PT  - JOURNAL ARTICLE
AU  - Justinová, Zuzana
AU  - Redhi, Godfrey H.
AU  - Goldberg, Steven R.
AU  - Ferré, Sergi
TI  - Differential Effects of Presynaptic versus Postsynaptic Adenosine A<sub>2A</sub> Receptor Blockade on Δ<sup>9</sup>-Tetrahydrocannabinol (THC) Self-Administration in Squirrel Monkeys
AID  - 10.1523/JNEUROSCI.5073-13.2014
DP  - 2014 May 07
TA  - The Journal of Neuroscience
PG  - 6480--6484
VI  - 34
IP  - 19
4099  - http://www.jneurosci.org/content/34/19/6480.short
4100  - http://www.jneurosci.org/content/34/19/6480.full
SO  - J. Neurosci.2014 May 07; 34
AB  - Different doses of an adenosine A2A receptor antagonist MSX-3 [3,7-dihydro-8-[(1E)-2-(3-ethoxyphenyl)ethenyl]-7 methyl-3-[3-(phosphooxy)propyl-1-(2 propynil)-1H-purine-2,6-dione] were found previously to either decrease or increase self-administration of cannabinoids delta-9-tetrahydrocannabinol (THC) or anandamide in squirrel monkeys. It was hypothesized that the decrease observed with a relatively low dose of MSX-3 was related to blockade of striatal presynaptic A2A receptors that modulate glutamatergic neurotransmission, whereas the increase observed with a higher dose was related to blockade of postsynaptic A2A receptors localized in striatopallidal neurons. This hypothesis was confirmed in the present study by testing the effects of the preferential presynaptic and postsynaptic A2A receptor antagonists SCH-442416 [2-(2-furanyl)-7-[3-(4-methoxyphenyl)propyl]-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] and KW-6002 [(E)-1, 3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione], respectively, in squirrel monkeys trained to intravenously self-administer THC. SCH-442416 produced a significant shift to the right of the THC self-administration dose–response curves, consistent with antagonism of the reinforcing effects of THC. Conversely, KW-6002 produced a significant shift to the left, consistent with potentiation of the reinforcing effects of THC. These results show that selectively blocking presynaptic A2A receptors could provide a new pharmacological approach to the treatment of marijuana dependence and underscore corticostriatal glutamatergic neurotransmission as a possible main mechanism involved in the rewarding effects of THC.