Control Of Behavior By Drug Injections

在人类身上有滥用责任的药物通常作为积极的增强剂，维持和加强导致它们在动物身上使用的行为，并在禁欲的动物中引发以前被消灭的寻求药物行为的复发。正在进行实验，以评估药物自我给药和复发行为背后的神经生物学和行为机制，以及药物操纵改变这种行为的能力。 我们以前的研究表明，选择性阻断突触前A2a受体可以为治疗大麻依赖提供一种新的药理学方法，并强调皮质纹状体谷氨酸能神经传递可能是参与大麻成分β-9-四氢大麻酚奖赏效应的主要机制。不同剂量的腺苷A2a受体拮抗剂Msx-3 3，7-dihydro-8-(1E)-2-(3-ethoxyphenyl)ethenyl-7甲基-3-3-(磷氧基)丙基-1-(2-丙苯基)-1H-嘌呤-2，6-二酮先前被发现可以减少或增加松鼠体内大麻类化合物THC或anandamide的自身给药。推测较低剂量的MSX-3引起的下降与阻断调节谷氨酸能神经传递的纹状体突触前A2A受体有关，而较高剂量的MSX-3引起的升高与阻断定位于纹状体苍白球神经元的突触后A2A受体有关。这一假说已在本研究中得到证实。本研究验证了选择性突触前和突触后A2a受体拮抗剂SCH-442416 2-(2-furanyl)-7-3-(4-methoxyphenyl)propyl-7H-pyrazolo4，3-e1，2，4triazolo1，5-cpyrimidin-5-amine和KW-442416(E)-1、3-diethyl-8-(3，4-dimethoxystyryl)-7-methyl-3，7-dihydro-1H-purine-2，6-dione，在训练给药的松鼠猴中的作用。SCH-442416使THC自身给药剂量-反应曲线显著右移，与THC增强效应的拮抗作用一致。相反，KW-6002产生了显著的左移，与THC的增强作用一致。这些结果表明，腺苷A2a受体是治疗大麻依赖药物开发的潜在靶点。 在大脑的奖赏回路中，7-烟碱型乙酰胆碱受体(7nAChRs)调节大麻的主要精神活性成分-9-四氢大麻酚(THC)的作用。犬尿酸(KYNA)是一种内源性7nAChRs的负变构调节剂。在这里，我们报告了犬尿氨酸3-单加氧酶(KMO)抑制剂Ro 61-8048提高了大脑KYNA水平，并减弱了大麻素诱导的奖赏相关脑区细胞外多巴胺的增加。在药物滥用的自我给药模型中，RO61-8048分别降低了THC和合成大麻素Win 55,212-2对松鼠和大鼠的奖赏效应，并防止了因再次暴露于大麻素或大麻素相关线索而导致的复吸。正性变构调节剂7nAChRs可阻止RO61-8048提高内源性KYNA水平的作用。尽管有明显的需求，但目前还没有被批准用于治疗大麻依赖的药物。调节KYNA为实现大麻戒断和防止复发提供了一种药理学策略。 与直接作用于大麻素受体的药物相比，增强内源性释放的大麻素配体在大脑中的作用可能会提供更安全和有效的治疗效果。脂肪酸酰胺水解酶抑制剂(FAAH)可防止大麻素受体和过氧化物酶体增殖物激活受体(PPAR)的内源性配体的破坏，延长并增强这些配体在自然释放时的作用。在一系列正在进行的实验中，我们正在评估FAAH抑制剂和PPAR激活剂在成瘾和认知(特别是学习和记忆)动物模型中的效果。这些研究表明，FAAH抑制剂可以产生潜在的治疗效果，一些是通过大麻素受体，另一些是通过PPAR。这些效果包括增强某些形式的学习，抵消尼古丁和酒精的奖励作用，缓解大麻和其他药物的戒断症状，防止复发--如恢复药物自我管理。由于FAAH抑制可能具有广泛的治疗作用，但也可能与大麻的一些不良反应相同，值得注意的是，在我们最近开发的一系列FAAH抑制剂的研究中，有几种具有THC样的增强和诱发复发的作用，但两种选择性的FAAH抑制剂URB597和URB694在尼古丁依赖的动物模型中具有潜在的有益作用，但没有迹象表明增强或诱发复发的作用。我们的研究仍在进行中，但初步证据表明，这些FAAH抑制剂可能会改善尼古丁依赖的治疗干预，并更好地理解尼古丁依赖的大脑机制。

Drugs that have abuse liability in humans typically serve as positive reinforcers to maintain and strengthen behavior leading to their administration in animals and provoke relapse to previously extinguished drug-seeking behavior in abstinent animals. Experiments are being conducted to assess neurobiological and behavioral mechanisms underlying drug self-administration and relapse behavior rats and monkeys, and the ability of pharmacological manipulations to modify such behavior. Our previous studies suggest that electively 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 of the marijuana constituent delta-9-tetrahydrocannabinol (THC).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 the cannabinoids 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-pyrazolo4,3-e1,2,4triazolo1,5-cpyrimidin-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 suggest the adenosine A2A receptor as a potential target for the development of medications to treat marijuana dependence. In the reward circuitry of the brain, α-7-nicotinic acetylcholine receptors (α7nAChRs) modulate effects of delta-9-tetrahydrocannabinol (THC), marijuana's main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of α7nAChRs. Here we report that the kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 increases brain KYNA levels and attenuates cannabinoid-induced increases in extracellular dopamine in reward-related brain areas. In the self-administration model of drug abuse, Ro 61-8048 reduced the rewarding effects of THC and the synthetic cannabinoid WIN 55,212-2 in squirrel monkeys and rats, respectively, and it also prevented relapse to drug-seeking induced by reexposure to cannabinoids or cannabinoid-associated cues. The effects of enhancing endogenous KYNA levels with Ro 61-8048 were prevented by positive allosteric modulators of α7nAChRs. Despite a clear need, there are no medications approved for treatment of marijuana dependence. Modulation of KYNA offers a pharmacological strategy for achieving abstinence from marijuana and preventing relapse. Enhancing the effects of endogenously-released cannabinoid ligands in the brain might provide therapeutic effects more safely and effectively than administering drugs that act directly at the cannabinoid receptor. Inhibitors of fatty acid amide hydrolase (FAAH) prevent the breakdown of endogenous ligands for cannabinoid receptors and peroxisome proliferator-activated receptors (PPAR), prolonging and enhancing the effects of these ligands when they are naturally released. In an ongoing series of experiments we are assessing the effects of FAAH inhibitors and PPAR activators in animal models of addiction and cognition (specifically learning and memory). These studies show that FAAH inhibitors can produce potentially therapeutic effects, some through cannabinoid receptors and some through PPAR. These effects include enhancing certain forms of learning, counteracting the rewarding effects of nicotine and alcohol, relieving symptoms of withdrawal from cannabis and other drugs, and protecting against relapse-like reinstatement of drug self-administration. Since FAAH inhibition might have a wide range of therapeutic actions but might also share some of the adverse effects of cannabis, it is noteworthy that in studies we have been conducting with a series of recently developed FAAH inhibitors, several had THC-like reinforcing and relapse-inducing effects but two selective FAAH inhibitors, URB597 and URB694, had potentially beneficial effects in animal models of nicotine dependence but no indication of reinforcing or relapse-inducing effects. Our research is ongoing but the preliminary evidence indicates that these FAAH inhibitors might lead to improved therapeutic interventions in nicotine dependence and a better understanding of the brain mechanisms underlying nicotine dependence.