Preclinical profile of a dopamine D1 potentiator suggests therapeutic utility in neurological and psychiatric disorders
| Autor: | Michelle M Menezes, Jeffrey M. Witkin, Kjell A. Svensson, Brian J. Eastwood, Eyassu Chernet, Michael J. O'Neill, Julie F. Falcone, Keith A. Wafford, Hong Wang, Linda K. Thompson, John W. Ryder, Stephen N. Mitchell, Junliang Hao, John Mehnert Schaus, Robert F. Bruns, Alex J. Harper, Meghane E. Masquelin, Deanna L Maren, Xia Li, Tracey K. Murray, Charles R. Yang, Elaine Shanks, Jason Katner, Linli Zhang, Guy Carter, James P. Beck, Patrick L. Love |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Agonist Male Parkinson's disease Reserpine medicine.drug_class Dopamine Agents Prefrontal Cortex Mice Transgenic Pharmacology Levodopa 03 medical and health sciences Cellular and Molecular Neuroscience Mice 0302 clinical medicine Dopamine receptor D1 Hypokinesia Dopamine medicine Animals Wakefulness Maze Learning Rivastigmine Blinking Receptors Dopamine D1 Potentiator medicine.disease Isoquinolines Macaca mulatta Corpus Striatum Mice Inbred C57BL Disease Models Animal 030104 developmental biology Psychotic Disorders medicine.symptom Nervous System Diseases Psychology Sleep 030217 neurology & neurosurgery medicine.drug Antipsychotic Agents |
| Zdroj: | Neuropharmacology. 128 |
| ISSN: | 1873-7064 |
| Popis: | DETQ, an allosteric potentiator of the dopamine D1 receptor, was tested in therapeutic models that were known to respond to D1 agonists. Because of a species difference in affinity for DETQ, all rodent experiments used transgenic mice expressing the human D1 receptor (hD1 mice). When given alone, DETQ reversed the locomotor depression caused by a low dose of reserpine. DETQ also acted synergistically with L-DOPA to reverse the strong hypokinesia seen with a higher dose of reserpine. These results indicate potential as both monotherapy and adjunct treatment in Parkinson's disease. DETQ markedly increased release of both acetylcholine and histamine in the prefrontal cortex, and increased levels of histamine metabolites in the striatum. In the hippocampus, the combination of DETQ and the cholinesterase inhibitor rivastigmine increased ACh to a greater degree than either agent alone. DETQ also increased phosphorylation of the AMPA receptor (GluR1) and the transcription factor CREB in the striatum, consistent with enhanced synaptic plasticity. In the Y-maze, DETQ increased arm entries but (unlike a D1 agonist) did not reduce spontaneous alternation between arms at high doses. DETQ enhanced wakefulness in EEG studies in hD1 mice and decreased immobility in the forced-swim test, a model for antidepressant-like activity. In rhesus monkeys, DETQ increased spontaneous eye-blink rate, a measure that is known to be depressed in Parkinson's disease. Together, these results provide support for potential utility of D1 potentiators in the treatment of several neuropsychiatric disorders, including Parkinson's disease, Alzheimer's disease, cognitive impairment in schizophrenia, and major depressive disorder. |
| Databáze: | OpenAIRE |
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