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AbstractDiscrimination and reversal of the classically conditioned eyeblink response depends on cerebellar–brainstem interactions with the hippocampus. Neonatal “binge” exposure to alcohol at doses of 5 g/kg/day or more has been shown to impair single‐cue eyeblink conditioning in both weanling and adult rats. The present study exposed neonatal rats to acute alcohol intubations across different developmental periods (postnatal day [PND] 4‐9 or PND7‐9) and tested them from PND26‐31 on discriminative classical eyeblink conditioning and reversal. A high dose of alcohol (5 g/kg/day) dramatically impaired conditioning relative to controls when exposure occurred over PND4‐9, but produced mild or no impairments when delivered over PND7‐9. These findings support previous claims that developmental exposure period plays a critical role in determining the deleterious effects of alcohol on the developing brain. A lower dose of alcohol (4 g/kg/day) delivered from PND4‐9—lower than has previously been shown to affect single‐cue eyeblink conditioning—also produced deficits on the discrimination task, suggesting that discrimination learning and acquisition of responding to CS+ during reversal may be especially sensitive behavioral indicators of alcohol‐induced brain damage in this rat model. © 2007 Wiley Periodicals, Inc. Dev Psychobiol 49: 243–257, 2007.

Dominance hierarchies are an important aspect of group-living as they determine individual access to resources. The existence of dominance ranks in access to space has not been described in socially monogamous, communally nesting prairie voles (Microtus ochrogaster). Here, we tested whether dominance could be assessed using the tube test. We also tested whether dominance related to alcohol intake, similar to what has been demonstrated in nonmonogamous species. Same-sex pairs of unfamiliar peers were tested in a series of three trials of the tube test, then paired and allowed individual access to alcohol and water for 4 days, and then tested again in the tube test. For all pairs, the same subjects won the majority of trials before and after alcohol drinking. The number of wins negatively correlated with alcohol intake on the first day of drinking and positively correlated with levels of Fos in the paraventricular nucleus of the hypothalamus following the tube test in a separate group of voles. Dominance was not related to Fos levels in other brain regions examined. Together, these results indicate that prairie voles quickly establish stable dominance ranks through a process possibly involving the hypothalamus and suggest that dominance is linked to alcohol drinking.

Adolescents frequently engage in risky behaviours such as binge drinking. Binge drinking, in turn, perturbs neurodevelopment reinforcing reward seeking behaviour in adulthood. Current animal models are limited in their portrayal of this behaviour and the assessment of neuroimmune involvement (specifically the role of Toll-like receptor 4 (TLR4)). Therefore, the aims of this project were to develop a more relevant animal model of adolescent alcohol exposure and to characterise its effects on TLR4 signalling and alcohol-related behaviours later life. Balb/c mice received a short (P22-P25), low dose alcohol binge during in early adolescence, and underwent tests to investigate anxiety (elevated plus maze), alcohol seeking (conditioned place preference) and binge drinking behaviour (drinking in the dark) in adulthood. Four doses of alcohol during adolescence increased alcohol-induced conditioned place preference and alcohol intake in adulthood. However, this model did not affect basal elevated plus maze performance. Subsequent analysis of nucleus accumbal mRNA, revealed increased expression of TLR4-related mRNAs in mice who received alcohol during adolescence. To further elucidate the role of TLR4, (+)-Naltrexone, a biased TLR4 antagonist was administered 30 min before or after the adolescent binge paradigm. When tested in adulthood, (+)-Naltrexone treated mice exhibited reduced alcohol intake however, alcohol seeking and anxiety behaviour was unaltered. This study highlights that even a small amount of alcohol, when given during a critical neurodevelopmental period, can potentiate alcohol-related behaviours and TLR4 activation later in life. Interestingly, attenuation of TLR4 before or after adolescent alcohol exposure reduced only binge alcohol intake in adulthood.

Previous studies have shown that a wide range of sedative/hypnotic agents, including ethanol, induce sleep when microinjected into the medial preoptic area (MPA) of the anterior hypothalamus. The mechanism by which ethanol acts at this site to induce sleep has not been clear, though possibilities include alterations of chloride channel function in the GABA(A)-benzodiazepine receptor complex, or increases in neuronal membrane fluidity. In order to explore the former possibility, we have microinjected into the MPA ethanol 0.24 and 0.47 microM, alone and in combination with the benzodiazepine receptor antagonist flumazenil, which has no effects on membrane fluidity or voltage-dependent calcium channel function. Ethanol microinjections significantly reduced sleep latency, and tended (P<0.06) to increase total sleep time. Flumazenil given by itself had no significant effects on sleep, but when given in combination with both doses of ethanol, blocked its hypnotic effects. These data suggest that the sleep-inducing action of ethanol microinjections into the MPA is mediated by ethanol-induced alteration of GABA(A)-benzodiazepine receptor function.

