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The water/ethanol system possesses complexities at the molecular level, which render its description a difficult task. For the elucidation of the system's hydrogen bonding features that are the key factors in its complex behavior, we conduct a Density Functional Theory analysis on relevant water/ethanol clusters inside implicit solvent cavities for the determination of the ethanol donor hydrogen bond strength. We record Attenuated Total Reflectance spectra of water/ethanol-OD solutions and utilize our density and refractive index measurements for post-processing. The application of the Badger–Bauer rule reveals a minimum in the strength of the ethanol donor hydrogen bond for a composition of xwater = 0.74. We attempt to analyze further this result by estimating the effect of the implicit solvent on the ethanol donor hydrogen bond strength, finding it to be incremental. A brief analysis of different cluster conformations is carried out to determine the cooperativity conditions that can potentially explain the observed minimum in the ethanol donor hydrogen bond strength. These observations are related to notions of microheterogeneity in water/alcohol mixtures and provide context toward a more elaborate picture of association in heteroclusters. [ABSTRACT FROM AUTHOR]

A hallmark of fetal alcohol spectrum disorders (FASD) is neurobehavioral deficits that still do not have effective treatment. Here, we present that reduction of Apolipoprotein E (APOE) is critically involved in neurobehavioral deficits in FASD. We show that prenatal alcohol exposure (PAE) changes chromatin accessibility of Apoe locus, and causes reduction of APOE levels in both the brain and peripheral blood in postnatal mice. Of note, postnatal administration of an APOE receptor agonist (APOE-RA) mitigates motor learning deficits and anxiety in those mice. Several molecular and electrophysiological properties essential for learning, which are altered by PAE, are restored by APOE-RA. Our human genome-wide association study further reveals that the interaction of PAE and a single nucleotide polymorphism in the APOE enhancer which chromatin is closed by PAE in mice is associated with lower scores in the delayed matching-to-sample task in children. APOE in the plasma is also reduced in PAE children, and the reduced level is associated with their lower cognitive performance. These findings suggest that controlling the APOE level can serve as an effective treatment for neurobehavioral deficits in FASD.

Alcohol use disorder (AUD) is frequently comorbid with anxiety disorders, yet whether alcohol abuse precedes or follows the expression of anxiety remains unclear. Rodents offer control over the first drink, an advantage when testing the causal link between anxiety and AUD. Here, we utilized a risk-avoidance task to determine anxiety-like behaviors before and after alcohol exposure. We found that alcohols anxiolytic efficacy varied among inbred mice and mice with high risk-avoidance showed heightened alcohol relief. While dopamine D1 receptors in the striatum are required for alcohols relief, their levels alone were not correlated with relief. Rather, the ratio between striatal D1 and D2 receptors was a determinant factor for risk-avoidance and alcohol relief. We show that increasing striatal D1 to D2 receptor ratio was sufficient to promote risk-avoidance and enhance alcohol relief, even at initial exposure. Mice with high D1 to D2 receptor ratio were more prone to continue drinking despite adverse effects, a hallmark of AUD. These findings suggest that an anxiety phenotype may be a predisposing factor for AUD.

Spectroscopic exploration of sulfur-centered hydrogen bonding involving a thiol group (S–H) as the hydrogen bond donor is scarce in the literature. Herein, we have investigated 1:1 complexes of 2-fluorothiophenol (2-FTP) with methanol (MeOH) and ethanol (EtOH) in the gas phase to examine the physical characteristics and strength of the S–H⋯O hydrogen bond. Structures, conformations, and the strength of the S–H⋯O interaction are investigated by measuring the electronic and Infrared (IR) spectra of the two complexes employing resonant two-photon ionization, UV–UV hole-burning, and IR–UV double resonance spectroscopic techniques combined with quantum chemical calculations. Three conformers of 2-FTP⋯MeOH and two conformers of 2-FTP⋯EtOH have been detected in the experiment. A comparison of the IR spectra obtained from the experiment with those of the low-energy conformers of 2-FTP⋯MeOH and 2-FTP⋯EtOH predicted from the theory confirms that all the observed conformers of the two complexes are primarily S–H⋯O hydrogen bonded. The IR red-shifts found in the S–H stretching frequencies in 2-FTP⋯MeOH and 2-FTP⋯EtOH concerning that in 2-FTP are ∼76 and ∼88 cm−1, respectively, which are much larger than that was reported earlier in the 2-FTP⋯H2O complex (30 cm−1). The strength and physical nature of different noncovalent interactions, including the S–H⋯O hydrogen bond existing in the complexes, are further analyzed using natural bond orbital analysis, quantum theory of atoms in molecules, and localized molecular orbital-energy decomposition analysis. The current investigation reveals that the S–H⋯O hydrogen bond can be strengthened by judicial choices of the hydrogen bond acceptors of higher proton affinities. [ABSTRACT FROM AUTHOR]

