Investigation On The Behavior And Related Neuro-Electrochemistry Of Potential Medications For The Treatment Of Substance Use Disorders.

临床研究表明，MOD作为精神兴奋剂使用障碍治疗的临床试验的最有利结果见于选定的患者亚群（例如，未显示与酒精滥用共病的可卡因成瘾者）。我们提供了最近的证据表明DAT是MODs的主要药理学靶点。因此，像可卡因和其他滥用的精神兴奋剂一样，MOD通过抑制多巴胺再摄取来降低DA的突触清除率。然而，由此产生的DA水平的刺激和MOD作为行为抑制剂的功效是同类产品中最低的。此外，我们的研究结果证实，MOD不工作作为一个行为的自我管理行为，其中滥用精神兴奋剂表现出高水平的强化疗效在不同的时间表的大鼠。最近，我们进一步探讨了MOD的神经化学和行为作用，以更好地表征其精神兴奋剂的特征。Swiss-Webster小鼠在NAS或NAC中植入微透析探针，以评估与滥用药物的急性强化作用相关的DA水平的变化。此外，在训练辨别10 mg/kg可卡因（i. p.）从盐水。MOD（17-300 mg/kg，i.p.）显著增加NAS和NAC DA水平，在最高剂量下在1小时达到300%，并且持续时间>6小时。 这些升高的DA水平并没有显示NAS和NAC之间的统计学显着的区域差异。MOD在56-100 mg/kg时产生可卡因样的主观效应，当在疗程开始前5分钟和60分钟给药时，当两者联合给药时，可卡因效应增强。 尽管与可卡因共享主观效应，但与可卡因相比，MOD的精神兴奋剂特征是独特的。 MOD在刺激NAS DA方面的效力和功效低于可卡因。此外，MOD的可卡因样主观效应在较低剂量和较早起效时间下获得，这比基于其多巴胺能效应的预期要早。我们的测试与MOD表明，虽然DA再摄取的抑制可能是一个主要的机制，潜在的MOD的治疗作用，非DA依赖性的行动可能发挥作用，其药理学概况。我们现在正在研究缝隙连接的潜力，以促进可卡因强化行动的MOD的影响。因此，即使MOD可能作为治疗特定成瘾人群的有效药物，用于精神兴奋剂使用障碍的有效药物仍然是未满足的医疗需求。 最近，纳洛酮和纳洛酮的（+）-对映体，被鉴定为TLR 4拮抗剂，已被报道减弱阿片类药物和兴奋剂滥用的临床前指标。 为了进一步研究这些化合物作为药物滥用治疗的潜力，我们扩展了以前的评估，以包括更广泛的剂量和程序。 我们测试了（+）-纳洛酮和（+）-纳洛酮给药对可卡因和海洛因的急性多巴胺能作用的影响，通过体内微透析测定;我们还测试了这些药物对可卡因和阿片受体激动剂瑞芬太尼的增强作用，在静脉内自我给药程序下，以及对可卡因的主观影响，通过大鼠的辨别刺激效应测定。 我们发现，预处理与（+）-纳洛酮或（+）-纳洛酮没有减弱，并在一定条件下增强刺激的多巴胺水平产生的可卡因或海洛因在NAS。 此外，虽然在（+）-纳洛酮和（+）-纳洛酮的最高剂量下获得可卡因或瑞芬太尼自我给药的衰减，但这些剂量也减弱了食物维持行为的速率，表明缺乏对药物注射强化的行为的选择性。 药物辨别研究未能证明（+）-纳洛酮或（+）-纳洛酮与可卡因的主观效应存在显著的相互作用。 因此，我们的研究没有证实TLR 4拮抗剂作为可卡因或阿片类药物使用障碍的潜在药物的建议。特别是，在广泛的剂量范围和实验条件下，（+）-纳洛酮和（+）-纳洛酮不能特异性阻断可卡因或阿片类激动剂的神经化学或行为滥用相关作用。 另一个令人感兴趣的话题是，有报道称，在奖励、压力、社会关系、学习和记忆过程中发挥作用的神经肽催产素也可能是药物使用障碍的潜在治疗方法。暴露于滥用药物后，内源性脑催产素系统发生改变。临床前研究已经调查了催产素是否可以逆转反复使用药物和酒精所产生的神经适应。此外，在可卡因、大麻和酒精依赖受试者中进行了一些小型临床研究。 在我们的临床前实验室的多巴胺能效应的催产素预处理，给大鼠鼻内或腹腔内，已被测试后静脉注射剂量增加的哌甲酯。虽然单独给予催产素不会对NAS中的DA水平产生任何显著变化，但与单独给予哌甲酯相比，它可以引起更大的哌甲酯诱导的多巴胺刺激。这种作用可能表明哌甲酯作用的增强。然而，初步的行为数据显示，催产素减弱了哌醋甲酯的强化作用，这是一种剂量依赖性作用，在自我给药过程中将整个剂量反应向下转移。这些结果表明，催产素可能是一个潜在的药物治疗精神兴奋剂依赖在人类中进行测试。

Clinical studies suggest that the most favorable outcomes from clinical trials with MOD administered as a psychostimulant use disorder treatment were seen in selected subpopulations of patients (e.g. cocaine addicts who did not show comorbidity with abuse of alcohol). We have provided recent evidence that the DAT is MODs main pharmacologic target. Thus, like cocaine and other abused psychostimulants, MOD reduces synaptic clearance of DA by inhibiting dopamine reuptake. However, the resulting stimulation of DA levels and the efficacy of MOD as a behavioral reinforcer are among the lowest in its class. Moreover, our results confirm that MOD does not work as a behavioral reinforcer in rats under different schedules of self-administration behavior in which abused psychostimulants demonstrate high levels of reinforcing efficacy. Recently, we have further explored the neurochemical and behavioral actions of MOD to better characterize its psychostimulant profile. Swiss-Webster mice were implanted with microdialysis probes in the NAS or NAC to evaluate changes in DA levels related to acute reinforcing actions of drugs of abuse. Additionally, subjective effects were studied in mice trained to discriminate 10 mg/kg cocaine (i.p.) from saline. MOD (17-300 mg/kg, i.p.) significantly increased NAS and NAC DA levels that at the highest doses reached 300% at 1 hour, and lasted >6 hours in duration. These elevated DA levels did not show statistically significant regional differences between the NAS and NAC. MOD produced cocaine-like subjective effects at 56-100 mg/kg when administered at 5 and 60 minutes before the start of the session, and enhanced cocaine effects when the two were administered in combination. Despite sharing subjective effects with cocaine, MODs psychostimulant profile was unique compared to that of cocaine. MOD had a lower potency and efficacy than cocaine in stimulating NAS DA. Additionally, the cocaine-like