The Role of the Neurokinin-1 Receptor in Stress-Induced Reinstatement of Alcohol and Cocaine Seeking

Neurokinin-1 receptors (NK1Rs) have been shown to mediate alcohol and opiate, but not cocaine reward in rodents. We recently reported that NK1R antagonism also blocks stress-induced reinstatement of alcohol seeking in rats, but it is presently unknown whether these antirelapse properties extend to other drug classes. Although some work has suggested that intracranial substance P (SP) infusion reinstates cocaine seeking following extinction, no studies have indicated a direct role for the NK1R in reinstatement of cocaine seeking. Here, we explored the effect of the NK1R antagonist L822429 on yohimbine-induced reinstatement of alcohol or cocaine seeking in Long–Evans rats. Consistent with our previous findings with footshock-induced reinstatement of alcohol seeking in Wistar rats, we found that L822429 attenuates yohimbine-induced reinstatement of alcohol seeking, but does not affect baseline alcohol self-administration. We observed a similar suppression of yohimbine-induced reinstatement of cocaine seeking by L822429, and found that Long–Evans rats exhibit greater sensitivity to NK1R antagonism than Wistar rats. Accordingly, Long–Evans rats exhibit differences in the expression of NK1Rs in some subcortical brain regions. Combined, our findings suggest that while NK1R antagonism differentially influences alcohol- and cocaine-related behavior, this receptor mediates stress-induced seeking of both drugs.     

Attenuation of Ethanol Withdrawal by Ceftriaxone-Induced Upregulation of Glutamate Transporter EAAT2

Alcohol withdrawal syndrome (AWS) is a potentially fatal outcome of severe alcohol dependence that presents a significant challenge to treatment. Although AWS is thought to be driven by a hyperglutamatergic brain state, benzodiazepines, which target the GABAergic system, comprise the first line of treatment for AWS. Using a rat model of ethanol withdrawal, we tested whether ceftriaxone, a β-lactam antibiotic known to increase the expression and activity of glutamate uptake transporter EAAT2, reduces the occurrence or severity of ethanol withdrawal manifestations. After a 2-week period of habituation to ethanol in two-bottle choice, alcohol-preferring (P) and Wistar rats received ethanol (4.0 g/kg) every 6 h for 3–5 consecutive days via gavage. Rats were then deprived of ethanol for 48 h during which time they received ceftriaxone (50 or 100 mg/kg, IP) or saline twice a day starting 12 h after the last ethanol administration. Withdrawal manifestations were captured by continuous video recording and coded. The evolution of ethanol withdrawal was markedly different for P rats vs Wistar rats, with withdrawal manifestations occurring >12 h later in P rats than in Wistar rats. Ceftriaxone 100 mg/kg per injection twice per day (200 mg/kg/day) reduced or abolished all manifestations of ethanol withdrawal in both rat variants and prevented withdrawal-induced escalation of alcohol intake. Finally, ceftriaxone treatment was associated with lasting upregulation of ethanol withdrawal-induced downregulation of EAAT2 in the striatum. Our data support the role of ceftriaxone in alleviating alcohol withdrawal and open a novel pharmacologic avenue that requires clinical evaluation in patients with AWS.     

Percutaneous ethanol ablation of intrahepatic arterial pseudoaneurysm: A case report

Hepatic arterial pseudoaneurysm is a rare but potentially fatal condition that requires prompt management. We report a case of hepatic arterial pseudoaneurysm developed after radiofrequency ablation of a hepatocellular carcinoma. The patient was successfully treated with percutaneous absolute ethanol injection under ultrasound guidance. Follow-up studies with ultrasound and computed tomography for 2 years after treatment revealed no evidence of local recurrence of hepatocellular carcinoma and of the pseudoaneurysm.     

