精神分裂症患者颞上回的大麻素受体密度没有显著性变化

目的近年来研究发现,在精神分裂症患者的内源性大麻素递质系统会出现异常变化,而颞上回在精神分裂症的病理生理机制中和幻听症状密切相关。因此,对照正常人群,我们研究了精神分裂症患者颞上回大麻素CB-1受体的密度变化。方法采用定量放射自显影技术,通过[~3HJSR141716A(CB-1受体选择性拮抗剂)和[~3H]CP-55940(CB-1受体激动剂)检测颞上回CB-1受体密度水平。死后脑组织由澳大利亚新南威尔士州组织资源中心提供。结果先前研究发现,精神分裂症患者与认知功能失常相关的额前叶,前、后扣带回皮质的CB-1受体密度水平有异常改变.与此相反,本研究发现在精神分裂症患者的由[~3H]SR141716A和[~3H]CP-55940检测的颞上回大麻素受体密度水平和对照组比较没有显著变化。结论我们认为颞上回大麻素CB-1受体和精神分裂症患者的发病及幻听症状无关。     

男性精神分裂症患者脑侧化与幻听的功能磁共振成像研究

目的利用事件相关功能磁共振成像（fMRI）在体研究精神分裂症伴有幻听的男性患者左右侧化声音激活脑区的差异，以验证幻听是由脑侧化异常产生的假说。方法男性健康志愿者13名（正常对照组），幻听和非幻听偏执型精神分裂症男性患者各13例，接受预先编制的左右侧化声音刺激，进行功能磁共振扫描。结果（1）组内比较：与右侧化声音刺激相比，正常对照组在辨别左侧化声音刺激时显著激活了左楔前叶和右旁中央小叶（FDR校正，P〈0．01，体素值〉10）；两个患者组组内左右侧化声音显著激活脑区比较，差异均无统计学意义。（2）组间比较：与幻听组相比，正常对照组在辨别左侧化声音刺激时右旁中央小叶显著激活；与非幻听组相比，正常对照组在辨别左侧化声音刺激时显著激活两侧颞上回、左楔前叶、两侧扣带回和左缘上回，而在辨别右侧化声音刺激时两侧颞上回、右颞中回和左脑岛显著激活；与非幻听组相比，幻听组无论在辨别左或右侧化声音刺激时均引起左侧颞横回激活（P〈0．001，未校正，体素值〉50）。结论精神分裂症患者正常的语言侧化减弱，而幻听的产生可能与左脑尤其是左颞横回的功能障碍有关。     

精神分裂症幻听患者汉语听觉语言皮质定位的脑磁图研究

目的 采用脑磁图(MEG)技术探讨男性精神分裂症幻听患者汉语听觉语言皮质的定位.方法 给予13例精神分裂症幻听患者和14名正常对照组双耳男、女声各100对词义相关及不相关的二个字汉语词汇刺激,并由MEG设备记录刺激后产生的听觉诱发磁场,将MEG采集数据叠加到核磁共振上获得磁源性影像.结果 ①患者组10例汉语听觉语言皮质定位在大脑半球双侧颞中、上回后部、额下回后部,2例在右侧额下回后部,1例在左侧颞上回后部.对照组10名定位于左侧颞中、上回后部,即Wernicke区,2名定位于右侧颞中回后部,2名定位在双侧颞上回后部.患者组定位在双侧比例明显高于对照组(76.92% vs 14.29%,x2=2.88,P＜0.05).②无论男声或女声刺激,患者组与对照组的中枢三维坐标在X轴上差异均有统计学意义(P＜0.05).结论 精神分裂症幻听患者的汉语语言皮质定位与正常人的位置不同,更靠近颞中、上回外侧部,这一改变可能是其听觉性语言认知功能障碍的神经病理学基础之一.     

