Targeting Glutamate Uptake To Treat Alcohol Use Disorders

Alcoholism is a serious public health concern that is characterized by the development of tolerance to alcohol's effects, increased consumption, loss of control over drinking and the development of physical dependence. This cycle is often times punctuated by periods of abstinence, craving and relapse. The development of tolerance and the expression of withdrawal effects, which manifest as dependence, have been to a great extent attributed to neuroadaptations within the mesocorticolimbic and extended amygdala systems. Alcohol affects various neurotransmitter systems in the brain including the adrenergic, cholinergic, dopaminergic, GABAergic, glutamatergic, peptidergic, and serotonergic systems. Due to the myriad of neurotransmitter and neuromodulator systems affected by alcohol, the efficacies of current pharmacotherapies targeting alcohol dependence are limited. Importantly, research findings of changes in glutamatergic neurotransmission induced by alcohol self- or experimenter-administration have resulted in a focus on therapies targeting glutamatergic receptors and normalization of glutamatergic neurotransmission. Glutamatergic receptors implicated in the effects of ethanol include the ionotropic glutamate receptors (AMPA, Kainate, and NMDA) and some metabotropic glutamate receptors. Regarding glutamatergic homeostasis, ceftriaxone, MS-153, and GPI-1046, which upregulate glutamate transporter 1 (GLT1) expression in mesocorticolimbic brain regions, reduce alcohol intake in genetic animal models of alcoholism. Given the hyperglutamatergic/hyperexcitable state of the central nervous system induced by chronic alcohol abuse and withdrawal, the evidence thus far indicates that a restoration of glutamatergic concentrations and activity within the mesocorticolimbic system and extended amygdala as well as multiple memory systems holds great promise for the treatment of alcohol dependence

Clinical audit of subjects with snoring & sleep apnoea/hypopnoea syndrome fitted with mandibular repositioning splint

SummarySnoring and obstructive sleep apnoea/hypopnoea syndrome (OSAHS) are often treated with mandibular repositioning splints (MRS), but the efficacy and satisfaction of them has not been comprehensively addressed. A survey on the use of and satisfaction with MRS was posted to 177 patients referred by a hospital orthodontic department for custom-fitting of a MRS. Data were analysed using non-parametric techniques. The response rate was 81% (n=144). Responders (30F, 114M) had mean (SD) age of 51 (11) years, apnoea+hypopnoea index (AHI) of 24 (21) per hr and Epworth Score of 10 (5) at diagnosis, and had been supplied with their MRS a median 7 (IQR 5–11) months previously. Fifty of the 144 patients (35%) had been offered continuous positive airway pressure (CPAP) treatment but had declined or abandoned this. Self-reported MRS use was 5 (2) h/night, with 74 of the 144 patients (51%) continuing to use MRS at least occasionally at a median 7 months after fitting. Survival analysis showed 12% still using MRS at 12 months. Epworth score fell slightly with MRS therapy [−2.4 (3.5); P=0.005] and 7 daytime and 2 nocturnal symptoms improved in MRS users (all P<0.05). Marital satisfaction did not change with MRS. Problems preventing MRS use in 70 non-users included: non-retention (n=12), sore mouth (n=13) or jaw (n=7), difficulties falling asleep (n=10) or breathing (n=7), excessive salivation (n=4), dental damage (n=4) and other problems (n=3). Continued use of MRS therapy was associated with a higher number of teeth, low marital satisfaction perceived by partners and greater improvement in symptoms reported by patients and partners. Continuance with MRS may be low and linked to tolerance problems

Time-course of extracellular nicotine and cotinine levels in rat brain following administration of nicotine: effects of route and ethanol coadministration

