Halogenated Metal-Binding Compounds from Shipworm Symbionts.

Bacteria use small molecules to impose strict regulation over the acquisition, uptake, and sequestration of transition metal ions. Low-abundance nutrient metals, such as Fe(III), need to be scavenged from the environment by high-affinity chelating molecules called siderophores. Conversely, metal ions that become toxic at high concentrations need to be sequestered and detoxified. Often, bacteria produce a suite of compounds that bind various metal ions at different affinities in order to maintain homeostasis. Turnerbactin, a triscatecholate siderophore isolated from the intracellular shipworm symbiont Teredinibacter turnerae T7901, is responsible for iron regulation and uptake. Herein, another series of compounds are described that complex with iron, copper, and molybdenum in solution. Teredinibactins belong to a class of metal-binding molecules that utilize a phenolate-thiazoline moiety in the coordination of metal ions. In contrast to other compounds in this class, such as yersiniabactin, the phenyl ring is decorated with a 2,4-dihydroxy-3-halo substitution pattern. UV-vis absorption spectroscopy based titration experiments with CuCl2 show the formation of an intermediate complex at substoichiometric concentrations and conversion to a copper-bound complex at 1:1 molar equiv.

Does increasing the number of channels during neuromuscular electrical stimulation reduce fatigability and produce larger contractions with less discomfort?

PURPOSE: Neuromuscular electrical stimulation (NMES) is often delivered at frequencies that recruit motor units (MUs) at unphysiologically high rates, leading to contraction fatigability. Rotating NMES pulses between multiple electrodes recruits subpopulations of MUs from each site, reducing MU firing rates and fatigability. This study was designed to determine whether rotating pulses between an increasing number of stimulation channels (cathodes) reduces contraction fatigability and increases the ability to generate torque during NMES. A secondary outcome was perceived discomfort. METHODS: Fifteen neurologically intact volunteers completed four sessions. NMES was delivered over the quadriceps through 1 (NMES1), 2 (NMES2), 4 (NMES4) or 8 (NMES8) channels. Fatigability was assessed over 100 contractions (1-s on/1-s off) at an initial contraction amplitude that was 20% of a maximal voluntary contraction. Torque-frequency relationships were characterized over six frequencies from 20 to 120 Hz. RESULTS: NMES4 and NMES8 resulted in less decline in peak torque (42 and 41%) over the 100 contractions than NMES1 and NMES2 (53 and 50% decline). Increasing frequency from 20 to 120 Hz increased torque by 7, 13, 21 and 24% MVC, for NMES1, NMES2, NMES4 and NMES8, respectively. Perceived discomfort was highest during NMES8. CONCLUSION: NMES4 and NMES8 reduced contraction fatigability and generated larger contractions across a range of frequencies than NMES1 and NMES2. NMES8 produced the most discomfort, likely due to small electrodes and high current density. During NMES, more is not better and rotating pulses between four channels may be optimal to reduce contraction fatigability and produce larger contractions with minimal discomfort compared to conventional NMES configurations.

Highly efficient 110-W closed-cycle cryogenically cooled Nd:YAG laser operating at 946 nm.

We report a new, to the best of our knowledge, record power and efficiency for a 946 nm Nd:YAG laser, producing >110W (5TWm-2sr-1) with a slope efficiency of 80%, with respect to absorbed pump power, and an optical-to-optical efficiency of 74%, with respect to incident power. To achieve this performance, we utilized a closed-cycle acoustic Stirling cryostat to maintain the gain medium temperature at ∼80K and direct in-band pumping with a volume-Bragg-grating stabilized diode laser bar operating at 868 nm. Daily operation, including cycling of the laser crystal temperature, akin to a comparable water-cooled solid-state laser system, is demonstrated.

Inhibition of Biofilm Formation by Modified Oxylipins from the Shipworm Symbiont Teredinibacter turnerae.

