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The objective of the present study is to investigate the role of α4, α5, α6 or β2 nAChR subunits in the antidepressant-like effect of bupropion. Adult male mice were treated with subcutaneous acute doses of bupropion (3 and 10 mg/kg) 30 min before the forced swim test (FST) in α4, α5, α6, or β2 nAChR subunit knockout (KO) and wild-type (WT) mice. In addition, the effects of β2* antagonist dihydro-β-erythroidine (DHβE, 3 mg/kg) on antidepressant-like effects of bupropion in C57BL/6 J mice were assessed. Our results showed that baseline immobility and climbing time did not differ between KO and corresponding WT mice except for β2 KO. Bupropion significantly decreased immobility time and increased climbing time in the α4, α6 and β2 nAChR KO mice in comparison to WT littermates, indicating that lack of these nAChR subunits enhanced antidepressant effects of bupropion. On the contrary, the α5 nAChR subunit deletion did not alter the FST behavior in the bupropion-treated mice. Not only in the transgenic mice, bupropion also showed antidepressant-like effects in the WT mice. In addition, DHβE pretreatment before bupropion administration resulted in decreased immobility time and increased climbing time. Taken together, the present study provides evidence on the involvement of α4*, α6*, and β2* (* indicates possible presence of other subunits) nAChRs in the antidepressant-like effects of bupropion in the FST., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Evidence suggests that there is an association between polymorphisms in the α5 nicotinic acetylcholine receptor (nAChR) subunit and risk of developing alcohol dependence in humans. The α5 nAChR subunit has also recently been shown to modulate some of the acute response to ethanol in mice. The aim of the current study was to further characterize the role of α5-containing (α5*) nAChRs in acute ethanol responsive behaviors, ethanol consumption and ethanol preference in mice. We conducted a battery of tests in male α5 knockout (KO) mice for a range of ethanol-induced behaviors including hypothermia, hypnosis, and anxiolysis. We also investigated the effects of α5* nAChR on ethanol reward using the Conditioned Place Preference (CPP) assay. Further, we tested the effects of gene deletion on drinking behaviors using the voluntary ethanol consumption in a two-bottle choice assay and Drinking in the Dark (DID, with or without stress) paradigm. We found that deletion of the α5 nAChR subunit enhanced ethanol-induced hypothermia, hypnosis, and an anxiolytic-like response in comparison to wild-type controls. The α5 KO mice showed reduced CPP for ethanol, suggesting that the rewarding properties of ethanol are decreased in mutant mice. Interestingly, Chrna5 gene deletion had no effect on basal ethanol drinking behavior, or ethanol metabolism, but did decrease ethanol intake in the DID paradigm following restraint stress. Taken together, we provide new evidence that α5 nAChRs are involved in some but not all of the behavioral effects of ethanol. Our results highlight the importance of nAChRs as a possible target for the treatment of alcohol dependence., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Despite synergistic increases in risks of various cancers, the incidence of concomitant smoking and drinking remains high. An additive or synergistic analgesic effect of combined alcohol and nicotine may contribute to their coabuse. Recently, we provided evidence that doses of alcohol and nicotine that are ineffective in inducing an antinociceptive effect alone, when combined, can induce such an effect. Moreover, this antinociceptive effect could be attenuated by pretreatment with the nonselective opioid antagonist naloxone. The purpose of this study was to determine the role of selective opioid receptor subtypes (micro, delta, and kappa) in mediating the antinociceptive effects of alcohol, nicotine, and their combination., Methods: Adult male Wistar rats were administered selective opioid antagonists, D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP, for micro receptor, 1.0 mg/kg), naltrindole (for delta receptors, 10 mg/kg), and norbinaltorphimine (nor-BNI, for kappa receptor, 10 mg/kg) before injection of alcohol, nicotine or their combination. The animals were tested in hot-plate and tail-flick assays, representing nociception mediated predominantly via brain or spinal pathways, respectively. All the injections were administered acutely and the nociceptive tests were carried out 20 minutes after alcohol and 10 minutes after nicotine administration., Results: In general, the antagonists were more effective in blocking the effects of alcohol, nicotine, or their combination in the tail-flick versus the hot-plate assay. CTAP was most effective in blocking the effects of alcohol alone and nicotine alone in the tail-flick test, whereas in the hot-plate test both CTAP and naltrindole were more effective than nor-BNI. All 3 antagonists had a very similar profile in attenuating the combination of alcohol and nicotine effect in the hot-plate assay. None of the antagonists had a significant effect against the highest alcohol-nicotine dose in this test. In the tail-flick test, however, CTAP and naltrindole were more effective than nor-BNI in attenuating the highest alcohol-nicotine dose., Conclusions: The data suggest the utility of all 3 opioid antagonists in blocking the effects of alcohol, nicotine, or their combination in spinally mediated antinociception. Although the supraspinally mediated antinociception was also attenuated by the opioid antagonists, further investigation of combination doses of these antagonists in fully blocking the supraspinal effects or attenuating voluntary alcohol and nicotine intake is warranted.

