Synthetic cannabinoids inhibit the dopamine transporter whereby increasing stimulated presynaptic net dopamine release in the rat striatum
Background: The interaction between the two major modulators of striatal synaptic plasticity, the endocannabinoid and dopaminergic systems, is a key issue to the better understanding of the basal ganglia�s physiology and its role in neuropsychiatric disorders. Endocannabinoids such as N-arachidonoylethanolamine (anandamide) and 2-arachidonoyl glycerol (2-AG) are released from medium spiny neurons upon depolarization or activation of metabotropic receptors such as D2-like dopamine receptors, and in turn, impose a frequency-dependent filter on corticostriatal glutamatergic terminals via the activation of presynaptic CB1 cannabinoid receptors (CB1Rs). Systemically administered CB1R agonists indirectly increase striatal and accumbal dopamine levels via the disinhibition of mesolimbic and nigral GABAergic control on dopaminergic cell bodies. However, the presence of functional presynaptic CB1Rs in dopaminergic terminals in the striatum is a controversial issue.
Aims and Methods: To resolve this question, we tested several endogenous and synthetic cannabinoid and vanilloid ligands on the uptake and depolarization-evoked release of dopamine in striatal nerve terminal preparations. :
Results: Synthetic CB1R agonists, WIN55212-2 and O-2545 as well as CB1R antagonists and inverse agonists, AM251, (-)-cannabidiol and O-2050 all inihibited the uptake dopamine up to the concentration of 10 micromol. Arachidonic acid but not its endogenous or synthetic CB1R agonist analogues, anandamide, 2-AG, R-methanandamide and ACEA, also slightly inhibited the uptake of dopamine. N-arachidonoyldopamine and oleoyldopamine but not palmytoyldopamine were the only endogenous substances with dopamine transporter (DAT) inhibitor properties. In contrast, none of the ligands affected the uptake of glutamate. WIN55212-2 and O-2545 as well as the selective DAT inhibitor, GBR12783 largely increased the high K -evoked release of dopamine. This effect of WIN55212-2 was occluded by GBR12783 and was prevented at 12 �C which is a typical method to inhibit the re-uptake of transmitters. Anandamide and 2-AG neither inhibited nor increased the K -evoked release of dopamine. None of these effects on the uptake or release were prevented by the CB1R antagonist/inverse agonist, AM251.
Discussion:This is the first report demonstrating with direct presynaptic tools that non-arachidonic acid-derivative CB1R ligands increase the amplitude and duration of evoked dopamine release via direct DAT blockade. In contrast, we found no evidence for presynaptic functional CB1Rs in dopaminergic terminals.
Conference:
11th Meeting of the Portuguese Society for Neuroscience, Braga, Portugal, 4 Jun - 6 Jun, 2009.
Presentation Type:
Poster Presentation
Topic:
Neuronal Communication
Citation:
Pandolfo
P,
Ferreira
SG and
Kofalvi
A
(2009). Synthetic cannabinoids inhibit the dopamine transporter whereby increasing stimulated presynaptic net dopamine release in the rat striatum.
Front. Neurosci.
Conference Abstract:
11th Meeting of the Portuguese Society for Neuroscience.
doi: 10.3389/conf.neuro.01.2009.11.128
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Received:
11 Aug 2009;
Published Online:
11 Aug 2009.
*
Correspondence:
Pablo Pandolfo, CSIC-UMH, Alicante, Portugal, pablopandolfo@gmail.com