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.
[Show abstract] [Hide abstract]
ABSTRACT: Repeated administration of ethanol (EtOH) in mice leads to behavioural sensitization, a progressive increase in locomotor activity. Since not all mice sensitize equally to EtOH, the objective of the present study was to determine whether variability in this response is associated with altered subunit gene expression of the N-methyl-d-aspartate receptor (NMDAR), a primary target of EtOH. We examined NR1, NR2A, and NR2B expression throughout the brain during the development phase of EtOH sensitization, as well as after a 14 day withdrawal period. Male DBA/2J mice received 5-6 injections of EtOH (2.2g/kg, i.p.) or saline (SAL) and were categorized as high- (HS) or low-sensitized (LS) on the basis of locomotor activity scores after the final injection. NMDAR subunits were analyzed by in situ hybridization in brains removed either immediately following the final EtOH injection or 14 days thereafter. At the end of development phase, LS mice showed increased NR2A expression in several brain areas compared to saline controls. LS animals also had greater NR1 expression in the nucleus accumbens core (+11%, p=0.05) and shell (+14%, p=0.04) compared to HS mice, and increased NR2B expression in hippocampal CA1 (+20%, p=0.05) relative to saline-treated animals. High-sensitized mice showed increased NR2A expression in the bed nucleus of the stria terminalis when compared to controls (+54%, p=0.02). No differences in gene expression between the treatment groups were seen 14 days after the final injection. These findings suggest that region-specific NMDAR subunits may play an important role in the variability associated with the induction of EtOH sensitization. Low-sensitized mice may be more sensitive to the NMDAR inhibitory effects of EtOH, with the NR1 and NR2A subunits potentially playing a key role in the failure to sensitize upon repeated EtOH exposure.Behavioural brain research 12/2013; DOI:10.1016/j.bbr.2013.11.037 · 3.39 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: We present sub-crystal-scale 238U–230Th zircon ages and 238U–230Th–226Ra plagioclase ages of bulk mineral separates from the Holocene (2.0–2.3ka) eruptions of the Rock Mesa (RM) and Devil's Hills (DH) rhyolites at South Sister volcano, Oregon. We link these age data with sub-crystal trace-element analyses of zircon and plagioclase to provide insight into the subvolcanic system at South Sister, as an example of a small-volume continental arc volcano. Our results document the presence of coeval yet physically-distinct regions within the magma reservoir and constrain the timescales over which these heterogeneities existed.Zircons from the RM and DH dominantly record ages from 20 to 80ka, with some grains recording ages >350ka, whereas plagioclase records 230Th–226Ra ages of 2.3–6.8ka (RM) and 4.0–9.6ka (DH-3) and a 238U–230Th age of 10±34ka (DH-3). We interpret zircons with agesEarth and Planetary Science Letters 01/2012; DOI:10.1016/j.epsl.2011.10.035 · 4.72 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Repeated exposure to ethanol in mice induces behavioural sensitization, a progressive increase in locomotor activity that is common to drugs of abuse. Not all mice however show sensitization to ethanol. The goal of the present study was to examine whether variability in the sensitization response to ethanol (EtOH) is differentially associated with regional brain changes in specific molecular markers associated with neuroplasticity, namely BDNF and its receptor trkB, and levels of phosphorylated cyclic AMP-regulated element-binding protein (pCREB), 14 days after withdrawal from chronic, intermittent EtOH exposure. Male DBA/2NCrl mice received 7 biweekly EtOH (2.2g/kg, i.p.) or saline (SAL) injections and were classified as Sensitized or Non-sensitized on the basis of final locomotor activity (LMA) scores. Brains were removed two weeks later for immunohistochemical and in situ hybridization analyses. Compared to SAL-treated and Non-sensitized mice, Sensitized animals showed a higher number of pCREB-immunoreactive cells in the nucleus accumbens shell (+68% and +50%, respectively) and in the bed nucleus of the stria terminalis (+ 61% and 46%, respectively), whereas SAL and Non-sensitized groups did not differ from each other. A different pattern was seen when BDNF and trkB mRNA levels were analyzed in the same groups. Non-sensitized mice displayed lower BDNF mRNA in several brain areas and significantly lower trkB levels throughout the brain when compared to either the Sensitized or to SAL groups, which did not differ from each other. These results indicate that sensitization to EtOH is differentially associated with increased pCREB levels in specific brain areas. The observed decrease in BDNF and trkB mRNA in the Non-sensitized group suggests the possibility that EtOH may have neurotoxic effects in a subpopulation of mice, which might in turn prevent the development of behavioural sensitization. The lack of a difference in BDNF and trkB mRNA expression between Sensitized and SAL mice suggests that EtOH sensitization may be mediated by mechanisms different from those mediating sensitization to other psychostimulants.Behavioural brain research 01/2013; DOI:10.1016/j.bbr.2012.12.035 · 3.39 Impact Factor