Effective Reduction in High Ethanol Drinking by Semisynthetic Tetracycline Derivatives

Abstract

Background New pharmacotherapies to treat Alcohol Use Disorders (AUD) are needed. Given the complex nature of AUD, there likely exist multiple novel drug targets. We, and others, have shown that the tetracycline drugs, minocycline and doxycycline, reduced ethanol drinking in mice. To test the hypothesis that suppression of high ethanol consumption is a general property of tetracyclines, we screened several derivatives for anti-drinking activity using the Drinking-In-the-Dark (DID) paradigm. Active drugs were studied further using the dose-response relationship. Methods Adult female and male C57BL/6J mice were singly housed and the DID paradigm was performed using 20% ethanol over a 4-day period. Mice were administered a tetracycline or its vehicle 20 h prior to drinking. Water and ethanol consumption was measured daily. Body weight was measured at the start of drug injections and after the final day of the experiment. Blood was collected for ethanol content measurement immediately following the final bout of drinking. Results Seven tetracyclines were tested at a 50 mg/kg dose. Only minocycline and tigecycline significantly reduced ethanol drinking, and doxycycline showed a strong effect-size trend towards reduced drinking. Subsequent studies with these three drugs revealed a dose-dependent decrease in ethanol consumption for both female and male mice, with sex differences in efficacy. Minocycline and doxycycline reduced water intake at higher doses, although to a lesser degree than their effects on ethanol drinking. Tigecycline did not negatively affect water intake. The rank order of potency for reduction in ethanol consumption was minocycline > doxycycline > tigecycline, indicating efficacy was not strictly related to their partition-coefficients (LogP) or distribution constants (LogD). Conclusions Due to its effectiveness in reducing high ethanol consumption coupled without an effect on water intake, tigecycline was found to be the most promising lead tetracycline compound for further study toward the development of a new pharmacotherapy for the treatment of AUD.

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

“…The primary purpose of the present study was to examine the ability of tigecycline to decrease EtOH intake in dependent and nondependent male and female mice following repeated cycles of CIE vapor or air exposure, respectively. Consistent with the results in nondependent mice with the “drinking in the dark” model of binge drinking in a companion paper (Syapin et al., ), tigecycline produced a dose‐dependent decrease in 2‐hour EtOH intake without influencing 22‐hour water intake versus saline injection. Interestingly, in the present study, the 80‐ and 100‐mg/kg tigecycline doses produced a similar suppression in EtOH intake in the dependent and nondependent mice versus vehicle injection, and those doses were more efficacious at reducing EtOH intake in the male versus female mice.…”

“…As tigecycline has been found in all tissues, including the cerebrospinal fluid and brain (Munyeza et al., ), and is thought to be eliminated in unmodified form primarily in the feces and to some extent in the urine, it is hard to resolve the differences. It is unclear why we found no suppression of EtOH intake on the day after tigecycline injection, while that same approach was effective to reduce acute binge drinking in our related study (Syapin et al., ).…”

“…The purpose of this study was to examine the ability of tigecycline to decrease EtOH intake in dependent and nondependent mice following repeated bouts of CIE vapor or control air exposure, respectively. Both males and females were tested, based on the finding that there were sex differences in the ability of tigecycline to significantly decrease binge EtOH intake (Syapin et al., ). Tigecycline is an FDA‐approved drug used specifically for methicillin‐resistant Staphylococcus aureus (MRSA) infection (Koomanachai et al., ).…”

Glial mechanisms underlying substance use disorders

“…Interestingly, the analgesic effects of morphine and oxycodone are potentiated by ibudilast or minocycline, without any change in plasma morphine levels (Hutchinson et al, 2008), suggesting that ibudilast may extend the intended analgesic effects of morphine, while dampening the unwanted rewarding effects. Alcohol consumption is also reduced by minocycline and ibudilast in the two-bottle choice, drinking-in-the-dark, and chronic intermittent access paradigms (Agrawal et al, 2011;Bell et al, 2015;Syapin et al, 2016). Ibudilast's inhibitory effect on alcohol consumption is seen in multiple strains of mice and rats, including strains selectively bred for high alcohol consumption .…”

Glial and neuroinflammatory targets for treating substance use disorders

“…Administration of putative microglia inhibitors, such as ibudilast and minocycline, reduce alcohol drinking in a 2-h and 24-h two-bottle choice paradigm, a drinking-in-the-dark procedure and a chronic intermittent access procedures using several established high alcohol-consuming rodent lines (Agrawal et al, 2011; Bell et al, 2013; Syapin et al, 2016). Similarly, stimulation PPARγ that is expressed in microglia also reduce alcohol drinking in a 3-h and 24-h two-bottle choice paradigm and a drinking-in-the-dark procedure, potentially through the anti-inflammatory properties of PPARγ agonists (Blednov et al, 2015; Ferguson et al, 2014; Stopponi et al, 2013).…”