Suppression by γ-Hydroxybutyric Acid of “Alcohol Deprivation Effect” in Rats: Preclinical Evidence of its anti-Relapse Properties

Colombo, Giancarlo; Carai, Mauro A M; Gessa, Gian Luigi

doi:10.3389/fpsyt.2012.00095

Cited by 9 publications

(6 citation statements)

References 42 publications

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“…The dose of 1.5mg/kg of R(+)‐Baclofen was also tested. All solutions were used at room temperature, and doses and routes of administration were chosen accordingly to the literature 29,34‐38 …”

Section: Methodsmentioning

confidence: 99%

Is R(+)‐Baclofen the best option for the future of Baclofen in alcohol dependence pharmacotherapy? Insights from the preclinical side

et al. 2020

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For several decades, studies conducted to evaluate the efficacy of RS(±)‐Baclofen in the treatment of alcohol dependence yielded contrasting results. Human and animal studies recently questioned the use of the racemic drug in patients since a potential important role of the different enantiomers has been revealed with an efficacy thought to reside with the active R(+)‐enantiomer. Here we conducted experiments in the postdependent rat model of alcohol dependence to compare the efficacy of R(+)‐Baclofen or S(−)‐Baclofen to that of RS(±)‐Baclofen on ethanol intake, seeking, and relapse. R(+)‐Baclofen was more effective than RS(±)‐Baclofen in reducing ethanol intake and seeking during acute withdrawal and during relapse after abstinence. We also used an original population approach in order to identify drug responders. We found a significant proportion of responders to S(−)‐Baclofen and RS(±)‐Baclofen, displaying an increase in ethanol intake, and this increasing effect on alcohol intake was not seen in the R(+)‐Baclofen group. At an intermediate dose of R(+)‐Baclofen, devoid of any motor side effects, we identified a very large proportion of responders (75%) with a large decrease in ethanol intake (90% decrease). Finally, the response to RS(±)‐Baclofen on ethanol intake was correlated to plasma level of Baclofen. R(+)‐Baclofen and RS(±)‐Baclofen were effective in reducing sucrose intake. Our study has important clinical implication since it suggests that the wide variability in the therapeutic responses of patients to RS(±)‐Baclofen may come from the sensitivity to the R(+)‐Baclofen but also to the one of the S(−)‐Baclofen that can promote an increase in ethanol intake.

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Section: Methodsmentioning

confidence: 99%

Is R(+)‐Baclofen the best option for the future of Baclofen in alcohol dependence pharmacotherapy? Insights from the preclinical side

et al. 2020

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“…In this regard, it is particularly interesting that γ-hydroxybutyric acid (GHB), which has been characterized as an agonist at GABA-B receptors (Andresen et al , 2011, Carai et al , 2008, Schep et al , 2012, Vienne et al , 2010), reduces alcohol consumption in animal models (Colombo et al , 2012), and is used to treat alcohol dependence and craving in Europe (Addolorato et al , 2011, Maremmani et al , 2011). Recently, GHB has been found to be a partial agonist at GABA-A receptors that contain α, β and δ (but not α, β and γ) subunits (Absalom et al , 2012).…”

Section: The Molecular Site Of Ethanol’s Action In the Cnsmentioning

confidence: 99%

The neurobiology of alcohol consumption and alcoholism: An integrative history

Tabakoff

Hoffman

2013

Pharmacology Biochemistry and Behavior

122

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Studies of the neurobiological predisposition to consume alcohol (ethanol) and to transition to uncontrolled drinking behavior (alcoholism), as well as studies of the effects of alcohol on brain function, started a logarithmic growth phase after the repeal of the 18th Amendment to the United States Constitution. Although the early studies were primitive by current technological standards, they clearly demonstrated the effects of alcohol on brain structure and function, and by the end of the 20th century left little doubt that alcoholism is a “disease” of the brain. This review traces the history of developments in the understanding of ethanol’s effects on the most prominent inhibitory and excitatory systems of brain (GABA and glutamate neurotransmission). This neurobiological information is integrated with knowledge of ethanol’s actions on other neurotransmitter systems to produce an anatomical and functional map of ethanol’s properties. Our intent is limited in scope, but is meant to provide context and integration of the actions of ethanol on the major neurobiologic systems which produce reinforcement for alcohol consumption and changes in brain chemistry that lead to addiction. The developmental history of neurobehavioral theories of the transition from alcohol drinking to alcohol addiction is presented and juxtaposed to the neurobiological findings. Depending on one’s point of view, we may, at this point in history, know more, or less, than we think we know about the neurobiology of alcoholism.

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“…In vivo, GET73 treatment at low, non-sedative doses (5–50 mg/kg) reduced alcohol intake and suppressed relapse in alcohol-preferring rats, as well as exerting anxiolytic effects [ 246 ]. These effects are similar to those seen with GHB administration [ 247 ]; however, GET73 was shown not to bind to either high- or low-affinity GHB binding sites in rat cortical membranes [ 246 ]. Recent studies indicate that GET73 may act as a negative allosteric modulator at the metabotropic glutamate subtype 5 receptor (mGluR5) [ 248 ]; however, the complete mechanism of action of GET73 remains unclear.…”

Section: Pharmacological Treatments For Audmentioning

confidence: 80%

Novel Agents for the Pharmacological Treatment of Alcohol Use Disorder

Burnette

Nieto

Grodin

et al. 2022

Drugs

103

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Alcohol use disorder (AUD) is a highly prevalent but severely under-treated disorder, with only three widely-approved pharmacotherapies. Given that AUD is a very heterogeneous disorder, it is unlikely that one single medication will be effective for all individuals with an AUD. As such, there is a need to develop new, more effective, and diverse pharmacological treatment options for AUD with the hopes of increasing utilization and improving care. In this qualitative literature review, we discuss the efficacy, mechanism of action, and tolerability of approved, repurposed, and novel pharmacotherapies for the treatment of AUD with a clinical perspective. Pharmacotherapies discussed include: disulfiram, acamprosate, naltrexone, nalmefene, topiramate, gabapentin, varenicline, baclofen, sodium oxybate, aripiprazole, ondansetron, mifepristone, ibudilast, suvorexant, prazosin, doxazosin, N-acetylcysteine, GET73, ASP8062, ABT-436, PF-5190457, and cannabidiol. Overall, many repurposed and novel agents discussed in this review demonstrate clinical effectiveness and promise for the future of AUD treatment. Importantly, these medications also offer potential improvements towards the advancement of precision medicine and personalized treatment for the heterogeneous AUD population. However, there remains a great need to improve access to treatment, increase the menu of approved pharmacological treatments, and de-stigmatize and increase treatment-seeking for AUD.

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Suppression by γ-Hydroxybutyric Acid of “Alcohol Deprivation Effect” in Rats: Preclinical Evidence of its anti-Relapse Properties

Cited by 9 publications

References 42 publications

Is R(+)‐Baclofen the best option for the future of Baclofen in alcohol dependence pharmacotherapy? Insights from the preclinical side

Is R(+)‐Baclofen the best option for the future of Baclofen in alcohol dependence pharmacotherapy? Insights from the preclinical side

The neurobiology of alcohol consumption and alcoholism: An integrative history

Novel Agents for the Pharmacological Treatment of Alcohol Use Disorder

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