Cannabinoids inhibit the synaptic uptake of adenosine and dopamine in the rat and mouse striatum.
Adenosine, dopamine and endocannabinoids strictly modulate the release of one another in the dorsolateral striatum thereby controlling synaptic plasticity. As a second level of interaction, they regulate the action of one another via receptor heteromer formation. Here we investigated a putative third level of interaction, i.e. the possible control by cannabinoids of synaptic dopamine and adenosine reuptake. We found that a large number of endo- and exogenous cannabinoid ligands inhibit the uptake of [(3)H]adenosine and [(3)H]dopamine in rat sriatal nerve terminals. Maximal effects were often comparable to those of the dopamine transporter inhibitor, GBR12783 and the equilibrative nucleoside transporter inhibitor, dipyridamole. Cannabinoid ligands were generally more potent to inhibit the uptake of adenosine than that of dopamine. The inhibitory effect was: (1) unrelated to the pharmacological profile(s) of the ligands at the cannabinoid CB(1), CB(2), GPR55 and at the vanilloid TRPV(1) receptors; (2) not prevented by the cannabinoid CB(1) receptor antagonist/inverse agonist, LY320135; and (3) maintained in the cannabinoid CB(1) receptor knockout mice. In the same experiments, only O-2050, cannabidiol, and WIN55212-3 inhibited the simultaneously measured DL-TBOA-sensitive uptake of [(14)C]glutamate. In summary, many cannabinoid ligands are able to inhibit the synaptic uptake of adenosine and dopamine. These effects are not mediated by cannabinoid CB(1) receptors, and should be an additional mechanism to consider when interpreting synaptic effects of cannabinoids.
Department of Pharmacology, Center of Biological Sciences, Federal University of Santa Catarina (UFSC), Florianópolis, SC, Brazil.
Pablo
P
Pandolfo
Vasco
V
Silveirinha
Alexandre
A
dos Santos-Rodrigues
Laurent
L
Venance
Catherine
C
Ledent
Reinaldo N
RN
Takahashi
Rodrigo A
RA
Cunha
Attila
A
Köfalvi
D000241:Adenosine / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology; D002186:Cannabinoids / Q000138:chemical synthesis / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005971:Glutamates / Q000378:metabolism; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism; D010944:Plants / Q000737:chemistry; D051381:Rats; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism*
D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D018765:Dopamine Uptake Inhibitors; D005971:Glutamates; D008024:Ligands; D000241:Adenosine; D004298:Dopamine