RATIONALE: Nicotine and ethanol are commonly coabused drugs, and nicotine-laced ethanol products are growing in popularity. However, little is known about time-course changes in extracellular nicotine and cotinine levels in rat models of ethanol and nicotine coabuse. OBJECTIVES: The objective of the present study was to determine the time-course changes in brain levels of nicotine and cotinine following subcutaneous (SC) and intragastric (IG) nicotine administration in alcohol-preferring (P) and Wistar rats. METHODS: In vivo microdialysis was used to collect dialysate samples from the nucleus accumbens shell (NACsh) for nicotine and cotinine determinations, following SC administration of (-)-nicotine (0.18, 0.35, and 0.70 mg/kg) in female P and Wistar rats or IG administration of (-)-nicotine (0.35 and 0.70 mg/kg) in 15 % (v/v) ethanol or water in female P rats. RESULTS: SC nicotine produced nicotine and cotinine dialysate levels as high as 51 and 14 ng/ml, respectively. IG administration of 15 % EtOH + 0.70 mg/kg nicotine in P rats resulted in maximal nicotine and cotinine dialysate levels of 19 and 14 ng/ml, respectively, whereas administration of 0.70 mg/kg nicotine in water resulted in maximal nicotine and cotinine levels of 21 and 25 ng/ml, respectively. Nicotine and cotinine levels were detectable within the first 15 and 45 min, respectively, after IG administration. CONCLUSIONS: Overall, the results of this study suggest that nicotine is rapidly adsorbed and produces relevant extracellular brain concentrations of nicotine and its pharmacologically active metabolite, cotinine. The persisting high brain concentrations of cotinine may contribute to nicotine addiction

The Ursinus Weekly, October 29, 1951

Sororities bid upperclassmen during week • Lachman named vice-president • Henning Prentis delivers Founders Day Address • Curtain Club reveals leads for Fall play • Y group hears talk; Four at conference • Pianist to perform in Bomberger Hall on November 8 • Frosh give show; Custom period ends • Junior bazaar slated • Ruby takes photos; Tentative dates set • Movie list made up • Editorials: Alumni spirit; And in this corner; Sororities, fraternities do nothing for Ursinus • Donahue, \u2751 alumnus, reports on life among Arabs in French Morocco • Letters to the editor • Jones to read Saki at English meeting • Practice teachers look for professional savoir faire • Optimistic graduates explore world • Garnet hands Ursinus soccer team third defeat by downing locals 10-1 • Ursinus hopes for upset in game with F&M eleven • Temptation of Norma Gorinowski • Soccer team downs alumni • Curtis Hall remains leader in football • Undefeated Owlettes down Ursinus; Locals down Chestnut Hill eleven • Fynan\u27s conversion gives 13-12 win over Wagner • Jr. Bearettes win to stay unbeaten • Ryan to speak at magic showhttps://digitalcommons.ursinus.edu/weekly/1525/thumbnail.jp

The Ursinus Weekly, November 19, 1951

Four soloists for Messiah concert named • Fraternities give out bids; Plan parties next week • Student-faculty talents presented for benefit of Campus Chest fund • Kiszonas is new senior class prexy • Red Cross disbands • WSGA hears plans for Student Union • Forum speaker says religious belief implies skeptical aspect • Curtain rises on Private Lives act tomorrow night • Nominees listed for \u2753 yearbook positions • Curtain Club play set for 2-night run • Student tells of conditions in Russia • Senior ball set • Campus Chest campaign reaches half-way mark • Haverford College student panel to argue army conscription here • Editorials: Thanksgiving, 1951; East is world headache • Gigi, French play, opens at Philadelphia theater • Alumni • Letters to the editor • Dr. McClure delivers lecture on education • If Collegeville were in Korea, this could happen • Thanksgiving: Pre and Post • Messiah tradition came with Dr. Philip • Bruins to play benefit in York • East Stroudsburg handed initial defeat by Belles • Bears defeated in finale by unbeaten Susquehanna • Curtis Hall wins interdorm title • Women begin to play in intramural hockey • Susquehanna completes unbeaten, untied year • Band attacked for disinterest • Soccer squad closes its season by losing to Franklin & Marshall team • Nevison lectures to Chem society • Intercollegiate bridge tournament to begin • Pediatrics talk given pre-medders • Square dance enjoyedhttps://digitalcommons.ursinus.edu/weekly/1528/thumbnail.jp

