R-(-)-ketamine modifies behavioral effects of morphine predicting efficacy as a novel therapy for opioid use disorder1.

Substance abuse disorder continues to have devastating consequences for individuals and society and current therapies are not sufficient to provide the magnitude of medical impact required. Although some evidence suggests the use of ketamine in treating various substance use related- symptoms, its adverse event profile including dissociation, dysphoria, and abuse liability limit its potential as a therapy. Here, we outline experiments to test our hypothesis that (R)-ketamine can both alleviate withdrawal symptoms and produce effects that help sustain abstinence. In morphine-dependent rats, (R)-ketamine alleviated naloxone-precipitated withdrawal signs. (R)-ketamine also blocked morphine-induced place preference in mice without inducing place preference on its own. We also evaluated whether (R)-ketamine would induce anhedonia, a counter-indicated effect for a drug abuse treatment agent. S-(+)- but not R-(-)-ketamine produced anhedonia-like responses in rats that electrically self-stimulated the medial forebrain bundle (ICSS). However, time-course studies of ICSS are needed to fully appreciate these differences. These data begin to support the claim that (R)-ketamine will dampen withdrawal symptoms and drug liking, factors known to contribute to the cycle of drug addiction. In addition, these data suggest that (R)-ketamine would not produce negative mood or anhedonia that could interfere with treatment. It is suggested that continued investigation of (R)-ketamine as a novel therapeutic for substance abuse disorder be given consideration by the preclinical and clinical research communities. This suggestion is further encouraged by a recent report on the efficacy of (R)-ketamine in treatment-resistant depressed patients at a dose with little measurable dissociative side-effects.

Pharmacological characterization of the response of the leech pharynx to acetylcholine.

In this study we document the sensitivity of the leech pharynx to acetylcholine and begin to characterize the acetylcholine receptor mediating this response by examining the effects of selective cholinergic agonists and antagonists on the contractile behavior of the pharynx. The order of potency derived from the EC50 of each agonist was (+/-)epibatidine > acetylcholine (in the presence of physostigmine) >> McN A-343 >> carbachol > nicotine. However, when response amplitude was considered, the order of potency to the tested agonists was (+/-)epibatidine >> nicotine >> McN A-343 >> carbachol > acetylcholine. Acetylcholine-induced contractions of the pharynx were antagonized by d-tubocurarine, but not by alpha-bungarotoxin, alpha-conotoxin M1, or mecamylamine. Application of high concentrations of hexamethonium (1 mM) augmented the acetylcholine-induced contractions. However, this augmentation was apparently due to inhibition of acetylcholinesterase by hexamethonium. The muscarinic antagonist atropine produced complex actions and apparently acted as a mixed agonist/antagonist. Atropine by itself produced an increase in basal tonus and increased the frequency and amplitude of phasic contractions. Atropine increased the peak tension of the acetylcholine-induced response; however, it reduced the amplitude of both the acetylcholine-induced increase in basal tonus and integrated area. Based on the pharmacological profile of the pharyngeal acetylcholine response, we conclude that the acetylcholine receptor mediating the response is a nicotinic receptor. However, the responsiveness of the pharynx to muscarinic agents diverges from that of a classical nicotinic receptor.

[Tolerance of Haemofusin in hemodilution and volume substitution]. / Untersuchungen zur Verträglichkeit von Haemofusin in der Hämodilution und Volumensubstitution.

In an open and uncontrolled trial the frequency and the type of adverse events were registered in patients who received Haemofusin, a hydroxyethyl starch solution, either for volume substitution or haemodilution. A total of 379 patients were investigated. No serious allergic reaction occurred. Headache, fever, rigor, light allergic reactions and nausea were documented in 17 patients. Even if one assumes that these observed concomitant events were caused by the hydroxyethyl starch, Haemofusin proved to be a well-tolerated colloid with a low rate of side effects (4.5%).