精神分裂症幻听患者初级听觉皮质的脑磁图研究

目的 探讨在不同频率纯音刺激下男性精神分裂症幻听患者初级听觉皮质的脑磁图(MEG)定位.方法 对均为右利手的10例男性精神分裂症幻听患者(研究组)和11名男性健康受试者(对照组),分别给予频率为0.5,2,4,8 kHz的纯音刺激,强度90 dB,持续200ms,刺激声间隔1 s.用脑磁图设备记录刺激后产生的听觉诱发磁场,并将MEG资料叠加到核磁共振成像以获得磁源性影像.结果 (1)对照组初级听觉皮质均定位于双侧颞横回;与对照组比较,研究组右侧初级听觉皮质位置更靠近颞横回外部,左侧明显偏向颞上回后外下部(P<0.05).(2)在分别给予2 kHz和4kHz纯音刺激时,研究组大脑双侧M100潜伏期[2 kHz:左(97±16)ms,右(97±10)ms,4 kHz:左(93±13)ms,右(99±14)ms]均短于对照组[2 kHz:左(121±15)ms,右(113±6)ms,4 kHz:左(113±13)ms,右(114±6)ms](均P<0.01),而波幅[2 kHz:左(89±10)fT,右(118±37)fT,4 kHz:左(81±9)fT,右(108±14)fT]高于对照组[2 kHz:左(73±12)fT,右(79±13)fT,4 kHz:左(69±14)fT,右(81±20)fT](均P<0.05～0.01).结论 男性精神分裂症幻听患者的初级听觉皮质位置与正常人不同,其M100波幅高,潜伏期短,这些功能及解剖结构的异常可能是精神分裂症幻听产生的病理生理机制之一.     

精神分裂症患者用药前后甲状腺素催乳素及糖脂代谢水平观察

正精神分裂症是最严重的一种精神疾病,病因不十分明确,患者在思维、情感、行为和感知等多方面存在精神不协调或功能障碍,出现幻听、幻视、兴趣减退现象,易反复发作,加重病情恶化,降低生活质量[1-2]。非典型抗精神病药物是近年来临床上应用较多的一类治疗精神分裂症药物,疗效较好,不良反应少[3]。本文探讨精神分裂症患者应用抗精神分裂药物前后甲状腺素、催乳素及糖脂代谢水平变化,现报道如下。     

首发精神分裂症患者的脑灰质减少

目的 采用基于体素的形态学(VBM)分析方法对高分辨磁共振图像进行分析,研究首发精神分裂症患者大脑灰质变化,探讨患者脑灰质改变与临床症状之间的关系.方法 对符合CCMD-3诊断标准的首发精神分裂症患者以及健康志愿者各16例进行脑结构核磁共振扫描,并应用VBM进行脑灰质体积分析.所有患者均完成阳性与阴性症状量表(PANSS)评估.结果 与健康对照相比,患者组灰质密度降低的脑区有右侧小脑(t=5.17,P＜0.001)、右侧顶上回(t=5.01,P＜0.001)、左侧颞上回至岛叶被盖(t=4.79,P＜0.001)、左侧额中回(t=4.71,P＜ 0.001)、左侧额下回(t=4.70,P＜0.001)、右侧舌回(t=4.62,P＜ 0.001)、左侧海马杏仁体(t=4.11,P＜0.001).患者组左侧Heschl's回的灰质密度与PANSS量表总分(r=-0.509,P=0.044)以及PANSS阳性症状量表得分(r=-0.554,P=0.026)呈显著负相关.结论 首发精神分裂症患者的脑灰质减少以左侧额、颞叶为主,其中左侧Heschl's回灰质变化与患者的精神病性症状有相关性.     

以妄想为主的男性精神分裂症患者脑局部一致性的功能磁共振研究

目的：探讨男性偏执型精神分裂症患者在静息状态下是否存在脑功能活动异常及其区域。方法：采用病例一对照研究方法,对20例以妄想为主的男性精神分裂症患者（患者组）和20名性别、年龄、受教育程度相匹配的正常对照者（正常对照组）进行功能磁共振成像（fMRI）扫描,分析静息状态下各脑区的局部一致性（regionalhomogeneity,ReHo）的差异。结果：设P〈0．05、体素范围（k值）≥85,与正常对照组比较,患者组双侧额上回、双侧颞中回、左额中回、左中央前回、左小脑脚和右扣带回局部一致性（ReHo值）减低,右颞上回和左颞下回ReHo值增高,而左梭状回ReHo值既有增高也有减低。结论：以妄想为主的男性精神分裂症患者在静息状态下可能存在广泛分布的脑区功能异常。     