Characterization of the GlnK protein of Escherichia coli

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75120/1/j.1365-2958.1999.01349.x.pd

Nonstationary Collisional Dynamics in Determining Nitric Oxide Laser-Induced Flourescence Spectra

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/77237/1/AIAA-8783-947.pd

Selective breeding for high alcohol consumption and response to nicotine: locomotor activity, dopaminergic in the mesolimbic system, and innate genetic differences in male and female alcohol-preferring, non-preferring, and replicate lines of high-alcohol drinking and low-alcohol drinking rats

Rationale There is evidence for a common genetic link between alcohol and nicotine dependence. Rodents selectively bred for high alcohol consumption/responsivity are also more likely to self-administer nicotine than controls. Objectives The experiments examined the response to systemic nicotine, the effects of nicotine within the drug reward pathway, and innate expression of nicotine-related genes in a brain region regulating drug reward/self-administration in multiple lines of rats selectively bred for high and low alcohol consumption. Methods The experiments examined the effects of systemic administration of nicotine on locomotor activity, the effects of nicotine administered directly into the (posterior ventral tegmental area; pVTA) on dopamine (DA) release in the nucleus accumbens shell (AcbSh), and innate mRNA levels of acetylcholine receptor genes in the pVTA were determined in 6 selectively bred high/low alcohol consuming and Wistar rat lines. Results The high alcohol-consuming rat lines had greater nicotine-induced locomotor activity compared to low alcohol-consuming rat lines. Microinjections of nicotine into the pVTA resulted in DA release in the AcbSh with the dose response curves for high alcohol-consuming rats shifted leftward and upward. Genetic analysis of the pVTA indicated P rats expressed higher levels of α2 and β4. Conclusion Selective breeding for high alcohol preference resulted in a genetically divergent behavioral and neurobiological sensitivity to nicotine. The observed behavioral and neurochemical differences between the rat lines would predict an increased likelihood of nicotine reinforcement. The data support the hypothesis of a common genetic basis for drug addiction and identifies potential receptor targets

Co‐administration of ethanol and nicotine heightens sensitivity to ethanol reward within the nucleus accumbens (NAc) shell and increasing NAc shell BDNF is sufficient to enhance ethanol reward in naïve Wistar rats

Alcohol use disorder most commonly presents as a polydrug disorder where greater than 85% are estimated to smoke. EtOH and nicotine (NIC) co‐abuse or exposure results in unique neuroadaptations that are linked to behaviors that promote drug use. The current experiments aimed to identify neuroadaptations within the mesolimbic pathway produced by concurrent EtOH and NIC exposure. The experiments used four overall groups of male Wistar rats consisting of vehicle, EtOH or NIC alone, and EtOH+NIC. Drug exposure through direct infusion into the posterior ventral tegmental area (pVTA) stimulated release of glutamate and dopamine in the nucleus accumbens (NAc) shell, which was quantified through high‐performance liquid chromatography. Additionally, brain‐derived neurotrophic factor (BDNF) protein levels were measured via enzyme‐linked immunosorbent assay (ELISA). A second experiment investigated the effects of drug pretreatment within the pVTA on the reinforcing properties of EtOH within the NAc shell through intracranial self‐administration (ICSA). The concluding experiment evaluated the effect of NAc shell pretreatment with BDNF on EtOH reward utilizing ICSA within that region. The data indicated that only EtOH+NIC administration into the pVTA simultaneously increased glutamate, dopamine, and BDNF in the NAc shell. Moreover, only pVTA pretreatment with EtOH+NIC enhanced the reinforcing properties of EtOH in the NAc shell. BDNF pretreatment in the NAc shell was also sufficient to enhance the reinforcing properties of EtOH in the NAc shell. The collected data suggest that concurrent EtOH+NIC exposure results in a distinct neurochemical response and neuroadaptations within the mesolimbic pathway that alter EtOH reward