Human Biodistribution and Dosimetry of (18)F-JNJ42259152, a Radioligand for Phosphodiesterase 10A Imaging.

Human biodistribution and dosimetry of (18)F-JNJ42259152, a radioligand for phosphodiesterase 10A imaging.

Filed under: Addiction Rehab

Eur J Nucl Med Mol Imaging. 2012 Nov 16;
Van Laere K, Ahmad RU, Hudyana H, Celen S, Dubois K, Schmidt ME, Bormans G, Koole M

PURPOSE: Phosphodiesterase 10A (PDE10A) is a cAMP/cGMP-hydrolysing enzyme with a central role in striatal signalling and implicated in neuropsychiatric disorders such as Huntington’s disease, Parkinson’s disease, schizophrenia and addiction. We have developed a novel PDE10A PET ligand, (18)F-JNJ42259152, and describe here its human dynamic biodistribution, safety and dosimetry. METHODS: Six male subjects (age range 23-67 years) underwent ten dynamic whole-body PET/CT scans over 6 h after bolus injection of 175.5?±?9.4 MBq (18)F-JNJ42259152. Source organs were delineated on PET/CT and individual organ doses and effective dose were determined using the OLINDA software. RESULTS: F-JNJ42259152 was readily taken up by the brain and showed exclusive retention in the brain, especially in the striatum with good washout starting after 20 min. The tracer was cleared through both the hepatobiliary and the urinary routes. No defluorination was observed. Organ absorbed doses were largest for the gallbladder (239 ?Sv/MBq) and upper large intestine (138 ?Sv/MBq). The mean effective dose was 24.9?±?4.1 ?Sv/MBq. No adverse events were encountered. CONCLUSION: In humans, (18)F-JNJ42259152 has an appropriate distribution, brain kinetics and safety. The estimated effective dose was within WHO class IIb with low interindividual variability. Therefore, the tracer is suitable for further kinetic evaluation in humans.
HubMed – addiction


Undernutrition upregulates fumarate hydratase in the rat nucleus accumbens.

Filed under: Addiction Rehab

Metab Brain Dis. 2012 Nov 20;
Lizárraga-Mollinedo E, Alvarez C, Fernández-Millán E, Escrivá F, González-Martín C, Salas E, Pérez-Ortiz JM, Alguacil LF

Previous comparative studies of fumarate hydratase (FH) protein density revealed that the enzyme was overexpressed in the striatum of rodents that are less influenced by rewarding stimuli, from cocaine to food. Therefore, we recently proposed FH as a potential striatal biomarker of brain reward deficiency and addiction vulnerability. This work has been focused to investigate FH activity in the Nucleus Accumbens (NAc) of undernourished rats, taking into account that malnutrition has been related to increased responsiveness to food and drug reward. To this end, we have studied adult female Wistar rats severely food restricted from the 16th day of intrauterine life until adulthood. Animals were sacrificed to dissect the NAc and obtain mitochondrial and cytosolic fractions after homogenisation and centrifugation. FH activity was measured by conversion of malate to fumarate, and protein levels were compared by Western blot analysis when fractions showed differences in activity. Undernutrition did not change cytosolic FH activity but led to a marked increase of mitochondrial FH activity (72 %) and protein content (50 %) in the NAc. This change was in the opposite direction that one would predict if it was related to addiction vulnerability of some kind, but strongly suggests that mitochondrial FH needs to be at some optimal level for normal reward responsiveness.
HubMed – addiction


Chicago sky blue 6B, a vesicular glutamate transporters inhibitor, attenuates methamphetamine-induced hyperactivity and behavioral sensitization in mice.

Filed under: Addiction Rehab

Behav Brain Res. 2012 Nov 14;
He Z, Yan L, Yong Z, Dong Z, Dong H, Gong Z

Several lines of evidence demonstrate that glutamatergic system plays an important role in drug addiction. The present study was designed to investigate the effects of Chicago sky blue 6B (CSB6B), a vesicular glutamate transporters (VGLUTs) inhibitor, on methamphetamine (METH) -induced behaviors in mice. Mice were induced behavioral sensitization to METH by subcutaneous injection of 1mg/kg METH once daily for 7 days and then challenged with 1mg/kg METH in 14th day. Intracerebroventricular administration of CSB6B (7.5ug) 2.5hours prior to METH was to observe its effects on METH -induced behavioral sensitization. Our results showed that the expressions of behavioral sensitization were significantly attenuated by intracerebroventricular administration of CSB6B 2.5hours prior to METH either during the development period or before methamphetamine challenge in mice, while CSB6B itself had no effect on locomotor activity. Meanwhile, pretreatment of CSB6B also attenuated hyperactivity caused by a single injection of METH in mice. These results demonstrated that CSB6B, a VGLUTs inhibitor, attenuated acute METH-induced hyperactivity and chronic METH-induced behavioral sensitization, which indicated that VGLUTs were involved in the effect of chronic METH-induced behavioral sensitization and may be a new target against the addiction of METH.
HubMed – addiction


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