Receptor-independent depression of DA and 5-HT uptake by cannabinoids in rat neocortex—involvement of Na+/K+-ATPase
| Autor: | Marc Steffens, Thomas J. Feuerstein |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Male
AM251 Serotonin medicine.medical_specialty Serotonin uptake Cannabinoid receptor Dopamine Morpholines medicine.medical_treatment Neocortex In Vitro Techniques Naphthalenes Ouabain Choline Cellular and Molecular Neuroscience chemistry.chemical_compound Adenosine Triphosphate Dopamine Uptake Inhibitors Receptor Cannabinoid CB1 Internal medicine medicine Cannabinoid receptor type 2 Animals Enzyme Inhibitors Na+/K+-ATPase Luciferases Arachidonic Acid Cannabinoids Chemistry Sodium Dodecyl Sulfate Cell Biology Anandamide Calcium Channel Blockers Benzoxazines Rats Endocrinology Luminescent Measurements Cannabinoid Sodium-Potassium-Exchanging ATPase Selective Serotonin Reuptake Inhibitors Synaptosomes medicine.drug |
| Zdroj: | Neurochemistry International. 44:529-538 |
| ISSN: | 0197-0186 |
| DOI: | 10.1016/j.neuint.2003.08.009 |
| Popis: | There is evidence that cannabinoids modulate the reuptake of some neurotransmitters in the central nervous system. In this study, we investigated the effects of the synthetic cannabinoid receptor agonist WIN55212-2, the endocannabinoid anandamide and the chemically related arachidonic acid on serotonin (5-HT) and dopamine (DA) uptake into rat neocortical synaptosomes. At micromolar concentrations, anandamide and arachidonic acid produced steep inhibition curves with Hill coefficients above unity. WIN55212-2 inhibited both DA and 5-HT uptake with Hill coefficients near unity, also within the micromolar range. The effect of WIN55212-2 was not mediated by cannabinoid receptors, since the CB1 receptor antagonist AM251 failed to diminish uptake inhibition by WIN55212-2 and since the Ki estimates of WIN55212-2 were outside the range of the dissociation constants of WIN55212-2 at both CB1 and CB2 receptors. A 100-fold higher concentration of DA, respectively 5-HT, did not induce a shift to the right of the WIN55212-2 concentration-inhibition curves, suggesting a carrier-independent mechanism. The Na(+)/K(+)-ATPase inhibitor ouabain concentration dependently inhibited 5-HT uptake. Possible drug effects on commercial Na(+)/K(+)-ATPase and synaptosomal ATP consumption were investigated using an ATP bioluminescence assay. Ouabain inhibited both commercial and synaptosomal Na(+)/K(+)-ATPase. WIN55212-2 had no effect on commercial Na(+)/K(+)-ATPase, but inhibited synaptosomal ATP consumption. Anandamide produced a sharp decrease in the activity of commercial Na(+)/K(+)-ATPase and on synaptosomal ATP consumption. Presence of ouabain significantly reduced the inhibitory effect of anandamide on synaptosomal ATP consumption, whereas the effect of WIN55212-2 remained unchanged. Our results show that cannabinoids and arachidonic acid inhibit DA and 5-HT uptake into rat neocortical synaptosomes. This effect is neither cannabinoid receptor-mediated nor due to competitive inhibition of membrane transporters, but is partly effected by a decreased Na(+)/K(+)-ATPase activity. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect