A Human Laboratory Pilot Study With Baclofen in Alcoholic Individuals.

A Human Laboratory Pilot Study with Baclofen in Alcoholic Individuals.

Filed under: Addiction Rehab

Pharmacol Biochem Behav. 2012 Dec 19;
Leggio L, Zywiak WH, McGeary JE, Edwards S, Fricchione SR, Shoaff JR, Addolorato G, Swift RM, Kenna GA

Preclinical and clinical studies show that the GABA(B) receptor agonist baclofen may represent a pharmacotherapy for alcohol dependence (AD). However, the mechanisms by which baclofen affects drinking are not well characterized, thus this pilot study investigated possible baclofen’s biobehavioral mechanisms. The design was a double-blind controlled randomized human laboratory pilot study. Fourteen non-treatment seeking alcohol-dependent heavy drinking subjects received either baclofen 10mgt.i.d. or an active placebo (cyproheptadine 2mgt.i.d., to control for sedation) for a 7-day period. At day 8, participants performed an alcohol cue-reactivity (CR) followed by an alcohol self-administration (ASA). Additionally, we explored possible moderators that might guide future larger studies, i.e. anxiety, family history and onset of alcoholism, and D4 dopamine receptor (DRD4) and 5-HTTLPR polymorphisms. The main results were a significant effect of baclofen for increasing stimulation (p=.001) and sedation (p<.01). Furthermore, when drinking during the ASA and the two days before was analyzed as a composite variable, there was a significant effect of baclofen to reduce alcohol consumption (p<.01). As for the exploratory analyses, baclofen's effects to increase alcohol sedation and to reduce alcohol consumption were limited to those individuals with DRD4 ?7 repeats (DRD4L). Yet, baclofen's effects on alcohol consumption were also moderated by 5-HTTLPR LL genotype. In conclusion, baclofen's ability to reduce alcohol drinking may be related to its effects on the biphasic effects of alcohol, but larger studies are needed to confirm these preliminary findings. HubMed – addiction


Heroin activates Bim via c-Jun N-terminal kinase/c-Jun pathway to mediate neuronal apoptosis.

Filed under: Addiction Rehab

Neuroscience. 2012 Dec 19;
Tan M, Li Z, Ma S, Luo J, Xu S, Lu A, Gan W, Su P, Lin H, Li S, Lai B

Heroin is reported to cause spongiform leukoencephalopathy (SLE) in heroin addicts and the exact mechanism has not yet been identified. In the present study, we found that heroin could induce apoptosis of primary cultured cerebellar granule cells (CGCs) and Bim was upregulated both transcriptionally and post-transcriptionally during CGCs apoptosis. Upregulated Bim translocated to mitochondria and Bax was activated under heroin treatment. Genetic knockdown of Bim using lentiviruses significantly prevented neuronal apoptosis induced by heroin. Meanwhile, c-Jun N-terminal kinase (JNK)/c-Jun pathway was activated in heroin induced apoptosis. Bim was demonstrated as a downstream target of JNK/c-Jun pathway in this process because pharmacological inhibition of JNK reduced the levels of Bim mRNA and protein. These results indicate that Bim plays a critical role in the neurotoxic process by heroin and JNK/c-Jun pathway acts upstream of Bim in regulating heroin induced neuronal death. This represents a detailed mechanism of heroin induced neuronal apoptosis and may provide a new and effective strategy to treat heroin-induced addiction and SLE. Abbreiviations: BH3, Bcl-2 homology 3; CGCs, cerebellar granule cells; DIV, days in vitro; JNK, c-Jun N-terminal kinase; NGF, nerve growth factor; NC, negative control; SLE, spongiform leukoencephalopathy.
HubMed – addiction


Reduced limbic metabolism and fronto-cortical volume in rats vulnerable to alcohol addiction.

Filed under: Addiction Rehab

Neuroimage. 2012 Dec 19;
Gozzi A, Agosta F, Massi M, Ciccocioppo R, Bifone A

Alcohol abuse is associated with long-term reductions in fronto-cortical volume and limbic metabolism. However, an unanswered question in alcohol research is whether these alterations are the sole consequence of chronic alcohol use, or contain heritable contributions reflecting biological propensity toward ethanol addiction. Animal models of genetic predisposition to alcohol dependence can be used to investigate the role of inborn brain abnormalities in the aetiology of alcoholism. Here we used magnetic resonance imaging (MRI) in e Marchigian Sardinian (msP) alcohol-preferring rats to assess the presence of inherited structural or functional brain alterations. Alcohol-naïve msP (N=22) and control rats (N=26) were subjected to basal cerebral blood volume (bCBV) mapping followed by voxel-based morphometry (VBM) of gray matter and tract-based spatial statistics mapping of white matter fractional anisotropy. msP rats exhibited significantly reduced bCBV, an established marker of resting brain function, in focal cortico-limbic and thalamic areas, together with reduced gray matter volume in the thalamus, ventral tegmental area, insular and cingulate cortex. No statistically significant differences in fractional anisotropy were observed between groups. These findings highlight the presence of inborn gray matter and metabolic abnormalities in alcohol-naïve msP rats, the localization and sign of which are remarkably similar to those mapped in abstinent alcoholics and subjects at high risk for alcohol dependence. Collectively, these results point for a significant role of heritable neurofunctional brain alterations in biological propensity toward ethanol addiction, and support the translational use of advanced imaging methods to describe the circuital determinants of vulnerability to drug addiction.
HubMed – addiction


The effects of N-methyl D-aspartate and B-adrenergic receptor antagonists on the reconsolidation of reward memory: A meta-analysis.

Filed under: Addiction Rehab

Neurosci Biobehav Rev. 2012 Dec 20;
Das RK, Freeman TP, Kamboj SK

Pharmacological memory reconsolidation blockade provides a potential mechanism for ameliorating the maladaptive reward memories underlying relapse in addiction. Two of the most promising classes of drug that interfere with reconsolidation and have translational potential for human use are N-methyl-D-aspartate receptor (NMDAR) and B-Adrenergic receptor (B-AR) antagonists. We used meta-analysis and meta-regression to assess the effects of these drugs on the reconsolidation of reward memory in preclinical models of addiction. Pharmacokinetic, mnemonic and methodological factors were assessed for their moderating impact on effect sizes. An analysis of 52 independent effect sizes (NMDAR=30, B-AR=22) found robust effects of both classes of drug on memory reconsolidation, but a far greater overall effect of NMDAR antagonism than B-AR antagonism. Significant moderating effects of drug dose, relapse process and primary reinforcer were found. The findings suggest that reward memory reconsolidation can be robustly targeted by NMDAR antagonists and to a lesser extent, by B-AR antagonists. Implications for future clinical work are discussed.
HubMed – addiction



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