Bart de Laat1, Yvonne E Kling2,3, Gwen Schroyen4, Maarten Ooms5, Jacob M Hooker6, Guy Bormans5, Koen Van Laere1,7, Jenny Ceccarini8,9. 1. Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium. 2. Department of Neurosciences, KU Leuven, Experimental Neurology and Leuven Brain Institute (LBI), Leuven, Belgium. 3. Center for Brain & Disease Research, Laboratory of Neurobiology, VIB, Leuven, Belgium. 4. Department of Imaging and Pathology, Translational MRI, KU Leuven, Leuven, Belgium. 5. Laboratory for Radiopharmaceutical Research, KU Leuven, Leuven, Belgium. 6. Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. 7. Division of Nuclear Medicine, University Hospitals Leuven, Leuven, Belgium. 8. Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium. jenny.ceccarini@uzleuven.be. 9. University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium. jenny.ceccarini@uzleuven.be.
Abstract
PURPOSE: Phosphodiesterase 10A (PDE10A) is a dual substrate enzyme highly enriched in dopamine-receptive striatal medium spiny neurons, which are involved in psychiatric disorders such as alcohol use disorders (AUD). Although preclinical studies suggest a correlation of PDE10A mRNA expression in neuronal and behavioral responses to alcohol intake, little is known about the effects of alcohol exposure on in vivo PDE10A activity in relation to apparent risk factors for AUD such as decision-making and anxiety. METHODS: We performed a longitudinal [18F]JNJ42259152 microPET study to evaluate PDE10A changes over a 9-week intermittent access to alcohol model, including 6 weeks of alcohol exposure, 2 weeks of abstinence followed by 1 week relapse. Parametric PDE10A-binding potential (BPND) images were generated using a Logan reference tissue model with cerebellum as reference region and were analyzed using both a volume-of-interest and voxel-based approach. Moreover, individual decision-making and anxiety levels were assessed with the rat Iowa Gambling Task and open-field test over the IAE model. RESULTS: We observed an increased alcohol preference especially in those animals that exhibited poor initial decision-making. The first 2 weeks of alcohol exposure resulted in an increased striatal PDE10A binding (> 10%). Comparing PDE10A-binding potential after 2 versus 4 weeks of exposure showed a significant decreased PDE10A in the caudate-putamen and nucleus accumbens (pFWE-corrected < 0.05). This striatal PDE10A decrease was related to alcohol consumption and preference. Normalization of striatal PDE10A to initial levels was observed after 1 week of relapse, apart from the globus pallidus. CONCLUSION: This study shows that chronic voluntary alcohol consumption induces a reversible increased PDE10A enzymatic availability in the striatum, which is related to the amount of alcohol preference. Thus, PDE10A-mediated signaling plays an important role in modulating the reinforcing effects of alcohol, and the data suggest that PDE10A inhibition may have beneficial behavioral effects on alcohol intake.
PURPOSE: Phosphodiesterase 10A (PDE10A) is a dual substrate enzyme highly enriched in dopamine-receptive striatal medium spiny neurons, which are involved in psychiatric disorders such as alcohol use disorders (AUD). Although preclinical studies suggest a correlation of PDE10A mRNA expression in neuronal and behavioral responses to alcohol intake, little is known about the effects of alcohol exposure on in vivo PDE10A activity in relation to apparent risk factors for AUD such as decision-making and anxiety. METHODS: We performed a longitudinal [18F]JNJ42259152 microPET study to evaluate PDE10A changes over a 9-week intermittent access to alcohol model, including 6 weeks of alcohol exposure, 2 weeks of abstinence followed by 1 week relapse. Parametric PDE10A-binding potential (BPND) images were generated using a Logan reference tissue model with cerebellum as reference region and were analyzed using both a volume-of-interest and voxel-based approach. Moreover, individual decision-making and anxiety levels were assessed with the rat Iowa Gambling Task and open-field test over the IAE model. RESULTS: We observed an increased alcohol preference especially in those animals that exhibited poor initial decision-making. The first 2 weeks of alcohol exposure resulted in an increased striatal PDE10A binding (> 10%). Comparing PDE10A-binding potential after 2 versus 4 weeks of exposure showed a significant decreased PDE10A in the caudate-putamen and nucleus accumbens (pFWE-corrected < 0.05). This striatal PDE10A decrease was related to alcohol consumption and preference. Normalization of striatal PDE10A to initial levels was observed after 1 week of relapse, apart from the globus pallidus. CONCLUSION: This study shows that chronic voluntary alcohol consumption induces a reversible increased PDE10A enzymatic availability in the striatum, which is related to the amount of alcohol preference. Thus, PDE10A-mediated signaling plays an important role in modulating the reinforcing effects of alcohol, and the data suggest that PDE10A inhibition may have beneficial behavioral effects on alcohol intake.
Authors: Thomas F Seeger; Brenda Bartlett; Timothy M Coskran; Jeffrey S Culp; Larry C James; David L Krull; Jerry Lanfear; Anne M Ryan; Christopher J Schmidt; Christine A Strick; Alison H Varghese; Robert D Williams; Patricia G Wylie; Frank S Menniti Journal: Brain Res Date: 2003-09-26 Impact factor: 3.252
Authors: Carolina García-Barroso; Ana Ugarte; Martín Martínez; Alberto J Rico; José Luis Lanciego; Rafael Franco; Julen Oyarzabal; Mar Cuadrado-Tejedor; Ana García-Osta Journal: J Alzheimers Dis Date: 2014 Impact factor: 4.472