Both alcohol and nicotine have been shown to possess antinociceptive or analgesic effects. An additive or synergistic antinociceptive effect induced by simultaneous administration of alcohol and nicotine could further contribute to their co-abuse. In this study, we sought to evaluate the antinociceptive effects of various combinations of ethanol and nicotine and to determine whether these effects could be blocked by an opioid antagonist. Adult male Wistar rats were treated with various doses of alcohol (0.1-2 g/kg), nicotine (0.01-2 mg/kg) or their combination and their behavior in tail flick test, reflective of spinal antinociception and hotplate test, mainly reflective of supraspinal antinociception were evaluated. Alcohol at the highest dose of 2 g/kg resulted in significant antinociceptive effects in both assays. Nicotine at 1 mg/kg resulted in significant antinociception in the hotplate; however, in the tail flick test a dose of 2 mg/kg was required for an antinociceptive effect. Combination of doses of alcohol and nicotine that were ineffective by themselves resulted in antinociceptive responses in both paradigms. These effects were attenuated by pretreatment with the non-selective opioid receptor antagonist naloxone. The data indicate that a combination of alcohol and nicotine can result in a synergistic antinociceptive response that is at least partially mediated by the opioid system. The analgesic effects induced by combination of alcohol and nicotine may be a contributory factor in their co-abuse.

Previous studies demonstrated that analogs of benztropine (BZT) possess high affinity for the dopamine (DA) transporter (DAT) but generally have behavioral effects different from those of cocaine, suggesting either unique actions at the DA transporter or that another action of these drugs interferes with cocaine-like effects. Because the parent compound has histamine-antagonistic effects, the affinity of its analogs for histamine H(1), H(2), and H(3) receptors were compared with DA transporter affinity to assess whether those differences predicted the amount of cocaine-like activity. All of the compounds displaced [(3)H]mepyramine from H(1), [(125)I]iodoaminopotentidine from H(2), and [(3)H]N-alpha-methylhistamine from H(3) histamine receptors with affinities ranging from 15.7 to 37,600, 218 to >4430, and 4040 to >150,000 nM, respectively. Affinities at histamine H(1) receptors were, respectively, approximately 25- or 300-fold greater than those at H(2) or H(3) histamine receptors. Relative affinities for H(1) and DAT binding did not reliably predict the degree of cocaine-like stimulation of locomotor activity. In addition, interactions of various histaminic agents with cocaine assessed whether an action at any of the histamine sites could interfere with cocaine-like effects. None of the histaminic agents fully substituted for cocaine in rats trained to discriminate 10 mg/kg cocaine from saline nor did any of the compounds antagonize or otherwise diminish the discriminative stimulus effects of cocaine. The results suggest that affinity for histamine receptors cannot account for the diminished cocaine-like effects of the BZT analogs and suggest alternatively that these compounds have actions different from those of cocaine but likely mediated by their interaction with the DAT.

ATP-gated K(+) channel openers produce antinociception that is attenuated by opioid receptor antagonists, indicating K-ATP openers produce antinociception, in part, via the release of endogenous opioid peptides. Utilizing the spinal perfusion method, male Sprague-Dawley rats were administered minoxidil intrathecally (i.t.) at doses ranging from 12.5 to 200 microg/rat for 3 min, tested for antinociception using the tail-flick test, and perfused with artificial cerebrospinal fluid (aCSF) to collect endogenous opioid peptides. Endogenous opioid peptide levels were measured by radioimmunoassay. Naltrindole, a delta-opioid receptor antagonist, at 4 mg/kg, subcutaneously (s.c.), blocked minoxidil-induced antinociception. beta-Funaltrexamine, a mu-opioid receptor antagonist, at 100 microg/rat, partially blocked minoxidil, whereas the kappa-opioid receptor antagonist nor-binaltorphimine, at a dose of 100 microg/rat, did not attenuate minoxidil. Although antagonists of the mu- and delta-opioid receptor attenuated minoxidil-induced antinociception, there was no increase in beta-endorphin, an endogenous ligand with affinity for both micro- and delta-opioid receptors or [Leu(5)]enkephalin, an endogenous ligand with affinity for delta-opioid receptors.

Our laboratory demonstrated that morphine exhibits a modulatory control over the glyburide-binding site (sulfonylurea receptor) of the ATP-gated K(+) channel. This study evaluated the effect of chronic morphine administration on the sulfonylurea receptor during tolerance and physical dependence. ICR and Swiss-Webster mice were rendered tolerant to morphine by pellet implantation and were withdrawn by pellet removal. Alterations in the B(max) and K(D) were evaluated in mouse spinal cord using the radiolabeled ATP-gated K(+) channel blocker glyburide. The ED(50) for Swiss-Webster mice shifted from 13 to 451 mg/kg and thus they were more tolerant to morphine than ICR mice (ED(50) shift from 12 to 120 mg/kg). Swiss-Webster mice were also dependent to morphine only when the morphine pellet was in place, unlike ICR mice, which were dependent for 48 h after morphine pellet removal. Glyburide binding increased during chronic morphine treatment in Swiss-Webster mice by over 2-fold (from 294 to 635 fmol/mg of protein). This was not observed in ICR mice. In Swiss-Webster mice, chronic morphine treatment also significantly increased the K(D) by 3-fold (from 0.38 to 1.1 nM), whereas there was no change in affinity for ICR mice. Both strains of mice remained tolerant for 2 days after spontaneous withdrawal from morphine. However, the only increases in the B(max) and K(D) of glyburide were observed in Swiss-Webster mice that were highly tolerant to morphine. These results indicate that a high degree of tolerance is needed to alter ATP-gated potassium channels.

Electroencephalogram monitoring is a valuable means of monitoring thalamocortical function in the comatose, sedated, or paralyzed patient in the intensive care unit. The following problems arise especially with long-term recordings that are beyond those experienced in the standard EEG laboratory: 1) faulty electrodes, either single- or multiple-scalp electrodes or ground or reference electrodes; 2) connections of electronic equipment; 3) induced artifacts from electronic devices and nonelectronic equipment; 4) electrode placement issues; and 5) biologic, including movement-related, artifacts. Continuous quality improvement strategies should be implemented to minimize problems. Prompt troubleshooting and regular review sessions are two important components.