The bioactivity-guided purification of the culture broth of the shipworm endosymbiont Teredinibacter turnerae strain 991H.S.0a.06 yielded a new fatty acid, turneroic acid (1), and two previously described oxylipins (2-3). Turneroic acid (1) is an 18-carbon fatty acid decorated by a hydroxy group and an epoxide ring. Compounds 1-3 inhibited bacterial biofilm formation in Staphylococcus epidermidis, while only 3 showed antimicrobial activity against planktonic S. epidermidis. Comparison of the bioactivity of 1-3 with structurally related compounds indicated the importance of the epoxide moiety for selective and potent biofilm inhibition.

Mindapyrroles A-C, Pyoluteorin Analogues from a Shipworm-Associated Bacterium.

Three new pyoluteorin analogues, mindapyrroles A-C (1-3), were purified from Pseudomonas aeruginosa strain 1682U.R.0a.27, a gill-associated bacterium isolated from the tissue homogenate of the giant shipworm Kuphus polythalamius. Mindapyrroles B and C inhibit the growth of multiple pathogenic bacteria, with mindapyrrole B (2) showing the most potent antimicrobial activity and widest selectivity index over mammalian cells. Preliminary structure-activity relationship analysis showed that dimerization of the pyoluteorin moiety through a C-C linkage is detrimental to the antimicrobial activity, but addition of an aerugine unit in the methylene bridge is favorable for both the antimicrobial activity and selectivity index.

Considerations for Clock Drawing Scoring Systems in Perioperative Anesthesia Settings.

The Clock Drawing Test is a cognitive screening tool gaining popularity in the perioperative setting. We compared 3 common scoring systems: (1) the Montreal Cognitive Assessment; (2) the Mini-Cog; and (3) the Libon scale. Three novice raters acquired interrater and intrarater reliability for each scoring system and then scored 738 preoperative clock drawings with each scoring system. Final scores correlated with each other but with notable discrepancies, indicating the need to attend to interrater and intrarater reliability when implementing any scoring approach in a clinical setting.

PI3K activation within ventromedial prefrontal cortex regulates the expression of drug-seeking in two rodent species.

Phosphatidylinositide 3-kinases (PI3Ks) are intracellular signal transducer enzymes that recruit protein kinase B (aka Akt) to the cell membrane, the subsequent activation of which regulates many cellular functions. PI3K/Akt activity is up-regulated within mesocorticolimbic structures in animal models of alcoholism, but less is known regarding PI3K/Akt activity in animal models of cocaine addiction. Given that prefrontal cortex (PFC) is grossly dysregulated in addiction, we studied how cocaine affects protein indices of PFC PI3K/Akt activity in rat and mouse models and examined the relevance of PI3K activity for cocaine-related learning. Immunoblotting of mouse medial PFC at 3 weeks withdrawal from a cocaine-sensitization regimen (seven injections of 30 mg/kg, intraperitoneal [IP]) revealed increased kinase activity, as did immunoblotting of tissue from the ventral PFC of rats with a history of long-access intravenous cocaine self-administration (0.25 mg/0.1 mL infusion; 10 days of 6 h/d cocaine access). Interestingly, increased Akt phosphorylation was observed in rat ventromedial PFC at both 3- and 30-day withdrawal only in animals re-exposed to cocaine-associated cues. A conditioned place-preference paradigm in mice and a cue-elicited drug-seeking test in rats were conducted to determine the functional relevance for elevated PI3K activity for addiction-related behavior. In both cases, an intra-PFC infusion of the PI3K inhibitor wortmannin (50µM) reduced drug-seeking behavior. Taken together, this cross-species, interdisciplinary, study provides convincing evidence that cocaine history produces an enduring increase in PI3K/Akt-dependent signaling within the more ventral aspect of the PFC that is relevant to behavioral reactivity to drug-associated cues/contexts. As such, PI3K inhibitors may well serve as an effective strategy for reducing drug cue reactivity and craving in cocaine addiction.