睡眠剥夺对大鼠脑干和海马大麻素CB-1受体的影响

目的探讨快速眼动(REM)睡眠剥夺(SD)对大鼠脑干和海马大麻素CB-1受体的影响。方法采用改良多平台睡眠剥夺法建立REM睡眠剥夺模型。将40只Sprague-Dawley大鼠随机分为空白对照组(CC)、环境对照组(TC),以及睡眠剥夺1d(SD1d)、3d(SD3d)和5d(SD5d)组,每组8只。应用逆转录-聚合酶链反应方法检测大鼠脑干及海马CB-1受体mRNA的表达,电镜观察其超微结构的改变。结果SD各组大鼠脑干与海马超微结构均有神经元凋亡,SD3d和SD5d组尤著。(1)脑干CB-1受体mRNA表达值SD1d组(0.789±0.139)和SD3d组(1.264±0.182)均高于CC组(0.420±0.054),且SD3d组高于SD1d组(P<0.05),SD5d组(0.678±0.145)与CC组的差异无统计学意义(P>0.05)。(2)海马CB-1受体mRNA表达值SD1d组(0.598±0.098)高于CC组(0.374±0.064),SD3d组(0.258±0.072)低于CC组,且SD3d组低于SD1d组(P<0.05);SD5d组(0.448±0.177)与CC组的差异无统计学意义(P>0.05)。结论REM睡眠剥夺能造成脑干及海马神经元的损伤,在不同睡眠剥夺时期CB-1受体mRNA表达不同,其中CB-1受体表达增强可能是一种自身稳定调节的保护机制。     

首发精神分裂症患者倒背数字作业的fMEI研究

目的利用功能磁共振成像(fMRI)探讨首发精神分裂症患者倒背数字作业激发图像的特点.方法 36例符合ICD-10诊断标准的(首发)精神分裂症患者及18名健康志愿者进行以倒背数字作业(backward digit span task, BDST)作为刺激模式、采用组块(block)设计的fMRI检查,经工作站处理后获功能图像.用阳性和阴性症状量表(PANSS)评价精神分裂症患者精神症状的严重程度. 结果 (1)健康志愿者与精神分裂症患者激活脑区的范围均较广泛,健康志愿者的左侧额上回、双侧额中回、左侧额下回、左侧中央前回、左侧顶上小叶、左侧缘上回、左侧颞下回及左侧枕颞外侧回等脑区均有明显激活.两组激活的脑区在额叶、颞叶、顶叶、枕叶及扣带回的分布,以及各脑区内部分布的差异均没有显著性(P>0.05).(2)健康志愿者与精神分裂症患者激活计数左侧额上回分别为16和11,左侧额下回分别为15和12,左侧中央前回分别为16和17,左侧颞下回分别为14和12,左侧顶上小叶分别为14和14,左侧缘上回分别为14和7,左侧枕颞外侧回分别为14和7,右侧中央前回分别为13和7,右侧枕颞外侧回分别为11和8,两组上述部位激活计数的差异均有显著性(P均＜0.05).(3)健康志愿者与精神分裂症患者左侧额叶背外侧的激活平均体积分别为(362±296)个体素和(79±101)个体素,差异有非常显著性(P=0.001);右侧顶叶后下部的激活平均体积分别为(448±273)个体素和(193±236)个体素,差异有显著性(P=0.039). 结论早期精神分裂症患者可能存在工作记忆缺陷,包括激活信息的保持及执行控制过程,激活信息的保持缺陷可能与左侧额叶腹外侧及顶叶后下部的功能低下有关,而执行控制缺陷可能与左侧额叶背外侧的功能低下有关.     

