Acute baclofen diminishes resting baseline blood flow to limbic structures: A perfusion fMRI study

Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA. franklin
Drug and alcohol dependence (Impact Factor: 3.42). 04/2012; 125(1-2):60-6. DOI: 10.1016/j.drugalcdep.2012.03.016
Source: PubMed


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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    • "Although the neurobiological mechanisms that underlie anxiety are not fully understood, studies have shown that dysfunction in limbic areas such as the amygdala and prefrontal interconnections such as the orbitofrontal and medial prefrontal cortex might be responsible (Cannistraro and Rauch, 2003; Milad and Rauch, 2007). Baclofen's action on these structures (Franklin et al., 2012; Young et al., 2014) could therefore serve to restore this function in alcohol patients with high levels of persisting anxiety, areas also hyper-responsive to drug cues (Franklin et al., 2012), which may dampen subjective expression of craving during stress and consequently risk of relapse. Preclinical studies have found that the actions of baclofen are modulated by anxiety status (high anxiety versus low anxiety rats) whereby high anxiety rats are particularly responsive to baclofen-induced locomotor behavioral changes (Falco et al., 2014). "
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    ABSTRACT: Baclofen has shown promise in treating substance use disorders and also reduced binge frequency in an open-label trial. This placebo-controlled, double-blind, crossover study further assessed the effects of baclofen on binge eating. Twelve individuals who self-reported binge eating completed the study. Data were collected during a run-in period (no drug or placebo), placebo phase (48 days), and baclofen phase (titrated up to 60 mg daily or the maximum tolerated dose, 48 days). All the participants were exposed to all conditions. Participants completed a binge diary daily, and the Binge Eating Scale (BES), Food Craving Inventory-II (FCI-II), and Hospital Anxiety and Depression Scale (HADS) at regular intervals throughout the study. Baclofen significantly reduced binge frequency relative to placebo and run-in (P<0.05). This confirms results from the previous open-label trial. Baclofen also produced slight, but significant, increases in depression symptomatology as assessed by the HADS. Binge severity (BES scores) and craving (FCI-II scores) were significantly reduced during placebo and baclofen phases, that is both measures exhibited significant placebo effects. Tiredness, fatigue, and upset stomach were the most commonly reported side-effects. These results indicate that baclofen may be a useful treatment for binge eating in some patients.
    Behavioural pharmacology 09/2012; 23(5-6):616-25. DOI:10.1097/FBP.0b013e328357bd62 · 2.15 Impact Factor
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    ABSTRACT: Nicotine dependence is difficult to treat, and the biological mechanisms that are involved are not entirely clear. There is an urgent need to develop better drugs and more effective treatments for clinical practice. A critical step towards accelerating progress in medication development is to understand the neurobehavioral effects of pharmacotherapies on clinical characteristics associated with nicotine dependence. This review sought to summarize the functional magnetic resonance imaging (fMRI) literature on smoking cessation with the aim to better understand the neural processes underlying the effects of nicotinic and non-nicotinic pharmacological smoking cessation treatments on specific symptoms of nicotine dependence and withdrawal. We conducted a search in Pubmed, Web of Science and PsycINFO databases with the keywords 'fMRI' or 'functional magnetic resonance imaging' and 'tobacco' or 'nicotine' or 'smok*'. The date of the most recent search was May 2012. The original studies that were included were those of smokers or nicotine-dependent individuals, published in the English language, with pharmacological treatment for nicotine dependence and use of fMRI with blood oxygen level-dependent (BOLD) imaging or continuous arterial spin labelling (CASL). No date limit was applied. Two of the authors read the abstracts of all studies found in the search (n = 1,260). The inclusion and exclusion criteria were applied, and 1,224 articles were excluded. In a second step, the same authors read the remaining 36 studies. Nineteen of the 36 articles were excluded. The results were tabulated by the number of individuals and their mean age, the main sample characteristics, smoking status, study type and methodology, and the main fMRI findings. Seventeen original fMRI studies involving pharmacological treatment of smokers were selected. The anterior and posterior cingulate cortex, medial and lateral orbitofrontal cortex, ventral striatum, amygdala, thalamus and insula are heavily involved in the maintenance of smoking and nicotine withdrawal. The effects of varenicline and bupropion in alleviating withdrawal symptoms and decreasing smoking correlated with modulation of the activities of these areas. Nicotine replacement therapy seems to improve cognitive symptoms related to withdrawal especially by modulating activities of the default-network regions; however, nicotine replacement does not necessarily alter the activities of neural circuits, such as the cingulate cortices, that are associated with nicotine addiction. The risk of bias in individual studies, and across studies, was not assessed, and no method of handling data and combining results of studies was carried out. Most importantly, positron emission tomography (PET) studies were not included in this review. fMRI studies delineate brain systems that contribute to cognitive deficits and reactivity to stimuli that generate the desire to smoke. Nicotinic and non-nicotinic pharmacotherapy may reduce smoking via distinct neural mechanisms of action. These findings should contribute to the development of new medications and discovery of early markers of the therapeutic response of cigarette smokers.
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