Systemic sclerosis medications and risk of scleroderma renal crisis.

BACKGROUND: Scleroderma Renal Crisis (SRC) is associated with significant morbidity and mortality. While prednisone is strongly associated with SRC, there are no previous large cohort studies that have evaluated ace inhibitor (ACEi) calcium channel blocker (CCB), angiotensin receptor blocker (ARB), endothelin receptor blocker (ERB), non-steroidal anti-inflammatory drug (NSAID), fluticasone, or mycophenolate mofetil (MMF) use in systemic sclerosis (SSc) and the risk of SRC. METHODS: In this retrospective cohort study of the entire military electronic medical record between 2005 and 2016, we compared the use of ACEi, ARB, CCB, NSAID, ERB, fluticasone, and MMF after SSc diagnosis for 31 cases who subsequently developed SRC to 322 SSc without SRC disease controls. RESULTS: ACEi was associated with an increased risk for SRC adjusted for age, race, and prednisone use [odds ratio (OR) 4.1, 95% confidence interval (CI) 1.6-10.2, P = 0.003]. On stratified analyses, ACEi was only associated with SRC in the presence [OR 5.3, 95% CI 1.1-29.2, p = 0.03], and not the absence of proteinuria. In addition, a doubling of ACEi dose [61% vs. 12%, p < 0.001) and achieving maximum ACEi dose [45% vs. 4%, p < 0.001] after SSc diagnosis was associated with future SRC. CCB, ARB, NSAIDs, ERB, fluticasone, and MMF use were not significantly associated with SRC. CONCLUSION: ACEi use at SSC diagnosis was associated with an increased risk for SRC. Results suggest that it may be a passive marker of known SRC risk factors, such as proteinuria, or evolving disease. SSC patients that require ACEi should be more closely monitored for SRC.

Integrating Molecular Networking and Biological Assays To Target the Isolation of a Cytotoxic Cyclic Octapeptide, Samoamide A, from an American Samoan Marine Cyanobacterium.

Integrating LC-MS/MS molecular networking and bioassay-guided fractionation enabled the targeted isolation of a new and bioactive cyclic octapeptide, samoamide A (1), from a sample of cf. Symploca sp. collected in American Samoa. The structure of 1 was established by detailed 1D and 2D NMR experiments, HRESIMS data, and chemical degradation/chromatographic (e.g., Marfey's analysis) studies. Pure compound 1 was shown to have in vitro cytotoxic activity against several human cancer cell lines in both traditional cell culture and zone inhibition bioassays. Although there was no particular selectivity between the cell lines tested for samoamide A, the most potent activity was observed against H460 human non-small-cell lung cancer cells (IC50 = 1.1 µM). Molecular modeling studies suggested that one possible mechanism of action for 1 is the inhibition of the enzyme dipeptidyl peptidase (CD26, DPP4) at a reported allosteric binding site, which could lead to many downstream pharmacological effects. However, this interaction was moderate when tested in vitro at up to 10 µM and only resulted in about 16% peptidase inhibition. Combining bioassay screening with the cheminformatics strategy of LC-MS/MS molecular networking as a discovery tool expedited the targeted isolation of a natural product possessing both a novel chemical structure and a desired biological activity.

Cocaine craving during protracted withdrawal requires PKCε priming within vmPFC.