subjective effects of MOD were obtained at lower doses and earlier onset times than expected based on its dopaminergic effects. Our tests with MOD suggest that although inhibition of DA reuptake may be a primary mechanism underlying MODs therapeutic actions, non DA-dependent actions may be playing a role in its pharmacological profile. We are now investigating the potential of GAP-junctions to facilitate the effects of MOD on cocaines reinforcing actions. Thus even if MOD might provide useful as a treatment for specific addicted populations, effective medications for psychostimulant use disorders are still an unmet medical need. Recently, the (+)-enantiomers of naloxone and naltrexone, identified as TLR4 antagonists, have been reported to attenuate preclinical indicators of both opioid and stimulant abuse. To further examine the potential of these compounds as drug-abuse treatments we extended the previous assessments to include a wider range of doses and procedures. We have tested the effects of administration of (+)-naloxone and (+)-naltrexone on the acute dopaminergic actions of cocaine and heroin determined by in vivo microdialysis; we have also tested these drugs on the reinforcing effects of cocaine and the opioid agonist, remifentanil, under intra-venous self-administration procedures, as well as on the subjective effects of cocaine determined by discriminative-stimulus effects in rats. We found that pretreatment with (+)-naloxone or (+)-naltrexone did not attenuate, and under certain conditions enhanced the stimulation of dopamine levels produced by cocaine or heroin in the NAS. Further, while an attenuation of either cocaine or remifentanil self-administration was obtained at the highest doses of (+)-naloxone and (+)-naltrexone, those doses also attenuated rates of food-maintained behaviors, indicating a lack of selectivity for behaviors reinforced with drug injections. Drug-discrimination studies failed to demonstrate a significant interaction of (+)-naloxone or (+)-naltrexone with the subjective effects of cocaine. Thus our studies do not confirm the suggested involvement of TLR4 antagonists as potential medications for cocaine or opioid use disorders. In particular, under a wide range of doses and experimental conditions, (+)-naloxone and (+)-naltrexone, did not specifically block neurochemical or behavioral abuse-related effects of cocaine or opioid agonists. Another topic of interest has been suggested by reports that the neuropeptide oxytocin, which plays a role in reward, stress, social affiliation, learning, and memory processes, might also be a potential treatment for substance use disorders. The endogenous brain oxytocin system is altered after exposure to drugs of abuse. Preclinical studies have investigated whether oxytocin can reverse the neuroadaptations occurring with repeated drug and alcohol use. In addition, a few small clinical studies have been conducted in cocaine, cannabis, and alcohol dependent subjects. In our preclinical laboratories the dopaminergic effects of oxytocin pretreatments, given intranasal or intraperitoneal to rats, have been tested after intravenous injection with increasing doses of methylphenidate. While oxytocin given alone does not produce any significant change to DA levels in the NAS, it can elicit a greater methylphenidate-induced stimulation of dopamine as compared to methylphenidate alone. This effect might indicate a potentiation of methylphenidate effects. However, preliminary behavioral data show that oxytocin blunts the reinforcing effects of methylphenidate, a dose-dependent effect that shifts the entire dose response downward in self-administration procedures. These results suggest that oxytocin might be tested in humans as a potential pharmacologic treatment for psychostimulant dependence.