Neuropharmacology
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Vulnerability to the addictive effects of drugs of abuse varies among individuals, but the biological basis of these differences are poorly known. This work tries to increase this knowledge by comparing the brain proteome of animals with different rate of extinction of cocaine-seeking behaviour. To achieve this goal, we used a place-preference paradigm to separate Sprague Dawley rats in two groups: rats that extinguished (E) and rats that did not extinguish (NE) cocaine-seeking behaviour after a five-day period of drug abstinence. ⋯ When comparing E SAL and NE SAL animals we found significant differences in the expression level of 5 proteins: ATP synthase subunit alpha, fumarate hydratase, transketolase, NADH dehydrogenase [ubiquinone] flavoprotein 2 and glutathione transferase omega-1. A single injection of COC differently alters the NAC proteome of E and NE rats; thus in E COC animals there was an alteration in the expression of 6 proteins, including dihydropyrimidinase-related protein 2 and NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10; whereas in NE COC rats 9 proteins were altered (including alpha-synuclein, peroxiredoxin-2 and peroxiredoxin-5). These proteins could be potential biomarkers of individual vulnerability to cocaine abuse and may be helpful in designing new treatments for cocaine addiction.
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There is poor experimental evidence concerning the effects of anesthetic doses of the non-competitive NMDA receptor antagonist ketamine on rodents' memory abilities. The present study was designed to investigate a) the long-term consequences of anesthetic ketamine on rats' non-spatial and spatial recognition memory; b) to evaluate whether or not these effects are related to the hypothermic properties of ketamine and c) to detect when the (amnestic) effects of ketamine on recognition memory were extinguished. ⋯ Pre-training administration of ketamine (100 mg/kg; i.p.) disrupted animals' performance in the object location task and to some extent also in the object recognition paradigm indicating that anesthetic ketamine impaired both spatial and non-spatial recognition memory. Hypothermia-induced by this NMDA receptor antagonist and the type (spatial vs. non-spatial) of the behavioral paradigm utilized seem to affect rats' recognition memory recovery.
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Persistent inflammatory nociception increases levels of endogenous opioids with affinity for delta opioid receptors in the ventromedial medulla and enhances the antinociceptive effects of the mu opioid receptor (MOPr) agonist [D-Ala2, N-Me-Phe4, Gly5-ol]enkephalin (DAMGO) [Hurley, R. W., Hammond, D. L., 2001. ⋯ Microinjection of the MOPr antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) in the LC did not exacerbate hyperalgesia in the ipsilateral hindpaw or produce hyperalgesia in the contralateral hindpaw of CFA-treated rats. The downregulation in MOPr is therefore unlikely to result from the induction of endogenous opioid tolerance in the LC. These results indicate that persistent inflammatory nociception alters the antinociceptive actions of MOPr agonists in the CNS by diverse mechanisms that are nucleus specific and likely to have different physiological implications.
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Both the clinical tolerability and the symptomatic effects of memantine in the treatment of Alzheimer's disease have been attributed to its moderate affinity (IC(50) around 1 microM at -70 mV) for NMDA receptor channels and associated fast, double exponential blocking/unblocking kinetics and strong voltage-dependency. Most of these biophysical data have been obtained from rodent receptors. Some substances show large species-specific differences, so using human rather than rodent receptors and tissue may highlight important differences in the effects of drugs. ⋯ Moreover, the rapid double exponential blocking kinetics (e.g. at 10 microM - onset tau(fast)=273+/-25 ms (weight 69%), onset tau(slow)=2756+/-296 ms, offset tau(fast)=415+/-82 ms (weight 38%) offset tau(slow)=5107+/-1204 ms) and partial untrapping (around 20%) previously reported for memantine on rodent receptors were confirmed for human receptors. Ketamine showed similar potency (IC(50) at -70 mV of 0.71+/-0.03 microM, Hill=0.84+/-0.02) but somewhat less pronounced voltage-dependency (delta=0.79+/-0.04), slower, single exponential kinetics (ketamine: k(on)=0.15+/-0.05 x 10(6)M(-1)s(-1), k(off)=0.22+/-0.05 s(-1)c.f. memantine following normalization k(on)=0.32+/-0.11 x 10(6)M(-1)s(-1), k(off)=0.53+/-0.10s(-1)) and was fully trapped. The present data closely match previously reported data from studies in rodent receptors and suggest that the proposed mechanism of action of memantine in Alzheimer's disease as a fast, voltage-dependent open-channel blocker of NMDA receptors can be confirmed for human NMDA receptors.
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Postoperative cognitive dysfunction (POCD) is a decline in cognitive performance after a surgery performed under anaesthesia. The exact roles of surgery and/or anaesthesia for facilitating POCD are unclear. This study investigates the effects of isoflurane anaesthesia on cognitive performance and cellular mechanisms involved in learning and memory function. ⋯ Blocking these receptors either with the NR2B selective antagonists ifenprodil or RO25-6981 (R-(R,S)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidine propranol), prevents the anaesthesia-induced improvement in cognitive function as well as enhancement of in vitro LTP. The anaesthesia-mediated effects on NR2B subunits were fully reversed to control levels seven days after anaesthesia. The present data suggests that isoflurane anaesthesia induces a hippocampus-specific elevation of NR2B subunit composition, enhances LTP in CA1 neurones, and produces hippocampal-dependent cognitive improvement.