Methadone maintenance treatment (MMT) is the most widely-used therapy in opioid dependence, but it is not effective in some patients, who relapse or drop out from treatment. Researchers at the IMIM and Hospital del Mar led by Marta Torrens, in collaboration with colleagues at the CRG, have found a possible explanation of why some people may not respond well to this treatment.
As the authors explain in their paper published this month in the journal European Neuropsychopharmacology, they carried out a genetic analysis on several patients, focusing on the gene ALDH5A1. This enzyme is involved in the catabolism of the neurotransmitter gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian central nervous system. ALDH5A1 comes in many forms, and the scientists found that subjects carrying the T variant allele had a higher risk to be nonresponders to methadone treatment. They hypothesized that this could be due to a reduction in the ALDH5A1 enzyme activity, which would increase endogenous GABA levels and therefore induce symptoms such as sedation and impaired psychomotor performance. These neuropsychological effects related with the reduction in enzyme activity could be responsible for a higher propensity to relapse in these genetically predisposed patients.
The findings could be helpful to predict which subjects with opioid dependence problems would probably not benefit from methadone maintenance treatment and could use other treatments instead, such as diamorphine.
Fonseca F, Gratacòs M, Escaramís G, De Cid R, Martín-Santos R, Farré M, Estivill X, Torrens M. ALDH5A1 variability in opioid dependent patients could influence response to methadone treatment. Eur Neuropsychopharmacol. 2013 Oct 18;
Cannabis has a long history of use as medicine, with historical evidence dating back more than 4000 years. The potential therapeutic benefits of cannabinoid compounds are huge, but this substance can also have negative effects. A recent paper by Andrés Ozaita and colleagues at the Neurophar laboratory of Rafael Maldonado (CEXS-UPF) has given new insights into the molecular mechanisms that underlie cannabinoid-mediated effects.
Using mice as a model system, the authors had previously shown that blocking the mTOR pathway prevented the amnesic-like effects of THC (a synthetic form of cannabinoid). In the present study, published in the journal Neuropsychopharmacology, they have gone further, proving that the inhibition of the mTOR pathway by the rapamycin derivative temsirolimus, prevents both the anxiogenic- and the amnesic-like effects produced by acute THC, but has no effect on THC-induced anxiolysis, hypothermia, hypolocomotion, and antinociception (lack of pain perception).
Therefore, treatment with temsirolimus could segregate the potentially beneficial effects of cannabinoid agonists, such as the decrease of pain and anxiety, from the negative effects, such as amnesia and an increase of anxiety. As the authors say, these results could help targeting the endocannabinoid system in order to prevent possible side effects.
Puighermanal E, Busquets-Garcia A, Gomis-González M, Marsicano G, Maldonado R, Ozaita A. Dissociation of the Pharmacological Effects of THC by mTOR Blockade. Neuropsychopharmacology. 2013 Jan 28;
Next July 18-25 a Cold Spring Harbour Laboratory (CSHL) summer course on “Cellular biology of addiction” will take place at the PRBB. The deadline for registration has just been extended until March 30, so hurry up!!
The course is organized by Rafael Maldonado, from the UPF and it is addressed both to experienced researchers and those new to the field. Its aim is to explain and discuss the latest advances and the major gaps in cell and molecular biology of drug addiction, although other subjects such as learning, memory and drug development will also be included.
The course is co-organized by Brigitte L. Kieffer from CERBM, University of Strasbourg, Chris Evans from the University of California, Los Angeles, USA and Antonello Bonci from the National Institute on Drug Abuse-NIDA, Baltimore, USA.
To see the speakers, costs and to register, you can go to the CSHL summer course website. Make sure you don’t miss this opportunity!
A publication in Amino Acids by researchers from UPF, CRG and other centers provides the first in vivo evidence of the involvement of the CHRNA5/A3/B4 gene cluster in nicotine addiction. It happens through modifying the activity of brain regions responsible for the balance between the rewarding and the aversive properties of this drug. CHRNA5/A3/B4 codes for the nicotinic acetylcholine receptor subunits A5, A3 and B4. Together they form the ligand-gated pentameric ion channels that modulate key physiological processes ranging from neurotransmission to cancer signaling. These receptors are activated by the neurotransmitter, acetylcholine, and the tobacco alkaloid, nicotine. Recently, the gene cluster received interest after a succession of linkage analyses and association studies identified multiple single-nucleotide polymorphisms in these genes that are associated with an increased risk for nicotine dependence and lung cancer.
To see the in vivo effects of the cluster, a transgenic mouse overexpressing the human CHRNA5/A3/B4 cluster was generated using a bacterial artificial chromosome. Transgenic mice showed increased functional receptors in brain regions where these subunits are highly expressed under normal physiological conditions. Moreover, they exhibited increased sensitivity to the pharmacological effects of nicotine. Transgenic mice also showed increased acquisition of nicotine self-administration.
Gallego X, Molas S, Amador-Arjona A, Marks MJ, Robles N, Murtra P, Armengol L, Fernández-Montes RD, Gratacòs M, Pumarola M, Cabrera R, Maldonado R, Sabrià J, Estivill X, Dierssen M. Overexpression of the CHRNA5/A3/B4 genomic cluster in mice increases the sensitivity to nicotine and modifies its reinforcing effects. Amino Acids. 2011 Nov 19
© 2010 Oncogene: Structure of the Nicotinic acetylcholine receptor (nAChR). (a) Schematic representation illustrating the pentameric arrangement of subunits in an assembled nAChR. (b) Conserved domains of a nAChR subunit including the amino (N) and carboxy (C) terminals, transmembrane segments (M1–M4) and the intracellular loop. (c) Assembly of heteromeric and homomeric nAChR subtypes. Individual nAChR subunits are represented as colored circles, with diamonds representing ligand-binding sites. Pentagons in the center of each pentamer represent the pore region.