Acute baclofen diminishes resting baseline blood flow to limbic structures: A perfusion fMRI study
ABSTRACT Preclinical and clinical evidence show that the GABA B agonist, baclofen is a promising treatment for addictive disorders; however, until recently its mechanism of action in the human brain was unknown. In previous work we utilized a laboratory model that included a medication versus placebo regimen to examine baclofen's actions on brain circuitry. Perfusion fMRI [measure of cerebral blood flow (CBF)] data acquired 'at rest' before and on the last day of the 21-day medication regimen showed that baclofen diminished CBF bilaterally in the VS, insula and medial orbitofrontal cortex (mOFC). In the present study, we hypothesized that a single dose of baclofen would have effects similar to repeated dosing.
To test our hypothesis, in a crossover design, CBF data were acquired using pseudo continuous arterial spin labeled (pCASL) perfusion fMRI. Subjects were either un-medicated or were administered a 20mg dose of baclofen approximately 110 min prior to scanning.
Acute baclofen diminished mOFC, amygdala, and ventral anterior insula CBF without causing sedation (family-wise error corrected at p=0.001).
Results demonstrate that similar to repeated dosing, an acute dose of baclofen blunts the 'limbic' substrate that is hyper-responsive to drugs and drug cues. Smokers often manage their craving and can remain abstinent for extended periods after quitting, however the risk of eventual relapse approaches 90%. Given that chronic medication may not be a practical solution to the long-term risk of relapse, acute baclofen may be useful on an 'as-needed' basis to block craving during 'at risk' situations.
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ABSTRACT: Aim: To conduct a double-blind, placebo-controlled randomized clinical trial of baclofen in the treatment of alcohol dependence. Methods: Out of 69 participants consecutively screened, 42 alcohol-dependent patients were randomized to receive placebo, baclofen 30 mg/day or baclofen 60 mg/day for 12 weeks. All subjects were offered BRENDA, a structured psychosocial therapy for alcohol dependence that seeks to improve motivation for change, enhance strategies to prevent relapse and encourage compliance with treatment. Results: Intention-to-treat analyses revealed that alcohol consumption (heavy drinking days, drinks per drinking day) significantly reduced across all three groups during the treatment period. There were no statistically significant advantages to treatment on time to first heavy drinking day (relapse) (P = 0.08), nor time to first drink (lapse) (P = 0.18). A post hoc analysis stratifying according to whether there had been a comorbid anxiety disorder, revealed a beneficial effect of baclofen 30 mg/day versus placebo on time to lapse and relapse (P < 0.05). There was also a beneficial effect for baclofen 60 mg/day relative to placebo on time to relapse in this comorbid group (P < 0.05). Both doses of baclofen were well tolerated. There were no serious adverse events. Conclusions: In spite of the small sample for a 3-arm clinical trial, this study suggests a specific role of baclofen in alcohol-dependent individuals with comorbid anxiety. Replication in larger, fully-powered studies is required.Alcohol and Alcoholism 09/2014; 49(6). DOI:10.1093/alcalc/agu062 · 2.09 Impact Factor
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ABSTRACT: Introduction: There is increasing evidence encouraging the development of drugs that positively modulate the γ-aminobutyric acid type B (GABAB) receptor for combating addiction. Compounds that target GABAB receptors are unique as anti-abuse therapies because of their impact against multiple addictive drugs. Areas covered: The authors present the basic information concerning the drug actions of GABA and GABAB receptor orthosteric agonists and positive allosteric modulators (PAM). Furthermore, they discuss several recent excellent reviews and newer results pertaining to GABAB receptor drug effects on responses to and self-administration of: alcohol (ethanol), nicotine, cocaine, (meth)amphetamine, and opioids. Preclinical and clinical data are considered. Expert opinion: Clinical data exist only for baclofen and mostly for alcohol use disorders. Additional trials are needed, but effects are promising. Whether PAMs, given alone or in combination with a direct GABAB receptor agonist, will be clinically effective and have fewer side effects requires investigation. The sedative effects of baclofen, a Food and Drug Administration (FDA)-approved drug, become less severe over time. Based on existing data, baclofen is well-tolerated. However, genetic and physiological differences are likely to contribute to individual responses to different therapeutic agents. The more immediate development of baclofen as a therapeutic for alcohol use disorders may be of significant benefit to some individuals.Expert Opinion on Drug Discovery 09/2014; 9(11):1-11. DOI:10.1517/17460441.2014.956076 · 3.47 Impact Factor
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ABSTRACT: Background A large proportion of adolescents drink alcohol, with many engaging in high-risk patterns of consumption, including binge drinking. Here, we systematically reviewed and synthesized the existing empirical literature on how consuming alcohol affects the developing human brain in alcohol-using (AU) youth. Methods For this systematic review, we began by conducting a literature search using the PubMED database to identify all available peer-reviewed magnetic resonance imaging (MRI) and functional magnetic resonance imaging (fMRI) studies of AU adolescents (aged 19 and under). All studies were screened against a strict set of criteria designed to constrain the impact of confounding factors, such as co-occurring psychiatric conditions. Results Twenty-one studies (10 MRI and 11 fMRI) met criteria for inclusion. A synthesis of the MRI studies suggested that overall, AU youth showed regional differences in brain structure as compared with non-AU youth, with smaller brain volumes and lower white matter integrity in relevant brain areas. In terms of fMRI outcomes, despite equivalent task performance between AU and non-AU youth, AU youth showed a broad pattern of lower task-relevant activation, and greater task-irrelevant activation. In addition, a pattern of gender differences was broadly observed for brain structure and function, with particularly striking effects among AU females. Conclusions Alcohol consumption during adolescence was associated with significant differences in structure and function in the developing human brain. However, this is a nascent field, with several limiting factors (e.g., small sample sizes, cross-sectional designs, presence of confounding factors) within many of the reviewed studies, meaning that results should be interpreted in light of the preliminary state of the field. Future longitudinal and large-scale studies are critical to replicate the existing findings, and to provide a more comprehensive and conclusive picture of the effect of alcohol consumption on the developing brain.07/2014; 5. DOI:10.1016/j.nicl.2014.06.011