Determination of total serum insulin (IRI) in insulin-treated diabetic patients

Summary A routine method is described for the determination of total IRI (imraunoreactive insulin) in insulintreated diabetics. The method involves an easy acid ethanol extraction, whereby antibody-bound IRI is dissociated and separated, together with the free IRI from the serum proteins and the antibodies. The recovery of IRI in this procedure is about 80%. After the separation, the isolated total IRI is measured in an immunoassay, using ethanol for the separation of free and antibody bound¹²⁵I-insulin. In 169 diabetic patients treated with insulin in doses of from 6 to 120 units/day, the fasting serum total IRI was between 6 and 4374 U/ml, with a mean of 392 U/ml. During treatment with insulin, the level of total IRI increased from normal values, registered during the first two months, to a higher level which became stable after about 5 months of treatment. The increase in IRI occurred simultaneously with the formation of antibodies. Insulin-resistant patients showed very high IRI levels.

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Bestimmung des Gesamtserum-Insulins (IRI) bei insulinbehandelten Diabetikern

Zusammenfassung Für die Bestimmung des Gesamt-IRI (immunoreaktiven Insulins) bei Diabetikern, die mit Insulin behandelt wurden, wird eine Routinemethode beschrieben. Die Methode schließt eine einfache SäureÄthanol-Extraktion ein, wobei das antikörpergebundene IRI dissoziiert und zusammen mit dem freien IRI von den Serumproteinen, einschließlich den Antikörpern, getrennt wird. Bei diesem Verfahren werden etwa 80% des IRI wiedergefunden. Nach der Trennung wird das isolierte Gesamt-IRI immunologisch gemessen. Für die Trennung des freien von dem an Antikörper gebundenen¹²⁵I-Insulin wird Äthanol verwendet. Bei 169 Diabetikern, die mit 6 bis 120 E Insulin/Tag behandelt wurden, lag das Nuchternserum-Gesamt-IRI zwischen 6 und 4374 E/ml (Mittelwert 392 E/ml). Im Laufe der Insulinbehandlung stieg das Gesamt-IRI von Normalwerten, die während der ersten 2 Monate registriert wurden, auf ein höheres Niveau an, das sich nach etwa 5 Monaten Behandlungsdauer stabilisierte. Der Anstieg des IRI erfolgte gleichzeitig mit der Bildung von Antikörpern. Bei insulinresistenten Patienten ergaben sich sehr hohe IRI-Konzentrationen.

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Determination de l'insuline totale chez les diabétiques traités a l'insuline

Résumé On décrit une méthode de routine pour le dosage de l'IRI (insuline immunoréactive) totale chez les diabétiques traités par l'insuline. La méthode comprend une extraction à l'acide-éthanol, très simple, pendant laquelle l'IRI liée aux anticorps est dissociée et séparée ainsi que l'IRI »libre« des protéines sériques, anticorps compris. La récupération de l'IRI par cette méthode est aux environs de 80%. Après la séparation, l'IRI totale isolée est mesurée par un dosage immunologique qui se sert de l'éthanol afin de séparer l'I¹²⁵-insuline libre de celle liée aux anticorps. Chez 169 malades diabétiques traités par l'insuline à des doses allant de 6 à 120 unités par jour, l'IRI totale sérique à jeun était de 6 à 4374 U/ml, avec une moyenne de 392 U/ml. Pendant le traitement par l'insuline le taux de l'IRI totale est passé des niveaux normaux, enregistrés pendant les deux premiers mois, à des niveaux plus éleévs qui se stabilisent 5 mois environ apres le début du traitement. L'augmentation de l'IRI coïncide avec la formation d'anticorps. Les malades insulino-résistants présentent des valeurs très hautes d'IRI.