AbstractAlcohol exposure during central nervous system (CNS) development can lead to fetal alcohol spectrum disorder (FASD). Human imaging studies have revealed significant white matter (WM) abnormalities linked to cognitive impairment in children with FASD; however, the underlying mechanisms remain unknown. Here, we evaluated both the acute and long‐term impacts of alcohol exposure on oligodendrocyte number and WM integrity in a third trimester‐equivalent mouse model of FASD, in which mouse pups were exposed to alcohol during the first 2 weeks of postnatal development. Our results demonstrate a 58% decrease in the number of mature oligodendrocytes (OLs) and a 75% decrease in the number of proliferating oligodendrocyte progenitor cells (OPCs) within the corpus callosum of alcohol‐exposed mice at postnatal day 16 (P16). Interestingly, neither mature OLs nor OPCs derived from the postnatal subventricular zone (SVZ) were numerically affected by alcohol exposure, indicating heterogeneity in susceptibility based on OL ontogenetic origin. Although mature OL and proliferating OPC numbers recovered by postnatal day 50 (P50), abnormalities in myelin protein expression and microstructure within the corpus callosum of alcohol‐exposed subjects persisted, as assessed by western immunoblotting of myelin basic protein (MBP; decreased expression) and MRI diffusion tensor imaging (DTI; decreased fractional anisotropy). These results indicate that third trimester‐equivalent alcohol exposure leads to an acute, albeit recoverable, decrease in OL lineage cell numbers, accompanied by enduring WM injury. Additionally, our finding of heterogeneity in alcohol susceptibility based on the developmental origin of OLs may have therapeutic implications in FASD and other disorders of WM development.

Abstract : Some serotonin 5‐HT3 receptor ligands of tropeine structure have been recently shown to modulate ionophore function and binding of glycine receptors. This led us to study the effects of the tropeines tropisetron and atropine on recombinant human glycine receptors transiently expressed in Xenopus oocytes by using whole‐cell voltage‐clamp electrophysiology. Glycine currents were inhibited by atropine in an apparently competitive manner and with considerable selectivity of the tropeines for α2 versus α1 subunits. Coexpression of β with α subunits and replacement of the N‐terminal region of the α1 subunits by the corresponding β segment resulted in similar increases in the inhibitory potencies. Our data suggest common sites of the tropeines for inhibition on the N‐terminal region of glycine receptors. The point mutations R271K and R271L of the α1 subunit decreased, whereas a T112A substitution increased, the inhibition constants (Ki) of the tropeines. These changes in the Ki values of the tropeines were associated with opposite changes in the EC50 of glycine. Selectivities for the tropeines versus glycine (EC50/Ki) varied within three orders of magnitude. These results, when expressed in terms of free energy changes, can be interpreted according to a two‐state receptor model.

Increasing evidence suggests that low to moderate ethanol ingestion protects against the deleterious effects of subsequent ischemia/reperfusion; however, the underlying mechanism has not been elucidated. In the present study, we showed that expression of the neuronal large-conductance, Ca2+-activated K+ channel (BKCa) α-subunit was upregulated in cultured neurons exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) compared with controls. Preconditioning with low-dose ethanol (10 mmol/L) increased cell survival rate in neurons subjected to OGD/R, attenuated the OGD/R-induced elevation of cytosolic Ca2+ levels, and reduced the number of apoptotic neurons. Western blots revealed that ethanol preconditioning upregulated expression of the anti-apoptotic protein Bcl-2 and downregulated the pro-apoptotic protein Bax. The protective effect of ethanol preconditioning was antagonized by a BKCa channel inhibitor, paxilline. Inside-out patches in primary neurons also demonstrated the direct activation of the BKCa channel by 10 mmol/L ethanol. The above results indicated that low-dose ethanol preconditioning exerts its neuroprotective effects by attenuating the elevation of cytosolic Ca2+ and preventing neuronal apoptosis, and this is mediated by BKCa channel activation.

Naltrexone, a compound with high affinity for the mu opioid receptor (MOP-R) reduces alcohol consumption. SoRI-9409 is a derivative of naltrexone that has highest affinity at delta opioid receptors (DOP-Rs). We have investigated the effects of SoRI-9409 on ethanol consumption to determine the consequences of altering the naltrexone compound to a form with increased efficacy at DOP-Rs.Effects of the opioid receptor antagonists, SoRI-9409 (0-30 mg/kg, IP), naltrexone (0-30 mg/kg, IP), or naltrindole (0-10 mg/kg, IP) on ethanol consumption was measured in high- and low-ethanol-consuming rats with two different drinking paradigms. SoRI-9409-, naltrexone-, and naltrindole-mediated inhibition of DOP-R-stimulated [(35)S]GTP gamma S binding was measured in brain membranes prepared from high-ethanol-consuming rats. The effects of SoRI-9409 on morphine-mediated analgesia, conditioned place preference, and anxiety were also examined.In high- but not low-ethanol-consuming animals, SoRI-9409 is threefold more effective and selective at reducing ethanol consumption when compared with naltrexone or naltrindole for up to 24 hours. SoRI-9409 administered daily for 28 days continuously reduced ethanol consumption, and when the administration of SoRI-9409 was terminated, the amount of ethanol consumed remained lower compared with vehicle-treated animals. Furthermore, SoRI-9409 inhibits DOP-R-stimulated [(35)S]GTP gamma S binding in brain membranes of high-ethanol-consuming rats.SoRI-9409 causes selective and long-lasting reductions of ethanol consumption. This suggests that compounds that have high affinity for DOP-Rs such as SoRI-9409 might be promising candidates for development as a novel therapeutic for the treatment of alcoholism.