Effects of naltrexone plus topiramate on ethanol self‐administration and tyrosine hydroxylase gene expression changes

Abstract

The purpose of this study was to evaluate the effects of naltrexone (0.7 mg/kg) and/or topiramate (25 mg/kg) on ethanol consumption and the motivation to drink in an oral-operant conditioning paradigm in C57BL/6 mice. Subsequent real-time polymerase chain reaction (PCR) experiments were performed to analyze gene expression changes in tyrosine hydroxylase (TH) in the ventral tegmental area (VTA). The administration of naltrexone significantly reduced ethanol consumption and the motivation to drink during the different stages of the experiment, whereas the treatment with topiramate resulted in a much lower effect. Interestingly, the administration of naltrexone plus topiramate reduced ethanol consumption markedly compared with single-drug treatment. The water self-administration paradigm was also performed using the same drugs and no differences were found between treatment groups. Real-time PCR analyses revealed that naltrexone significantly normalized the increase of TH gene expression in the VTA induced by ethanol, whereas the administration of topiramate did not produce any significant effect. In the ethanol self-administration procedure, the combination of both drugs further reduced TH gene expression, reaching statistical significance compared with the vehicle, naltrexone or topiramate groups. Taken together, these findings indicate that the administration of naltrexone plus topiramate further reduced ethanol consumption and the motivation to drink in comparison with single-drug treatment. This action may be due, at least in part, to a greater decrease in TH gene expression in the VTA. These results suggest that the combination of both drugs deserves further exploration for the treatment of problems related to alcohol consumption.

The efficacy of a low dose combination of topiramate and naltrexone on ethanol reinforcement and consumption in rat models

“…Navarette et al (2013) demonstrated that this combination reduced tyrosine hydroxylase in the ventral-tegmental area further than either alone, while simultaneously reducing ethanol reinforcement suggesting that its efficacy may be due to its effects on ethanol-mediated dopamine release within the mesolimbic pathway. Tyrosine hydroxylase has also been shown to be upregulated after chronic ethanol exposure (Ortiz et al 1995), along with the dysfunction of other pathways, such as GABA and opioid peptides that occur in this allosteric state (Koob, 2003).…”

“…The combination of topiramate and ondansetron has also been reported to effectively reduce ethanol consumption in heavy drinking rats, with better efficacy of the combination than either alone for reducing relapse behavior (Lynch et al 2011). Additionally, the combination of topiramate and naltrexone was found to reduce ethanol self-administration in mice under limited-access conditions (Navarrete et al 2013). Here, we found the combination of naltrexone and topiramate reduced both ethanol consumption and reinforcement in models of prolonged ethanol access, with better efficacy of the combination than either alone for reducing ethanol consumption, and better efficacy than topiramate alone for reducing ethanol reinforcement.…”

“…Low doses of each medication, which either do not affect or only modestly affect alcohol-related behaviors on their own, were selected in an attempt to maximize their combined efficacy while minimizing potential side-effects. A similar low-dose naltrexone-topiramate combination approach was recently found to effectively reduce alcohol consumption and reinforcement in mice consuming ethanol under sub-chronic and limited access conditions (Navarrete et al 2013). In this study, effects of treatments on ethanol consumption were assessed in groups of rats given access to ethanol under a 24-hr, three-bottle, free-choice paradigm.…”

Acute ethanol treatment upregulates th1, th2, and hdc in larval zebrafish in stable networks

“…Although the changes in dopamine levels are well known, the acute effect of ethanol on the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, is not well-understood, with some evidence reporting an increase in th mRNA levels (Oliva et al, 2008). A chronic treatment with ethanol has been shown to increase th mRNA levels in the rat brain (Lee et al, 2005; Navarrete et al, 2013), but there is also evidence suggesting that TH protein levels decrease after chronic ethanol treatment (Kashem et al, 2012). …”

Oral operant ethanol self-administration in the absence of explicit cues, food restriction, water restriction and ethanol fading in C57BL/6J mice

“…This opioid antagonist has previously been shown to decrease mouse operant responding maintained by EtOH (Middaugh et al 1999b; Navarrete et al 2013) and mouse EtOH intake during DID and two-bottle choice paradigms (Phillips et al 1997; Kamdar et al 2007). In the absence of any effect on water vehicle controls, naltrexone was effective at inhibiting 15% EtOH in water intake at sub-intoxicating doses consistent with its therapeutic profile in alcoholics.…”