Small anionic nickel clusters with ethanol are investigated with a combination of mass-selective infrared photodissociation spectroscopy in a molecular beam and density functional theory simulations at the BLYP/6-311g(d,p) and TPSSh/def2-TZVPP level. In this context, the O–H stretching vibration of the ethanol is analyzed to obtain information about the structural motif, the geometry of the metal core, and the spin state of the clusters. For the [Ni2(EtOH)]− and [Ni3(EtOH)]− clusters, we assign quartet states of motifs with a hydrogen bond from the ethanol to the linear nickel core. The aggregation of a further ethanol molecule, yielding the [Ni3(EtOH)2]− cluster, results in the formation of a cooperative hydrogen bond network between the nickel core and the two ethanol molecules. [ABSTRACT FROM AUTHOR]

The consumption of alcohol and caffeine affects the lives of billions of individuals worldwide. Although recent evidence indicates that caffeine impairs the reinforcing properties of alcohol, a characterization of its effects on alcohol-stimulated mesolimbic dopamine (DA) function was lacking. Acting as the pro-drug of salsolinol, alcohol excites DA neurons in the posterior ventral tegmental area (pVTA) and increases DA release in the nucleus accumbens shell (AcbSh). Here we show that caffeine, via antagonistic activity on A2A adenosine receptors (A2AR), prevents alcohol-dependent activation of mesolimbic DA function as assessed, in-vivo, by brain microdialysis of AcbSh DA and, in-vitro, by electrophysiological recordings of pVTA DA neuronal firing. Accordingly, while the A1R antagonist DPCPX fails to prevent the effects of alcohol on DA function, both caffeine and the A2AR antagonist SCH 58261 prevent alcohol-dependent pVTA generation of salsolinol and increase in AcbSh DA in-vivo, as well as alcohol-dependent excitation of pVTA DA neurons in-vitro. However, caffeine also prevents direct salsolinol- and morphine-stimulated DA function, suggesting that it can exert these inhibitory effects also independently from affecting alcohol-induced salsolinol formation or bioavailability. Finally, untargeted metabolomics of the pVTA showcases that caffeine antagonizes alcohol-mediated effects on molecules (e.g. phosphatidylcholines, fatty amides, carnitines) involved in lipid signaling and energy metabolism, which could represent an additional salsolinol-independent mechanism of caffeine in impairing alcohol-mediated stimulation of mesolimbic DA transmission. In conclusion, the outcomes of this study strengthen the potential of caffeine, as well as of A2AR antagonists, for future development of preventive/therapeutic strategies for alcohol use disorder.

A π-type hydrogen bonding between the OH group and the π electron is a crucial factor for the conformational preference of the molecular structure with a flexible group. However, the information on the effect of the substituent on the OH/π interaction is insufficient. The laser-induced fluorescence (LIF) excitation, the dispersed fluorescence (DF), the IR–UV hole-burning, and the IR dip spectra of jet-cooled 2-(4-methoxyphenyl)ethanol were measured for the first time. Almost all bands observed in the spectral region of 35 550–36 500 cm−1 in the LIF excitation spectrum were successfully assigned with the DF and the IR–UV hole-burning spectra coupled with the quantum chemical calculation at M06-2x/6-311G and MP2/6-311G levels. Five conformers were found in the LIF excitation spectrum. The most stable conformer was Ggπ, and the second most stable conformer was Ggπ′ (the trans rotamer of the methoxy group for Ggπ). Ggπ and Ggπ′ had the OH group directed toward the π electron system of the benzene ring. The OH stretching frequency of Ggπ/Ggπ′ of MPE in the IR dip spectra was red-shifted against that of Ggπ of phenylethanol, indicating that the introduction of the methoxy group would enhance the intramolecular OH/π interaction. In addition, the torsional vibration between the benzene ring and the side chain (−CH2CH2OH) (mode 63) was observed in the DF spectra of the Ggπ–00 and Ggπ′–00 band excitation, but their intensities were rather different, resulting from the different orientation of the OH group for each conformer toward the π electron system. The methoxy group would increase the negative charge on the benzene ring and would enhance the intramolecular OH/π interaction through the electrostatic interaction. [ABSTRACT FROM AUTHOR]