Functional magnetic resonance imaging reveals different neural substrates for the effects of orexin-1 and orexin-2 receptor antagonists
| Autor: | Nicola Cesari, Laura Piccoli, Angelo Bifone, David Amantini, Prisca Martinelli, Marinella Antolini, Dino Montanari, Alessandro Gozzi, Mauro Corsi, Mario Massagrande, Giuliano Turrini, Michela Tessari |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Activity Cycles
Receptors Neuropeptide Anatomy and Physiology Dopamine lcsh:Medicine Aminopyridines Brain mapping Biochemistry Receptors G-Protein-Coupled Dioxanes Behavioral Neuroscience Piperidines Orexin Receptors Receptor lcsh:Science Drug Dependence Psychiatry Brain Mapping Multidisciplinary medicine.diagnostic_test Behavior Animal Chemistry fMRI Substance Abuse Neurochemistry Animal Models Neurotransmitters phMRI Magnetic Resonance Imaging Orexin receptor Mental Health Neurology Behavioral Pharmacology Medicine Neurochemicals medicine.drug Research Article medicine.medical_specialty Drugs and Devices brain Neuroimaging Arousal Model Organisms Reward Internal medicine Orexigenic medicine Animals Biology Motivation Phenylurea Compounds lcsh:R Neuropeptides Conditioned place preference Orexin Rats Amphetamine Endocrinology Rat lcsh:Q Functional magnetic resonance imaging Physiological Processes Sleep Sleep Disorders Neuroscience |
| Zdroj: | PLoS ONE PLoS ONE, Vol 6, Iss 1, p e16406 (2011) |
| Popis: | Orexins are neuro-modulatory peptides involved in the control of diverse physiological functions through interaction with two receptors, orexin-1 (OX1R) and orexin-2 (OX2R). Recent evidence in pre-clinical models points toward a putative dichotomic role of the two receptors, with OX2R predominantly involved in the regulation of the sleep/wake cycle and arousal, and the OX1R being more specifically involved in reward processing and motivated behaviour. However, the specific neural substrates underlying these distinct processes in the rat brain remain to be elucidated. Here we used functional magnetic resonance imaging (fMRI) in the rat to map the modulatory effect of selective OXR blockade on the functional response produced by D-amphetamine, a psychostimulant and arousing drug that stimulates orexigenic activity. OXR blockade was produced by GSK1059865 and JNJ1037049, two novel OX1R and OX2R antagonists with unprecedented selectivity at the counter receptor type. Both drugs inhibited the functional response to D-amphetamine albeit with distinct neuroanatomical patterns: GSK1059865 focally modulated functional responses in striatal terminals, whereas JNJ1037049 induced a widespread pattern of attenuation characterised by a prominent cortical involvement. At the same doses tested in the fMRI study, JNJ1037049 exhibited robust hypnotic properties, while GSK1059865 failed to display significant sleep-promoting effects, but significantly reduced drug-seeking behaviour in cocaine-induced conditioned place preference. Collectively, these findings highlight an essential contribution of the OX2R in modulating cortical activity and arousal, an effect that is consistent with the robust hypnotic effect exhibited by JNJ1037049. The subcortical and striatal pattern observed with GSK1059865 represent a possible neurofunctional correlate for the modulatory role of OX1R in controlling reward-processing and goal-oriented behaviours in the rat. |
| Databáze: | OpenAIRE |
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