MOTORNEURON DISEASE: VEGF treatment of ALS

Alcoholism is linked to disruption of the biological clock Alcohol and drug addiction are complex disorders with environmental, drug-induced and genetic components. It is likely that multiple genes contribute to the development of an addictive disease. There is a growing body of evidence implicating circadian clock genes in mechanisms of drug-abuse related behaviours. The clock genes, including, Per1, Per2, Cry1 and Cry2, underlie the ability of the biological clock to provide endogenous rhythms of physiological functions with a periodicity of 24 hours, without any environmental cues. These genes regulate oscillations in the levels of the transcription factor complex, CLOCK-BMAL1, in the suprachiasmatic nucleus of the hypothalamus. Such oscillations are generated by inhibitory feedback loops, in which the protein products of the clock genes down-regulate their own transcription. This study by Spanagel focuses on one such clock gene, Per2, and its role in alcoholism. They investigated a Per2 mutant mouse, in which the Per2 protein is rendered nonfunctional. As a result, neurochemically these mutant mice exhibited serious disturbances in the glutamatergic system. A significant reduction in the astrocytic expression of the EAAT1 glutamate transporter, which clears glutamate from the synaptic cleft, produced a three-fold increase in extracellular glutamate in the ventral striatum. On a behavioural level, the Per2 mutant mice voluntarily consumed more alcohol compared to wild-type mice. On administration of acamprosate, an anti-relapse drug, the Per2 mutants showed a reduction in augmented extracellular glutamate levels in the nucleus accumbens and their alcohol consumption was normalised to below wild-type levels. This latter finding lends support to the theory that acamprosate acts by reducing the hyperglutamatergic state in alcohol-dependents. In humans Spanagel found that the Per2 gene had an analogous function in the regulation of alcohol consumption. By sequencing the Per2 gene of alcohol-dependents, they identified a haplotype of four gene variants associated specifically with the subjects with low alcohol consumption. In summary, Spanagel identifies glutamate to be the link between disruption of the Per2 and increased alcohol consumption. It is proposed that glutamate alters the alcohol reinforcement processes in the brain, most likely via modulation of the dopamine reward pathways. In the clinic, acamprosate increases abstinence rates in just 10-20% of cases compared to placebo. Further research is required to determine if certain polymorphisms in the Per2 gene confer a positive acamprosate response. Thus it would be possible to predict if a patient would benefit from this therapy. LMS & SJT Spanagel R, Pendyala, Abarca C, Zghoul T, Sanchis-Segura C, Magnone M, Lascorz J, depner M, Holzberg D, Soyka M, Schreiber S, Matsuda F, Lathrop M, Schumann G, Albrecht U. The clock gene Per 2 influences the glutamatergic system and modulates alcohol consumption. NATURE MEDICINE 2005;11:35-42.