In individuals with a history of drug taking, the capacity of drug-associated cues to elicit indices of drug craving intensifies or incubates with the passage of time during drug abstinence. This incubation of cocaine craving, as well as difficulties with learning to suppress drug-seeking behavior during protracted withdrawal, are associated with a time-dependent deregulation of ventromedial prefrontal cortex (vmPFC) function. As the molecular bases for cocaine-related vmPFC deregulation remain elusive, the present study assayed the consequences of extended access to intravenous cocaine (6 hours/day; 0.25 mg/infusion for 10 day) on the activational state of protein kinase C epsilon (PKCε), an enzyme highly implicated in drug-induced neuroplasticity. The opportunity to engage in cocaine seeking during cocaine abstinence time-dependently altered PKCε phosphorylation within vmPFC, with reduced and increased p-PKCε expression observed in early (3 days) and protracted (30 days) withdrawal, respectively. This effect was more robust within the ventromedial versus dorsomedial PFC, was not observed in comparable cocaine-experienced rats not tested for drug-seeking behavior and was distinct from the rise in phosphorylated extracellular signal-regulated kinase observed in cocaine-seeking rats. Further, the impact of inhibiting PKCε translocation within the vmPFC using TAT infusion proteins upon cue-elicited responding was determined and inhibition coinciding with the period of testing attenuated cocaine-seeking behavior, with an effect also apparent the next day. In contrast, inhibitor pretreatment prior to testing during early withdrawal was without effect. Thus, a history of excessive cocaine taking influences the cue reactivity of important intracellular signaling molecules within the vmPFC, with PKCε playing a critical role in the manifestation of cue-elicited cocaine seeking during protracted drug withdrawal.

Prefrontal glutamate correlates of methamphetamine sensitization and preference.

Methamphetamine (MA) is a widely misused, highly addictive psychostimulant that elicits pronounced deficits in neurocognitive function related to hypo-functioning of the prefrontal cortex (PFC). Our understanding of how repeated MA impacts excitatory glutamatergic transmission within the PFC is limited, as is information about the relationship between PFC glutamate and addiction vulnerability/resiliency. In vivo microdialysis and immunoblotting studies characterized the effects of MA (ten injections of 2 mg/kg, i.p.) upon extracellular glutamate in C57BL/6J mice and upon glutamate receptor and transporter expression, within the medial PFC. Glutamatergic correlates of both genetic and idiopathic variance in MA preference/intake were determined through studies of high vs. low MA-drinking selectively bred mouse lines (MAHDR vs. MALDR, respectively) and inbred C57BL/6J mice exhibiting spontaneously divergent place-conditioning phenotypes. Repeated MA sensitized drug-induced glutamate release and lowered indices of N-methyl-d-aspartate receptor expression in C57BL/6J mice, but did not alter basal extracellular glutamate content or total protein expression of Homer proteins, or metabotropic or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors. Elevated basal glutamate, blunted MA-induced glutamate release and ERK activation, as well as reduced protein expression of mGlu2/3 and Homer2a/b were all correlated biochemical traits of selection for high vs. low MA drinking, and Homer2a/b levels were inversely correlated with the motivational valence of MA in C57BL/6J mice. These data provide novel evidence that repeated, low-dose MA is sufficient to perturb pre- and post-synaptic aspects of glutamate transmission within the medial PFC and that glutamate anomalies within this region may contribute to both genetic and idiopathic variance in MA addiction vulnerability/resiliency.

Wave-Number-Dependent Gilbert Damping in Metallic Ferromagnets.

A wave-number-dependent dissipative term to magnetization dynamics, mirroring the conservative term associated with exchange, has been proposed recently for ferromagnetic metals. We present measurements of wave-number-(k-)dependent Gilbert damping in three metallic ferromagnets, NiFe, Co, and CoFeB, using perpendicular spin wave resonance up to 26 GHz. In the thinnest films accessible, where classical eddy-current damping is negligible, size effects of Gilbert damping for the lowest and first excited modes support the existence of a k^{2} term. The new term is clearly separable from interfacial damping typically attributed to spin pumping. Higher-order modes in thicker films do not show evidence of enhanced damping, attributed to a complicating role of conductivity and inhomogeneous broadening. Our extracted magnitude of the k^{2} term, Δα_{kE}^{*}=Δα_{0}^{*}+A_{k}^{*}k^{2}, where A_{k}^{*}=0.08-0.1 nm^{2} in the three materials, is an order of magnitude lower than that identified in prior experiments on patterned elements.

