Neurosteroid-BZ combinations: Strategy for reducing abuse and sedation
神经类固醇-BZ 组合:减少滥用和镇静的策略
基本信息
- 批准号:8637969
- 负责人:
- 金额:$ 42.23万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-06-15 至 2017-04-30
- 项目状态:已结题
- 来源:
- 关键词:Adverse drug effectAdverse effectsAnti-Anxiety AgentsAnticonvulsantsAnxietyAnxiety DisordersAtaxiaAversive StimulusBehaviorBenzodiazepinesBrainCharacteristicsClinicalClonazepamConflict (Psychology)DataDevelopmentDiazepamDoseDrug CombinationsEffectivenessFemaleFutureGoalsGonadal Steroid HormonesInjection of therapeutic agentIntravenousInvestigationLaboratoriesLuteal PhaseMacaca mulattaMeasuresMediatingMenstrual cycleModelingModern MedicineMonkeysMotorMuscle relaxantsNaturePharmaceutical PreparationsPharmacologyPilot ProjectsPosturePregnanoloneProceduresProgesteronePsychotropic DrugsResearchRestRoleScheduleSedation procedureSelf AdministrationSleepSleep DisordersTestingTherapeutic Indexbaseganaxolonehypnoticimprovedneurosteroidsnovelnovel strategiespre-clinicalprogramsreceptorsedativesex
项目摘要
DESCRIPTION (provided by applicant): Benzodiazepines (BZs) are prescribed widely as anxiolytics, hypnotics, muscle relaxants, and anticonvulsants. Although BZs are among the safest psychoactive drugs in modern medicine, their utility is often limited by unwanted side effects such as abuse liability and sedative-motor effects. The overall goal of this application is
to determine quantitatively the extent to which combining a BZ with another type of GABAA modulator, a neuroactive steroid, results in enhanced anxiolytic-like effects but not enhanced unwanted side-effects. Specific Aim 1 will evaluate the hypothesis that neuroactive steroids that act at GABAA receptors will enhance the anxiolytic-like effects of BZ-type drugs in a supra-additive manner. Conventional BZs produce characteristic increases in operant behavior that are suppressed by aversive stimuli, i.e., induce "anti-conflict" effects. Using a rhesus monkey conflict procedure, we will evaluate the anxiolytic-like effects of conventional BZs (e.g., clonazepam), alone or in combination with neuroactive steroids (e.g., ganaxolone, pregnanolone). Specific Aim 2 will evaluate the hypothesis that neuroactive steroids that act at GABAA receptors will alter the self-administration of BZ-type drugs in an infra-additive manner. These studies will employ a progressive-ratio (PR) schedule of intravenous drug injection to examine the reinforcing effectiveness of BZs, either alone or in combination with neuroactive steroids. Specific Aim 3 will initiate investigation of the combined effects of neuroactive steroid and BZ-type drugs in a novel observation procedure that distinguishes different levels of sedation and motor function. We will use observational procedures recently developed in our laboratory that dissociate ataxia-like effects, sleep/rest-associated postures, moderate and deep sedation. In all studies, mechanism of action will be assessed by testing receptor subtype-specific GABAA compounds. All combination data will be evaluated with isobolographic/dose-addition analysis in order to determine if effects of drug combinations are additive, supra-additive, or infra-additive. Finally, we will conduct targeted studies with female monkeys to begin
to investigate the role of the menstrual cycle in mediating the sedative-motor effects of BZs, based on the observation that endogenous neuroactive steroid levels increase with the progesterone surge during the luteal phase. This pilot study should provide a springboard for evaluating sex as a factor in BZ and neuroactive steroid pharmacology in future applications. The ultimate goal for this research program is to provide critical preclinical information for development of a broadly effective combination product with an improved side effect profile for treating anxiety disorders.
描述(由申请人提供):苯二氮卓类药物(BZs)被广泛用作抗焦虑药、催眠药、肌肉松弛剂和抗惊厥药。虽然bz是现代医学中最安全的精神药物之一,但它们的效用往往受到不良副作用的限制,如滥用风险和镇静运动效应。这个应用程序的总体目标是
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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JAMES K ROWLETT其他文献
JAMES K ROWLETT的其他文献
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{{ truncateString('JAMES K ROWLETT', 18)}}的其他基金
Tolerance and Physical Dependence after Chronic Benzodiazepine Treatment
慢性苯二氮卓治疗后的耐受性和身体依赖性
- 批准号:
10162574 - 财政年份:2017
- 资助金额:
$ 42.23万 - 项目类别:
Neurosteroid-BZ combinations: Strategy for reducing abuse and sedation
神经类固醇-BZ 组合:减少滥用和镇静的策略
- 批准号:
8322247 - 财政年份:2012
- 资助金额:
$ 42.23万 - 项目类别:
Neurosteroid-BZ combinations: Strategy for reducing abuse and sedation
神经类固醇-BZ 组合:减少滥用和镇静的策略
- 批准号:
8759232 - 财政年份:2012
- 资助金额:
$ 42.23万 - 项目类别:
Neurosteroid-BZ combinations: Strategy for reducing abuse and sedation
神经类固醇-BZ 组合:减少滥用和镇静的策略
- 批准号:
8485568 - 财政年份:2012
- 资助金额:
$ 42.23万 - 项目类别:
Neurosteroid-BZ combinations: Strategy for reducing abuse and sedation
神经类固醇-BZ 组合:减少滥用和镇静的策略
- 批准号:
9069773 - 财政年份:2012
- 资助金额:
$ 42.23万 - 项目类别:
NOVEL GABA(A) MODULATORS AS COGNITIVE ENHANCERS
作为认知增强剂的新型 GABA(A) 调节剂
- 批准号:
8357997 - 财政年份:2011
- 资助金额:
$ 42.23万 - 项目类别:
SEX DIFFERENCES IN THE ABUSE-RELATED EFFECTS OF BENZODIAZEPINES
苯二氮卓类药物滥用相关影响的性别差异
- 批准号:
8357972 - 财政年份:2011
- 资助金额:
$ 42.23万 - 项目类别:
THERAPEUTIC EFFECTS AND ABUSE OF GABA(A) MODULATORS
GABA(A) 调节剂的治疗效果和滥用
- 批准号:
8357917 - 财政年份:2011
- 资助金额:
$ 42.23万 - 项目类别:
COGNITION AND NEUROPATHOLOGY ASSOCIATED WITH TYPE 2 DIABETES
与 2 型糖尿病相关的认知和神经病理学
- 批准号:
8357973 - 财政年份:2011
- 资助金额:
$ 42.23万 - 项目类别:
Novel GABA-A Modulators as Cognitive Enhancers
作为认知增强剂的新型 GABA-A 调节剂
- 批准号:
8129770 - 财政年份:2010
- 资助金额:
$ 42.23万 - 项目类别:
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