The neuronal KCNQ channel opener retigabine inhibits locomotor activity and reduces forebrain excitatory responses to the psychostimulants cocaine, methylphenidate and phencyclidine
| Autor: | Jens D. Mikkelsen, Naheed R. Mirza, Henrik H. Hansen, Pia Weikop, Jørgen Scheel-Krüger, Jesper T. Andreasen |
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| Rok vydání: | 2007 |
| Předmět: |
Male
Dopamine Phencyclidine Substantia nigra Striatum Motor Activity Phenylenediamines Nucleus accumbens Pharmacology Receptors N-Methyl-D-Aspartate chemistry.chemical_compound Prosencephalon Cocaine Membrane Transport Modulators Basal ganglia medicine Animals Rats Wistar KCNQ Potassium Channels Chemistry Retigabine Dopaminergic Rats Ventral tegmental area medicine.anatomical_structure nervous system Methylphenidate Central Nervous System Stimulants Carbamates Excitatory Amino Acid Antagonists Proto-Oncogene Proteins c-fos Neuroscience medicine.drug |
| Zdroj: | European Journal of Pharmacology. 570:77-88 |
| ISSN: | 0014-2999 |
| DOI: | 10.1016/j.ejphar.2007.05.029 |
| Popis: | Many central stimulating drugs have a pronounced stimulatory effect on striatal and cortical activity which is associated to enhanced function of mesencephalic dopaminergic neurons. Mesencephalic KCNQ (also termed K(v)7) potassium channels suppress the basal activity of dopaminergic neurons in the substantia nigra and ventral tegmental area. These regions have extensive dopaminergic projections to the striatum and cortex, and positive modulation of KCNQ channel function may therefore potentially reduce the reinforcing impact of central stimulating drugs. We studied the effects of the principal neuronal KCNQ channel opener, retigabine, in rats exposed acutely to cocaine, methylphenidate (dopamine reuptake inhibitors) or phencyclidine (PCP, a psychotomimetic NMDA receptor antagonist). Retigabine (> or =1.0 mg/kg) inhibited cocaine, methylphenidate and PCP-stimulated locomotor activity. Also, retigabine reduced spontaneous locomotor activity. The inhibitory effect of retigabine on psychostimulant-induced locomotor activity was accompanied by a marked reduction in c-Fos expression, in particular the nucleus accumbens and primary motor cortex were responsive to retigabine pre-treatment. Notably, retigabine also reduced basal extracellular levels of striatal dopamine metabolites and partially prevented dopamine overflow in the striatum induced by dopamine reuptake blockade. In combination, these data suggest that retigabine reduces striatal and cortical excitability, thereby attenuating excitatory effects of central stimulating drugs in dopamine-rich areas of the rat forebrain. KCNQ channel openers may therefore be of potential relevance in the treatment of addiction states caused by abuse of psychostimulants. |
| Databáze: | OpenAIRE |
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