Cocaine-elicited imbalances in ventromedial prefrontal cortex Homer1 versus Homer2 expression: implications for relapse.

Withdrawal from a history of extended access to self-administered cocaine produces a time-dependent intensification of drug seeking, which might relate to a cocaine-induced imbalance in the relative expression of constitutively expressed Homer1 versus Homer2 isoforms within the ventromedial aspect of the prefrontal cortex (vmPFC). Thus, we employed immunoblotting to examine the relation between cue-reinforced lever pressing at 3- versus 30-day withdrawal from a 10-day history of extended access (6 hours/day) to intravenous cocaine (0.25 mg/infusion) or saline (Sal6h), and the expression of Homer1b/c and Homer2a/b within the vmPFC versus the more dorsomedial aspect of this structure (dmPFC). Behavioral studies employed adeno-associated virus (AAV) vectors to reverse cocaine-elicited changes in the relative expression of Homer1 versus Homer2 isoforms and tested animals for cocaine prime-, and cue-induced responding following extinction training. Cocaine self-administration elevated both Homer1b/c and Homer2a/b levels within the vmPFC at 3-day withdrawal, and the rise in Homer2a/b persisted for at least 30 days. dmPFC Homer levels did not change as a function of self-administration history. Reversing the relative increase in Homer2 versus Homer1 expression via Homer1c overexpression or Homer2b knockdown failed to influence cue-reinforced lever pressing when animals were tested in a drug-free state, but both AAV treatments prevented cocaine-primed reinstatement of lever-pressing behavior. These data suggest that a cocaine-elicited imbalance in the relative expression of constitutively expressed Homer2 versus Homer1 within the vmPFC is necessary for the capacity of cocaine to reinstate drug-seeking behavior, posing drug-induced changes in vmPFC Homer expression as a molecular trigger contributing to drug-elicited relapse.

Deficits in ventromedial prefrontal cortex group 1 metabotropic glutamate receptor function mediate resistance to extinction during protracted withdrawal from an extensive history of cocaine self-administration.

Anomalies in prefrontal cortex (PFC) function are posited to underpin difficulties in learning to suppress drug-seeking behavior during abstinence. Because group 1 metabotropic glutamate receptors (mGluRs) regulate drug-related learning, we assayed the consequences of extended access to intravenous cocaine (6 h/d; 0.25 mg/infusion for 10 d) on the PFC expression of group 1 mGluRs and the relevance of observed changes for cocaine seeking. After protracted withdrawal, cocaine-experienced animals exhibited a time-dependent intensification of cue-induced cocaine-seeking behavior and an impaired extinction of this behavior. These behavioral phenomena were associated with a time-dependent reduction in mGluR1/5 expression within ventromedial PFC (vmPFC) of cocaine-experienced animals exposed to extinction testing but not in untested ones. Interestingly, pharmacological manipulations of vmPFC mGluR1/5 produced no immediate effects on cue-induced cocaine-seeking behavior but produced residual effects on a subsequent test for cocaine seeking. At 3 d withdrawal, cocaine-experienced rats infused intra-vmPFC with mGluR1/5 antagonists, either before or after an initial test for cocaine seeking, persisted in their cocaine seeking akin to cocaine-experienced rats in protracted withdrawal. Conversely, cocaine-experienced rats infused with an mGluR1/5 agonist before the initial test for cocaine-seeking at 30 d withdrawal exhibited a facilitation of extinction learning. These data indicate that cue-elicited deficits in vmPFC group 1 mGluR function mediate resistance to extinction during protracted withdrawal from a history of extensive cocaine self-administration and pose pharmacological stimulation of these receptors as a potential approach to facilitate learned suppression of drug-seeking behavior that may aid drug abstinence.

