Investigation On The Behavior And Related Neuro-Electrochemistry Of Potential Medications For The Treatment Of Substance Use Disorders.
对治疗物质使用障碍的潜在药物的行为和相关神经电化学的调查。
基本信息
- 批准号:9353059
- 负责人:
- 金额:$ 89.07万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:AcuteAgonistAlcohol abuseAlcohol consumptionAlcohol dependenceAreaAttenuatedAutoreceptorsBackBehaviorBehavior monitoringBehavioralBrainBrain DiseasesCannabisCarrier ProteinsChemosensitizationClinical ResearchClinical TrialsCocaineComorbidityDataDiseaseDopamineDopamine ReceptorDoseDrug AddictionDrug abuseDrug usageElectrochemistryEngineeringExposure toFoodGoalsHeroinHourHumanImplantInjection of therapeutic agentInvestigationKnock-outLaboratoriesLeadLearningMediatingMedicalMembraneMetabolic PathwayMethylphenidateMicrodialysisModafinilModelingMonitorMotor ActivityMusNaloxoneNaltrexoneNerveNeurobiologyNeuronsNeuropeptidesNeurotransmittersNucleus AccumbensOpioidOutcomeOxytocinPathologicPatientsPharmaceutical PreparationsPhysiologicalPlayPopulationProceduresProteinsPsychostimulant dependenceRattusReportingResearch Project GrantsRewardsRoleSalineScanningScheduleSelf AdministrationSignal TransductionSleep DisordersStimulusSubstance Use DisorderSynapsesSynaptic ReceptorsSystemTLR4 geneTestingTherapeuticTimeTrainingVenousWorkanalogattenuationbasecocaine usedopamine systemdopamine transporterdrug discriminationdrug of abusedrug testingearly onsetenantiomerfeedingin vivointerestintraperitonealintravenous injectionmemory processmethamphetamine useneuroadaptationneurochemistryopioid abuseopioid use disorderpre-clinicalpreclinical studypsychostimulantregional differencereinforced behaviorreinforcerremifentanilresponsereuptakesocial stressstimulant abuse
项目摘要
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.
临床研究表明,将MOD作为一种精神刺激剂使用障碍治疗的临床试验中,最有利的结果是在选定的患者亚群中(例如,没有表现出与酗酒共病的可卡因成瘾者)。我们提供的最新证据表明,DAT是MODS的主要药理靶点。因此,像可卡因和其他滥用的精神刺激剂一样,MOD通过抑制多巴胺的再摄取来减少DA的突触清除。然而,由此产生的DA水平的刺激和MOD作为行为增强剂的有效性在同类中是最低的。此外,我们的结果证实,在滥用精神刺激剂表现出高水平强化效果的不同自我给药行为时间表下,MOD不能作为行为增强剂发挥作用。最近,我们进一步探索了MOD的神经化学和行为作用,以更好地表征其精神刺激性。在瑞士-韦氏小鼠的NAS或NAC内植入微透析探头,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,还研究了受训辨别10 mg/kg可卡因的小鼠的主观影响。从生理盐水中。MOD(17-300 mg/kg,ip)显著增加NAS和NAC DA水平,最高剂量在1小时达到300%,并持续6小时。这些升高的DA水平在NAS和NAC之间没有统计上的显著地区差异。MOD在会议开始前5分钟和60分钟给药时,在56-100 mg/kg范围内产生类似可卡因的主观效应,当两者联合给药时,可卡因效应增强。尽管与可卡因有相同的主观影响,但与可卡因相比,MODS的精神刺激剂特征是独一无二的。MOD刺激NAS DA的效力和效率低于可卡因。此外,基于其多巴胺能效应,MOD的可卡因样主观效应在较低的剂量和比预期更早的起效时间内获得。我们对MOD的试验表明,尽管抑制DA再摄取可能是MODS治疗作用的主要机制,但非DA依赖的作用可能在其药理学特征中发挥作用。我们现在正在研究缝隙连接的可能性,以促进MOD对古柯碱增强作用的影响。因此,即使MOD可能为特定的成瘾人群提供有用的治疗,但治疗精神刺激剂使用障碍的有效药物仍然是一个未得到满足的医疗需求。
