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Rationale It has been suggested that the increase in serotonin transmission induced by indirect agonists such as fenfluramine and fluoxetine attenuates cue-elicited reinstatement of cocaine-seeking in rats through a 5-HT 2C receptor-dependent mechanism. Objective We investigated whether Ro 60-0175, a nonselective 5-HT 2B–2C agonist, influences cue-elicited reinstatement of cocaine-seeking behavior. We evaluated the 5-HT 2C receptor’s role in Ro 60-0175 by studying its interaction with SB-242,084, a selective 5-HT 2C antagonist. The study also explored whether Ro 60-0175 influences cue-elicited seeking behavior associated with sucrose, a highly palatable nutritive reinforcer. Materials and methods Different groups of free-feeding rats were trained to associate discriminative stimuli (S D s) with the availability of cocaine or a sucrose pellet or no-reward in two-lever operant cages. Cocaine and sucrose pellets were available under an FR1 schedule of reinforcement, and each reinforcer was followed by a 20-s timeout signaled by a cue light coming above the active lever. After extinction of reinforced responding in the absence of cue, the reinforcer-associated stimuli were reintroduced in reinstatement sessions in which reinforcers were withheld. Results Ro 60-0175, at IP doses from 0.1 to 1 mg/kg, dose-dependently reduced cocaine-seeking behavior, while 1 mg/kg had no such effect for the sucrose pellet. Pretreatment with 1 mg/kg SC SB-242,084 completely prevented the effect on cocaine-seeking behavior. Conclusions These findings, provided they can be extrapolated to abstinent human addicts, suggest therapeutic potential for the selective 5-HT 2C agonist in preventing cue-controlled cocaine-seeking and relapse.

PurposeWhether skin disinfection of the surgical site using chlorhexidine-alcohol is superior to povidone-iodine-alcohol in reducing reoperation and surgical site infection rates after major cardiac surgery remains unclear.MethodsCLEAN 2 was a multicenter, open-label, randomized, two-arm, assessor-blind, superiority trial conducted in eight French hospitals. We randomly assigned adult patients undergoing major heart or aortic surgery via sternotomy, with or without saphenous vein or radial artery harvesting, to have all surgical sites disinfected with either 2% chlorhexidine-alcohol or 5% povidone-iodine-alcohol. The primary outcome was any resternotomy by day 90 or any reoperation at the peripheral surgical site by day 30.ResultsOf 3242 patients (1621 in the chlorhexidine-alcohol group [median age, 69 years; 1276 (78.7%) men] and 1621 in the povidone-iodine-alcohol group [median age, 69 years; 1247 (76.9%) men], the percentage required reoperation within 90 days was similar (7.7% [125/1621] in the chlorhexidine-alcohol group vs 7.5% [121/1621] in the povidone-iodine-alcohol group; risk difference, 0.25 [95% confidence interval (CI), − 1.58–2.07], P = 0.79). The incidence of surgical site infections at the sternum or peripheral sites was similar (4% [65/1621] in the chlorhexidine-alcohol group vs 3.3% [53/1621] in the povidone-iodine-alcohol group; risk difference, 0.74 [95% CI − 0.55–2.03], P = 0.26). Length of hospital stay, intensive care unit or hospital readmission, mortality and surgical site adverse events were similar between the two groups.ConclusionAmong patients requiring sternotomy for major heart or aortic surgery, skin disinfection at the surgical site using chlorhexidine-alcohol was not superior to povidone-iodine-alcohol for reducing reoperation and surgical site infection rates.

