Differential Effects of Presynaptic versus Postsynaptic Adenosine A2A Receptor Blockade on Δ9-Tetrahydrocannabinol (THC) Self-Administration in Squirrel Monkeys
Differential Effects of Presynaptic versus Postsynaptic Adenosine A2A Receptor Blockade on Δ9-Tetrahydrocannabinol (THC) Self-Administration in Squirrel Monkeys
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DOI：
10.1523/jneurosci.5073-13.2014
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发表时间：
2014-05-07
影响因子：
5.3
通讯作者：
Ferre, Sergi
中科院分区：
文献类型：
--
作者：
Justinova, Zuzana;Redhi, Godfrey H.;Ferre, Sergi
先前发现不同剂量的腺苷A（2A）受体拮抗剂MSX-3 [3，7-二氢-8-[（1 E）-2-（3-乙氧基苯基）乙烯基]-7甲基-3-[3（磷氧）丙基-1-（2-丙炔）-1H-嘌呤-2，6-二酮]可减少或增加松鼠猴大麻素δ-9-四氢大麻酚（THC）或大麻素的自我给药。假设用相对低剂量的MSX-3观察到的减少与调节多巴胺能神经传递的纹状体突触前A（2A）受体的阻断有关，而用较高剂量观察到的增加与位于纹状体苍白球神经元中的突触后A（2A）受体的阻断有关。本研究通过测试优先突触前和突触后A（2A）受体拮抗剂SCH-442416的作用证实了这一假设[2- 3]。（2-呋喃基）-7-[3-（4-甲氧基苯基）丙基]-7H-吡唑并[4，3-e][1，2，4]三唑并[1，5-c]嘧啶-5-胺]和KW-6002 [（E）-1，3-二乙基-8-（3，4-二甲氧基苯乙烯基）-7-甲基-3，7-二氢-1H-嘌呤-2，6-二酮]。SCH-442416使THC自身给药剂量-反应曲线显著向右偏移，与THC增强效应的拮抗作用一致。相反，KW-6002产生了向左的显著偏移，与THC的增强作用的增强一致。这些结果表明，选择性地阻断突触前A（2A）受体可以提供一种新的药理学方法来治疗大麻依赖，并强调皮质纹状体多巴胺能神经传递作为一个可能的主要机制参与THC的奖励作用。
Different doses of an adenosine A(2A) 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 A(2A) receptors that modulate glutamatergic neurotransmission, whereas the increase observed with a higher dose was related to blockade of postsynapticA(2A) receptors localized in striatopallidal neurons. This hypothesis was confirmed in the present study by testing the effects of the preferential presynaptic and postsynaptic A(2A) 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 selfadminister 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 A(2A) 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.