosen because it corresponds to the end of the locomotor behavior test but still falls within the peak of the locomotor stimulant effect of ethanol (Meyer and Phillips, 2007). Blood ethanol concentrations were determined according to a modified method previously published (for details, see Yonamine et al., 2003). "
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    ABSTRACT: 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.
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