The non-selective opioid receptor antagonist naltrexone reduces cocaine-induced reinstatement of drug-seeking behaviour in abstinent rats. The current study sought to determine whether the opioid system is also involved in cocaine-seeking behaviour induced by cocaine-associated stimuli in abstinent rats. Adult male rats were trained to press a lever either to self-administer cocaine or to obtain sucrose pellets in the presence of distinctive discriminative and conditioned stimuli. After a period of extinction, re-exposure to cocaine-associated cues selectively elicited robust and enduring responding at the active lever; sucrose pellet-associated cues revived seeking behaviour less pronouncedly. Pretreatment with naltrexone (0.25, 1, 2.5 mg/kg s.c., 20 min before reinstatement tests) dose dependently prevented cue-induced cocaine-seeking behaviour, whereas (2.5 mg/kg s.c.) did not affect the degree of cue-induced sucrose-seeking behaviour. These results provide the first evidence that naltrexone influences cocaine seeking induced by conditioned stimuli in abstinent rats; this effect appears selective for cocaine reinstatement as opposed to a non-drug reinforcer.

Rationale: It has been suggested that the increase in serotonin transmission induced by indirect agonists such as fenfluramine and fluoxetine attenuates cue-elicited reinstatement of cocaine-seeking in rats through a 5-HT sub(2C) receptor-dependent mechanism. Objective: We investigated whether Ro 60-0175, a nonselective 5-HT sub(2B-2C) agonist, influences cue-elicited reinstatement of cocaine-seeking behavior. We evaluated the 5-HT sub(2C) receptor's role in Ro 60-0175 by studying its interaction with SB-242,084, a selective 5-HT sub(2C) antagonist. The study also explored whether Ro 60-0175 influences cue-elicited seeking behavior associated with sucrose, a highly palatable nutritive reinforcer. Materials and methods: Different groups of free-feeding rats were trained to associate discriminative stimuli (S super(D)s) with the availability of cocaine or a sucrose pellet or no-reward in two-lever operant cages. Cocaine and sucrose pellets were available under an FR1 schedule of reinforcement, and each reinforcer was followed by a 20-s timeout signaled by a cue light coming above the active lever. After extinction of reinforced responding in the absence of cue, the reinforcer-associated stimuli were reintroduced in reinstatement sessions in which reinforcers were withheld. Results: Ro 60-0175, at IP doses from 0.1 to 1 mg/kg, dose-dependently reduced cocaine-seeking behavior, while 1 mg/kg had no such effect for the sucrose pellet. Pretreatment with 1 mg/kg SC SB-242,084 completely prevented the effect on cocaine-seeking behavior. Conclusions: These findings, provided they can be extrapolated to abstinent human addicts, suggest therapeutic potential for the selective 5-HT sub(2C) agonist in preventing cue-controlled cocaine-seeking and relapse.

Chemokine and opioid receptors are G-protein-coupled receptors that play important roles in both the central nervous system and the immune system. The long-term goal of our research is to establish whether opioids regulate the activity of the chemokine receptor CXCR4 (one of the major HIV co-receptors) in the brain. In this research, we studied the anatomical distribution of functional receptors in young and adult animals by using the [ 35 S]GTPγS “binding” assay as an indication of G-protein activation by CXCL12 (the natural CXCR4 ligand) or by μ-opioid agonists. Brain slices or homogenates from Holtzmann rats of different ages (from 2 to 21 days old and adult animals) were treated with CXCL12 (0.001–100 nM), d -ala2,MePhe4,gly-ol5]enkephalin (DAMGO; 0.0003–10 μM) or morphine (0.0003–10 μM) and then processed for the assay. Our results show stimulation of both μ-OR and CXCR4 in several brain areas, including cortex and hippocampus ( p  < 0.001); this effect is dose and age dependent, and the magnitude of response varies among different brain regions. Furthermore, AMD3100 (100 ng/ml), a specific CXCR4 antagonist, abolished CXCL12 stimulation in all the brain regions analyzed ( p  < 0.001). Our findings suggest a similar pattern of expression for μ-OR and CXCR4 in the brain, supporting the possibility of an interaction between the two G-protein-coupled receptors in vivo. This might be relevant to the role of opiates in HIV neuropathogenesis.

