Biofilm is bacterial population adherent to each other and to surfaces or interfaces, often enclosed by a matrix. Various biomolecules contribute to the establishment of biofilms, yet the process of building a biofilm is still under active investigation. Indole is known as a metabolite of amino acid tryptophan, which, however, has recently been proved to participate in various aspects of bacterial life including virulence induction, cell cycle regulation, acid resistance, and especially, signaling biofilm formation. Moreover, indole is also proposed to be a novel signal involved in quorum sensing, a bacterial cooperation behavior sometimes concerning the biofilm formation. Here the signaling role and molecular mechanism of indole on bacterial biofilm formation are reviewed, as well discussed is its relation to bacterial living adaptivity.

Buprenorphine’s clinical use is approved for the treatment of heroin addiction; however, evidence supporting its efficacy in cocaine abuse also exists. While for heroin it has been demonstrated that the effect of buprenorphine is mediated by its ability to activate μ-opioid peptide receptor (MOP) receptors, the mechanism through which it attenuates cocaine intake remains elusive. We explored this mechanism using operant models where rodents were trained to chronically self-administer cocaine for 2 hours daily. Buprenorphine (0.3, 1.0 and 3.0 mg/kg) given intraperitoneally 90 minutes before access to cocaine significantly and dose dependently reduced its intake. Pre-treatment with naltrexone or with the selective nociceptin/orphanin FQ peptide (NOP) antagonist SB-612111 did not prevent buprenorphine-induced reduction of cocaine intake. However, when naltrexone and SB-612111 were combined, the effect of buprenorphine on cocaine was completely prevented. To confirm that co-activation of MOP and NOP receptors is the underlying mechanism through which buprenorphine reduces cocaine intake, three compounds, namely, AT-034, AT-201 and AT-202, with a range of affinity and intrinsic activity profiles for MOP and NOP receptors, but weak ability for kappa-opioid peptide receptor (KOP) transmission, were tested. Consistent with our hypothesis based on buprenorphine’s effects, results demonstrated that AT-034 and AT-201, which co-activate MOP and NOP receptors, reduced cocaine self-administration like buprenorphine. AT-202, which selectively stimulates NOP receptors, was not effective. Together, these data demonstrate that for buprenorphine, co-activation of MOP and NOP receptors is essential to reduce cocaine consumption. These results open new vistas on the treatment of cocaine addiction by developing compounds with mixed MOP/NOP agonist properties.

Cocaine addiction is a widespread psychiatric condition still waiting for approved efficacious medications. Previous studies suggested that simultaneous activation of nociceptin opioid (NOP) and mu opioid (MOP) receptors could be a successful strategy to treat cocaine addiction, but the paucity of molecules co-activating both receptors with comparable potency has hampered this line of research. Cebranopadol is a non-selective opioid agonist that at nanomolar concentration activates both NOP and MOP receptors and that recently reached phase-III clinical trials for cancer pain treatment. Here, we tested the effect of cebranopadol on cocaine self-administration (SA) in the rat. We found that under a fixed-ratio-5 schedule of reinforcement, cebranopadol (25 and 50 µg/kg) decreased cocaine but not saccharin SA, indicating a specific inhibition of psychostimulant consumption. In addition, cebranopadol (50 µg/kg) decreased the motivation for cocaine as detected by reduction of the break point measured in a progressive-ratio paradigm. Next, we found that cebranopadol retains its effect on cocaine consumption throughout a 7-day chronic treatment, suggesting a lack of tolerance development toward its effect. Finally, we found that only simultaneous blockade of NOP and MOP receptors by concomitant administration of the NOP antagonist SB-612111 (30 mg/kg) and naltrexone (2.5 mg/kg) reversed cebranopadol-induced decrease of cocaine SA, demonstrating that cebranopadol activates both NOP and classical opioid receptors to exert its effect. Our data, together with the fairly advanced clinical development of cebranopadol and its good tolerability profile in humans, indicate that cebranopadol is an appealing candidate for cocaine addiction treatment.

Cocaine dependence is a psychiatric condition for which effective medications are still lacking. Published data indicate that an increase in nociceptin/orphanin FQ (N/OFQ) transmission by NOP receptor activation attenuates cocaine-induced place conditioning and the locomotor sensitization effects of cocaine. This suggests that the activation of the N/OFQ receptor (NOP) may attenuate the motivation for psychostimulants. To further explore this possibility, we investigated the effect of the potent and selective NOP receptor agonist Ro 64-6198 on cocaine intake under 1 h short access (ShA) and 6 h long access (LgA) operant self-administration conditions in rats. We used Marchigian Sardinian alcohol-preferring (msP) rats and Wistar control rats. msP rats were used because we recently found that this rat line, originally selected for excessive alcohol drinking and preference, exhibits a greater propensity to escalate cocaine self-administration following LgA training. msP rats are also characterized by innate overexpression of the N/OFQ-NOP system compared with Wistar rats. Wistar and msP rats both exhibited an increase in cocaine self-administration under LgA conditions, with a higher trend toward escalation in msP rats. In Wistar rats, the intraperitoneal administration of Ro 64-6198 (0. 1 and 3 mg/kg) significantly decreased ShA cocaine self-administration. In Wistar rats that underwent LgA cocaine self-administration training, Ro 64-6198 induced no significant effect either during the first hour of self-administration or after the entire 6 h session. In msP rats, Ro 64-6198 significantly reduced cocaine self-administration both under ShA conditions and in the first hour of the LgA session. At the end of the 6 h session, the effect of Ro 64-6198 was no longer observed in msP rats. The highest dose of Ro 64-6198 (3 mg/kg) did not affect saccharin self-administration in msP rats but reduced saccharin self-administration in Wistar rats. Altogether, these data suggest that NOP receptor activation attenuates cocaine self-administration, and this effect tends to be more pronounced in a rat line with innately higher NOP receptor expression and that more robustly escalates cocaine intake.

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