     

Adolescent but not adult Sprague-Dawley rats display goal-directed responding after reward devaluation

Alcohol drinking is typically initiated in adolescence, with use sometimes escalating to problematic levels. Escalation of drinking is often associated with a shift in drinking motives, with goal-directed initial use later transitioning to more habitual behavior. This study assessed whether adolescents are more sensitive than adults to habit formation when indexed via insensitivity to reward devaluation in an operant task for food reward. Adolescent and adult Sprague-Dawley rats were trained on either a random ratio (RR) or random interval (RI) schedule before undergoing devaluation. Adolescent animals on both schedules increased the number of lever presses across all training days. In contrast, adults in the RR group increased the number of lever presses across days whereas RI adults remained relatively stable. In response to pellet devaluation, only adolescents exhibited reduced responding, suggestive of goal-directed behavior, whereas no age differences were evident following control (home cage chow) devaluation. Contrary to our hypothesis, adolescents (but not adults) displayed goal-directed responding indexed via sensitivity to reward devaluation. These findings suggest that adolescents are not necessarily more likely to develop habits than adults, and hence other factors may contribute to the greater propensity of adolescents to engage in and escalate alcohol use.     

Anti-Periodontitis Effect of Ethanol Extracts of Alpinia Katsumadai Seeds

Oral microbes are intimately associated with many oral and systemic diseases. Ongoing research is seeking to elucidate drugs that prevent and treat microbial diseases. Various functions of Alpinia Katsumadai seed extracts have been reported such as their anti-viral, anti-oxidant, anti-inflammatory, anti-puritic, anti-emetic, and cytoprotective effects. Here, we investigated the anti-periodontitis effect of an ethanol extract of Alpinia Katsumadai seeds (EEAKSs) on dental plaque bacteria (DPB)-induced inflammation and bone resorption. DPB and Porphyromonas gingivalis (P. gingivalis) were cultured and lipopolysaccharide (LPS) was extracted. Prostaglandin E₂ (PGE₂) and cyclooxygenase 2 (COX-2) levels were estimated using ELISA. Cytotoxicity was also verified. Proteases were screened using a protease antibody array method. Osteoclastic bone resorption was also investigated. EEAKSs suppressed P. gingivalis growth on agar plates. LPS prepared from dental plaque bacteria (DPB-LPS) and P. gingivalis (PG-LPS) significantly increased PGE₂ and COX2 levels in immortalized gingival fibroblasts (IGFs), immortalized human oral keratinocytes (IHOKs), and RAW264.7 macrophage cells. However, DPB-LPS and PG-LPS-induced PGE₂ and COX-2 increases were effectively abolished by EEAKS treatment at non-cytotoxic concentrations. In the protease antibody array, matrix metalloproteinase (MMP)-2, MMP-3, MMP-7, kallikrein 10, cathepsin D, and cathepsin V levels were increased by PG-LPS stimulation. However, increases in protease levels except for cathepsin D were suppressed by EEAKS treatment. In addition, RANKL-induced osteoclast differentiation was significantly inhibited by EEAKS treatment, leading to reductions in resorption pit formation. These results suggest that EEAKSs exerted a beneficial oral health effect to help prevent DPB-mediated periodontal disease.     

Effect of Moderate Wine Consumption on Oxidative Stress Markers in Coronary Heart Disease Patients

Evidence from research studies reports that wine consumption is associated with lower cardiovascular disease risk, partly through the amelioration of oxidative stress. The aim of the present study was to examine the effect of regular light to moderate wine consumption from coronary heart disease (CHD) patients compared to the effect induced by alcohol intake without the presence of wine microconstituents, on oxidation-induced macromolecular damage as well as on endogenous antioxidant enzyme activity. A randomized, single-blind, controlled, three-arm parallel intervention was carried out, in which 64 CHD patients were allocated to three intervention groups. Group A consumed no alcohol, and Group B (wine) and Group C (ethanol) consumed 27 g of alcohol/day for 8 weeks. Blood and urine samples were collected at baseline and at 4 and 8 weeks. Urine oxidized guanine species levels, protein carbonyls, thiobarbituric acid substances (TBARS) levels, as well as superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities, were measured. Oxidized guanine species and protein carbonyl levels were significantly increased in the ethanol group during the intervention and were significantly decreased in the wine group. These results support the idea that wine’s bioactive compounds may exert antioxidant actions that counteract the macromolecular oxidative damage induced by alcohol in CHD patients.