Fourier transform microwave and millimeter-wave spectroscopy of bromoiodomethane, CH2BrI.

Bromoiodomethane, CH2BrI, is a molecule of natural origin emitted in significant amount into the marine boundary layer. It can easily be decomposed by solar radiation, releasing Br and I atoms in the troposphere, which in turn impacts the atmospheric chemistry. Spectroscopy is an invaluable tool to monitor species present in the atmosphere. Since no high-resolution spectroscopic studies are available for this dihalomethane, we have investigated the rotational spectra of the two bromine isotopologues of CH2BrI in its vibrational ground state in the microwave and millimeter-wave regions. Transitions of b-type have been recorded by Fourier transform microwave spectroscopy below 25 GHz while both a- and b-type spectral lines have been measured below 230 GHz. Observed transitions correspond to energy levels with J ≤ 132 and Ka ≤ 14. Molecular constants including those describing the nuclear quadrupole coupling tensors for (79)Br, (81)Br, and (127)I were accurately determined from the least-squares analysis of a total of 1873 distinct transition frequencies (of which 943 belong to the CH2(79)BrI isotopologue). An experimental (r0) structure of the title species has been derived from the two sets of rotational constants.

Medical schools producing the most physical medicine and rehabilitation residents: An analysis of matriculating residents from 2017 to 2021.

BACKGROUND: Residency choice is often influenced by experiences in medical school. It is unclear what potential factors contribute to medical schools producing higher numbers of physical medicine & rehabilitation (PM&R) residents. OBJECTIVE: To identify the medical schools producing the most PM&R residents from 2017 to 2021 and potential influencing factors toward this production. DESIGN: Descriptive, cross-sectional study. SETTING: Accreditation Council for Graduate Medical Education accredited PM&R programs; allopathic/osteopathic/international medical schools. INTERVENTIONS: REDCap Survey. PARTICIPANTS: Representatives from medical schools producing the most PM&R residents. METHODS: The medical schools that produced the most PM&R residents from 2017 to 2021 were identified using publicly available information on the internet. A subgroup of the highest producing schools were surveyed to determine potential factors that contributed to production of PM&R residents. MAIN OUTCOME MEASURE: Medical schools with the highest number of matriculated PM&R residents from 2017 to 2021; potential factors influencing matriculating PM&R residents. RESULTS: The medical school that produced the most PM&R residents from 2017 to 2021 was New York Institute of Technology College of Osteopathic Medicine. Nine of the 11 medical schools producing the most PM&R residents were osteopathic. Of osteopathic graduates applying to residency, 2.87% matriculated into PM&R residencies compared to 1.21% of allopathic graduates (p < .001), though a greater number of allopathic graduates overall were represented. Among survey respondents 93.3% (14/15) attributed exposure to PM&R faculty/residents and exposure to PM&R through medical school curriculum as perceived factors contributing to production of PM&R residents. CONCLUSION: Osteopathic medical schools accounted for most of the schools producing the highest number of PM&R residents. A statistically significant higher percentage of osteopathic graduates were found to pursue PM&R as a career compared to allopathic counterparts although the total number of students entering PM&R was greater from allopathic schools. Potential factors contributing to medical students pursuing PM&R included faculty/resident involvement with medical students, and PM&R exposure through curriculum or interest groups.

The high intensity diffractometer for residual stress analysis (HIDRA), a third generation residual stress mapping neutron diffractometer at the high flux isotope reactor.

This paper describes the hardware and software upgrades, operation, and performance of the high intensity diffractometer for residual stress analysis (HIDRA) instrument, a residual stress mapping neutron diffractometer located at the High Flux Isotope Reactor at Oak Ridge National Laboratory in Oak Ridge Tennessee, USA. Following a major upgrade in 2018, the new instrument has a single 3He multiwire 2D 30 × 30 cm2 position sensitive detector, yielding a field of view of 17° 2θ. The increase in the field of view (from 4° 2θ) from the previous model instrument has contributed to the tremendous improvement in the out of plane solid angle such that the 3D count rate could be obtained easily. Accordingly, the hardware, software, Data Acquisition System (DAS), and so on have also been updated. Finally, all these enhanced features of HIDRA have been ably demonstrated by conducting multi directional diffraction measurements in the quenched 750-T74 aluminum, and the evolved and improved strain/stress mappings are presented.