最近,被确认为TLR4拮抗剂的纳洛酮和纳曲酮的(+)对映体被报道可以减弱阿片类药物和兴奋剂滥用的临床前指标。为了进一步审查这些化合物作为药物滥用治疗方法的潜力,我们将以前的评估扩大到包括更广泛的剂量和程序。我们用在体微透析法测定了(+)-纳洛酮和(+)-纳曲酮对可卡因和海洛因急性多巴胺能作用的影响,并在大鼠静脉给药过程中测试了这些药物对可卡因和阿片激动剂瑞芬太尼的增强作用,以及对可卡因的主观效应的影响。我们发现,(+)-纳洛酮或(+)-纳曲酮的预处理不能减弱NAS,并且在一定条件下增强了对可卡因或海洛因产生的多巴胺水平的刺激。此外,虽然在(+)-纳洛酮和(+)-纳曲酮的最高剂量下,可卡因或瑞芬太尼的自我给药都得到了减弱,但这些剂量也会减弱食物维持行为的比率,这表明缺乏对注射药物强化的行为的选择性。药物识别研究未能证明(+)-纳洛酮或(+)-纳曲酮与可卡因的主观影响存在显著的相互作用。因此,我们的研究没有证实TLR4拮抗剂作为治疗可卡因或阿片类药物使用障碍的潜在药物的建议。特别是,在广泛的剂量和实验条件下,(+)-纳洛酮和(+)-纳曲酮并不具体阻止可卡因或阿片类激动剂与神经化学或行为滥用有关的影响。
另一个令人感兴趣的话题是,有报道称,神经肽催产素在奖赏、压力、社会联系、学习和记忆过程中发挥作用,也可能是治疗物质使用障碍的潜在方法。在接触滥用药物后,内源性大脑催产素系统会发生变化。临床前研究已经调查了催产素是否可以逆转因反复使用药物和酒精而发生的神经适应。此外,还对可卡因、大麻和酒精依赖的受试者进行了一些小型临床研究。在我们的临床前实验室中,大鼠在静脉注射增加剂量的哌醋甲酯后,已经测试了催产素预处理的多巴胺能效应,无论是鼻内给药还是腹膜内给药。虽然单独给予催产素不会对NAS中的DA水平产生任何显著的变化,但与单独给予哌醋甲酯相比,它可以诱导更大的由哌醋甲酯诱导的多巴胺刺激。这一效应可能表明哌醋甲酯效应的增强。然而,初步的行为数据显示,催产素减弱了哌醋甲酯的增强效应,这种剂量依赖效应在自我给药过程中会使整个剂量反应向下移动。这些结果表明,催产素可能会作为一种治疗精神刺激性药物依赖的潜在药物在人类身上进行测试。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Gianluigi Tanda其他文献
Gianluigi Tanda的其他文献
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{{ truncateString('Gianluigi Tanda', 18)}}的其他基金
Investigation On The Behavior And Related Neuro-Electrochemistry Of Potential Medications For The Treatment Of Substance Use Disorders.
对治疗物质使用障碍的潜在药物的行为和相关神经电化学的调查。
- 批准号:
10699661 - 财政年份:
- 资助金额:
$ 89.07万 - 项目类别:
Investigation On The Behavior And Related Neuro-Electrochemistry Of Potential Medications For The Treatment Of Substance Use Disorders.
对治疗物质使用障碍的潜在药物的行为和相关神经电化学的调查。
- 批准号:
10004434 - 财政年份:
- 资助金额:
$ 89.07万 - 项目类别:
Endocannabinoid and other brain receptor systems roles in neurochemical and reinforcing effects of abused drugs
内源性大麻素和其他大脑受体系统在神经化学和增强滥用药物作用中的作用
- 批准号:
10267545 - 财政年份:
- 资助金额:
$ 89.07万 - 项目类别:
Investigation On The Behavior And Related Neuro-Electrochemistry Of Potential Medications For The Treatment Of Substance Use Disorders.
对治疗物质使用障碍的潜在药物的行为和相关神经电化学的调查。
- 批准号:
9555600 - 财政年份:
- 资助金额:
$ 89.07万 - 项目类别:
Endocannabinoid roles in neurochemical and reinforcing effects of abused drugs
内源性大麻素在神经化学中的作用和增强滥用药物的作用
- 批准号:
10004430 - 财政年份:
- 资助金额:
$ 89.07万 - 项目类别:
Investigation On The Behavior And Related Neuro-Electrochemistry Of Potential Medications For The Treatment Of Substance Use Disorders.
对治疗物质使用障碍的潜在药物的行为和相关神经电化学的调查。
- 批准号:
10928578 - 财政年份:
- 资助金额:
$ 89.07万 - 项目类别:
Endocannabinoid roles in neurochemical and reinforcing effects of abused drugs
内源性大麻素在神经化学中的作用和增强滥用药物的作用
- 批准号:
9555598 - 财政年份:
- 资助金额:
$ 89.07万 - 项目类别:
Investigation On The Behavior And Related Neuro-Electrochemistry Of Potential Medications For The Treatment Of Substance Use Disorders.
对治疗物质使用障碍的潜在药物的行为和相关神经电化学的调查。
- 批准号:
10267557 - 财政年份:
- 资助金额:
$ 89.07万 - 项目类别:
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