Tigecycline Reduces Ethanol Intake in Dependent and Nondependent Male and Female C57BL/6J Mice

Abstract

Background The chronic intermittent ethanol (CIE) paradigm is valuable for screening compounds for efficacy to reduce drinking traits related to alcohol use disorder (AUD), as it measures alcohol consumption and preference under physical dependence conditions. Air control treated animals allow simultaneous testing of similarly treated, non-dependent animals. As a consequence, we used CIE to test the hypothesis that tigecycline, a semi-synthetic tetracycline similar to minocycline and doxycycline, would reduce alcohol consumption regardless of dependence status. Methods Adult C57BL/6J female and male mice were tested for tigecycline efficacy to reduce ethanol consumption using a standard CIE paradigm. The ability of tigecycline to decrease 2-bottle choice of 15% ethanol (15E) versus water intake in dependent (CIE-vapor) and non-dependent (air-treated) male and female mice was tested after four cycles of CIE vapor or air exposure using a within-subjects design and a dose response. Drug doses of 0, 40, 60, 80, 100 mg/kg in saline were administered intraperitoneally (0.01 mL/g body weight) and in random order, with a 1 hr pretreatment time. Baseline 15E intake was re-established prior to administration of subsequent injections, with a maximum of two drug injections tested per week. Results Tigecycline was found to effectively reduce high alcohol consumption in both dependent and non-dependent female and male mice. Conclusions Our data suggest that tigecycline may be a promising drug with novel pharmacotherapeutic characteristics for the treatment of mild to severe AUD in both sexes.

Repurposing Tigecycline for the Treatment of Alcohol Use Disorder

“…In this commentary, Syapin and colleagues () explore how tigecycline outperforms doxycycline and minocycline in reducing binge alcohol drinking in the dark (DID). In agreement with their findings, Bergeson and colleagues () further elucidate how tigecycline can reliably reduce alcohol dependence in a combined chronic intermittent ethanol (CIE) vapor and 2‐bottle choice alcohol consumption model (Fig. ).…”

“…Therefore, these results should be strengthened by future studies that test tigecycline on rodent models (i.e., high‐alcohol‐preferring P‐rat or HAD1 rat model) known for their inherent high baseline of alcohol consumption (Bell et al., ). Taken together, Syapin and colleagues () and Bergeson and colleagues () indicate that tigecycline shows significant efficacy in reducing binge alcohol intake as well as alcohol consumption in alcohol‐dependent male and female mice.…”

“…Although tigecycline appears to be the least efficacious in reducing alcohol consumption, its advantages lie in that it does not alter water intake or induce toxicity, a shared effect of doxycycline and minocycline. The evidence for reduction in male and female DID alcohol consumption by semi‐synthetic tetracyclines provided by Syapin and colleagues () is further strengthened in a second investigation by Bergeson and colleagues (), which specifically focuses on the ability of tigecycline to significantly dampen alcohol dependence in a combined CIE vapor and 2‐bottle choice alcohol consumption model. In this study, Bergeson and colleagues show that tigecycline was efficacious in reducing alcohol consumption in both male and female C57BL/6J mice, without affecting water consumption.…”

“…As Syapin and colleagues () and Bergeson and colleagues () point out in their discussion, follow‐up mechanistic studies are indeed warranted to understand how this class of antibiotics function to reduce alcohol consumption. One mechanism worthy of consideration is the potential effect of tigecycline on the expression of genes that regulate synaptic levels of glutamate.…”

Binge Ethanol Consumption Increases Inflammatory Pain Responses and Mechanical and Cold Sensitivity: Tigecycline Treatment Efficacy Shows Sex Differences

“…We, and others, have recently shown that treatment with tetracycline analogs reduced alcohol consumption and other alcohol‐mediated responses (Agrawal et al., , ; McIver et al., ), and tetracycline reduction of pain has been well studied since the first evidence was reported in the 1990s (Bastos et al., ). Here, due to our companion studies showing efficacy to reduce binge and dependence drinking as well as alcohol withdrawal symptoms (Bergeson et al., ; Martinez et al., ; Syapin et al., ), we focus on tigecycline (TYGACIL, Pfizer), the first glycylcycline–tetracycline to be approved as an antibiotic by the U.S. Food and Drug Administration (Falagas et al., ). Although some studies have demonstrated effective properties of minocycline (second‐generation semisynthetic tetracycline derivative) in the formalin (Cho et al., ) and surgically‐induced neuropathic pain models (Padi and Kulkarni, ), the novel analgesic properties of tetracycline‐like compounds need to be investigated further, especially if tigecycline, or a derivative, is to become an important AUD treatment.…”