Resistance mechanisms for Gram-negative bacteria-specific lipopeptides, turnercyclamycins, differ from that of colistin.

IMPORTANCE: Bacterial resistance to antibiotics is a crisis. Acinetobacter baumannii is among the CDC urgent threat pathogens in part for this reason. Lipopeptides known as turnercyclamycins are produced by symbiotic bacteria that normally live in marine mollusks, where they may be involved in shaping their symbiotic niche. Turnercyclamycins killed Gram-negative pathogens including drug-resistant Acinetobacter, but how do the mechanisms of resistance compare to other lipopeptide drugs? Here, we define resistance from a truncation of MlaA, a protein involved in regulating bacterial membrane phospholipids. Intriguingly, this resistance mechanism only affected one turnercyclamycin variant, which differed only in two atoms in the lipid tail of the compounds. We could not obtain significant resistance to the second turnercyclamycin variant, which was also effective in an infection model. This study reveals an unexpected subtlety in resistance to lipopeptide antibiotics, which may be useful in the design and development of antibiotics to combat drug resistance.

Penetration depth of transverse spin current in ultrathin ferromagnets.

We report a novel depth dependence for the penetration of spin current into ultrathin ferromagnets. Ferromagnetic resonance measurements show that transverse spin current pumped into three structurally distinct ferromagnets is attenuated, on reflection, by an amount proportional to the ferromagnetic layer thickness, saturating abruptly at 1.2 ± 0.1 nm. The observed power-law decay, differing significantly from the (exponential) characteristic-length dependence for longitudinal spin current, confirms models of spin momentum transfer which have been inaccessible to experiment.

Nucleus accumbens mGluR5-associated signaling regulates binge alcohol drinking under drinking-in-the-dark procedures.

BACKGROUND: Alcohol increases the expression of Group 1 metabotropic glutamate receptors (mGluRs) and their associated scaffolding protein Homer2 and stimulates phosphatidylinositol 3-kinase (PI3K) within the nucleus accumbens (NAC). Moreover, functional studies suggest that NAC Group 1 mGluR/Homer2/PI3K signaling may be a potential target for pharmacotherapeutic intervention in alcoholism. METHODS: Immunoblotting was conducted to examine the effects of alcohol consumption under drinking-in-the-dark (DID) procedures on Group 1 mGluR-associated proteins in C57BL/6J (B6) mice. Follow-up behavioral studies examined the importance of Group 1 mGluR/Homer2/PI3K signaling within the NAC shell for limited-access alcohol drinking. Finally, immunoblotting examined whether the NAC expression of Group 1 mGluR-associated proteins is a genetic correlate of high alcohol drinking using a selectively bred high DID (HDID-1) mouse line. RESULTS: Limited-access alcohol drinking under DID procedures up-regulated NAC shell Homer2 levels, concomitant with increases in mGluR5 and NR2B. Intra-NAC shell blockade of mGluR5, Homer2, or PI3K signaling, as well as transgenic disruption of the Homer binding site on mGluR5, decreased alcohol consumption in B6 mice. Moreover, transgenic disruption of the Homer binding site on mGluR5 and Homer2 deletion both prevented the attenuating effect of mGluR5 and PI3K blockade upon intake. Finally, the basal NAC shell protein expression of mGluR1 and Homer2 was increased in offspring of HDID-1 animals. CONCLUSIONS: Taken together, these data further implicate Group 1 mGluR signaling through Homer2 within the NAC in excessive alcohol consumption.