Gamma-hydroxybutyric acid (GHB) is an endogenous brain substance that has diverse neuropharmacological actions, including rewarding properties in different animal species and in humans. As other drugs of abuse, GHB affects the firing of ventral tegmental neurons (VTA) in anaesthetized animals and hyperpolarizes dopaminergic neurons in VTA slices. However, no direct behavioural data on the effects of GHB applied in the VTA or in the target regions of its dopaminergic neurons, e.g. the nucleus accumbens (NAc), are available. Here, we investigated the effects of various doses of intravenous GHB in maintaining self-administration (from 0.001 to 10 mg/kg per infusion), and its ability to induce conditioned place preference (CPP) in rats when given orally (175–350 mg/kg) or injected directly either in the VTA or NAc (from 10 to 300 μg/0.5 μl per side). Our results indicate that while only 0.01 mg/kg per infusion GHB maintained self-administration, although not on every test day, 350 mg/kg GHB given orally induced CPP. CPP was also observed when GHB was injected in the VTA (30–100 μg/0.5 μl per side) but not in the NAc. Together with recent in-vitro findings, these results suggest that the rewarding properties of GHB mainly occur via disinhibition of VTA dopaminergic neurons.

Chemokine and opioid receptors are G-protein-coupled receptors that play important roles in both the central nervous system and the immune system. The long-term goal of our research is to establish whether opioids regulate the activity of the chemokine receptor CXCR4 (one of the major HIV co-receptors) in the brain. In this research, we studied the anatomical distribution of functional receptors in young and adult animals by using the [S]GTP gamma S 'binding' assay as an indication of G-protein activation by CXCL12 (the natural CXCR4 ligand) or by is a subset of -opioid agonists. Brain slices or homogenates from Holtzmann rats of different ages (from 2 to 21 days old and adult animals) were treated with CXCL12 (0.001--100 nM), d-ala2,MePhe4,gly-ol5]enkephalin (DAMGO; 0.0003--10 is a subset of M) or morphine (0.0003--10 is a subset of M) and then processed for the assay. Our results show stimulation of both is a subset of -OR and CXCR4 in several brain areas, including cortex and hippocampus (p<0.001); this effect is dose and age dependent, and the magnitude of response varies among different brain regions. Furthermore, AMD3100 (100 ng/ml), a specific CXCR4 antagonist, abolished CXCL12 stimulation in all the brain regions analyzed (p<0.001). Our findings suggest a similar pattern of expression for is a subset of -OR and CXCR4 in the brain, supporting the possibility of an interaction between the two G-protein-coupled receptors in vivo. This might be relevant to the role of opiates in HIV neuropathogenesis.

Chemokine and opioid receptors are G-protein-coupled receptors that play important roles in both the central nervous system and the immune system. The long-term goal of our research is to establish whether opioids regulate the activity of the chemokine receptor CXCR4 (one of the major HIV co-receptors) in the brain. In this research, we studied the anatomical distribution of functional receptors in young and adult animals by using the [(35)S]GTPgammaS \"binding\" assay as an indication of G-protein activation by CXCL12 (the natural CXCR4 ligand) or by mu-opioid agonists. Brain slices or homogenates from Holtzmann rats of different ages (from 2 to 21 days old and adult animals) were treated with CXCL12 (0.001-100 nM), D: -ala2,MePhe4,gly-ol5]enkephalin (DAMGO; 0.0003-10 microM) or morphine (0.0003-10 microM) and then processed for the assay. Our results show stimulation of both mu-OR and CXCR4 in several brain areas, including cortex and hippocampus (p < 0.001); this effect is dose and age dependent, and the magnitude of response varies among different brain regions. Furthermore, AMD3100 (100 ng/ml), a specific CXCR4 antagonist, abolished CXCL12 stimulation in all the brain regions analyzed (p < 0.001). Our findings suggest a similar pattern of expression for mu-OR and CXCR4 in the brain, supporting the possibility of an interaction between the two G-protein-coupled receptors in vivo. This might be relevant to the role of opiates in HIV neuropathogenesis.