癫痫持续状态大鼠模型的GABA_A受体亚单位α1的mRNA表达及[~3H]Flunitrazepam受体配体结合的变化

目的 :本实验研究大鼠癫痫持续状态动物模型的海马等部位 GABAA受体α1亚单位基因表达和受体一配体结合的变化。方法 :成年雄性大鼠经腹腔内注射 32 0～ 34 0± 5 .87毫克 /公斤毛果芸香碱 (Pilocarpine)以制成癫痫持续状态动物模型 ,能在癫痫持续状态 (定义为在皮质脑电图上显示痫性放电的至少 40分钟的持续性痫性发作 )下存活的大鼠在 1小时和 2小时后处于死 ,分别研究 GABA受体基因表达和放射结合位点 ,用原位杂交方法来测定脑部 m RNA水平 ,用 [3H]flunirazepam标记 GABAA 受体 benzodiazepam结合位点。结果 :动物痫性发作 2小时后海马的 CA1和CA3区域 GABAA受体 α1亚单位 m RNA显著下降 ,但是齿状回的 α1m RNA没有变化。 [3H]flunirazepam标记受体 -配体放射结合在持续 2小时持续痫性发作后可见海马的 CA1及 CA3和齿状回中均见下降 ,1小时的持续痫性发作尚未引起海马区域的任何α1m RNA或 [3H]flunirazepam受体 -配体放射结合的任何改变 ,并用结晶染色 1及 2小时后的大脑海马部位。结论 :本研究结果提示大鼠的癫痫持续状态可诱发海马区 GABAA 受体 α1基因表达的改变和 [3H]flinirazepam受体 -配体结合的下降 ,上述改变可能使大脑更容易形成慢性癫痫病灶     

Selective antagonist [3H]SR141716A binding to cannabinoid CB1 receptors is increased in the anterior cingulate cortex in schizophrenia

Previous studies suggest that long-term cannabis use causes cognitive impairment, including lack of motivation and impaired attention, conditions that also resemble core negative symptoms of schizophrenia. The anterior cingulate cortex (ACC) plays an important role in normal cognition, particularly in relation to motivation and attention. This could suggest that changes in the cannabinoid (CB) system might be present in the ACC of patients suffering schizophrenia. The present study examined the distribution and density of CB1 cannabinoid receptors in the left ACC taken postmortem from patients with schizophrenia (n=10) and matched control subjects (n=9). Radioligand binding of [3H]SR141716A, an antagonist that specifically targets CB1 receptors of the endogenous cannabinoid system, was examined on ACC sections using quantitative autoradiography. CB1 receptors had a homogeneous distribution among the layers of ACC. A significant 64% increase in [3H]SR141716A specific binding to CB1 receptors was found in the schizophrenia group as compared to the control group (mean+/-S.E.M.: 46.15+/-6.22 versus 28.02+/-4.20 fmol/mg estimated tissue equivalents; p=0.03). The present results support the suggestion that changes in the endogenous cannabinoid system in the ACC may be involved in the pathology of schizophrenia particularly in relation to negative symptoms.     

Anandamide and WIN 55212-2 inhibit cyclic AMP formation through G-protein-coupled receptors distinct from CB1 cannabinoid receptors in cultured astrocytes

The effects of anandamide and the cannabinoid receptor agonists WIN 55212-2 and CP 55940 on the evoked formation of cyclic AMP were compared in cultured neurons and astrocytes from the cerebral cortex and striatum of mouse embryos. The three compounds inhibited the isoproterenol-induced accumulation of cyclic AMP in neuronal cells, and these responses were blocked by the selective CB1 receptor antagonist SR 141716A. The three agonists were more potent in cortical than striatal neurons. Interestingly, WIN 55212-2, CP 55940 and anandamide also inhibited the isoproterenol-evoked accumulation of cyclic AMP in astrocytes but, in contrast to WIN 55212-2 and CP 55940, anandamide was much more potent in striatal than cortical astrocytes. Inhibition was prevented by pertussis toxin pretreatment, but not blocked by SR 141716A. Therefore, G-protein-coupled receptors, distinct from CB1 receptors, are involved in these astrocytic responses. Moreover, specific binding sites for [3H]-SR 141716A were found in neurons but not astrocytes. Furthermore, using a polyclonal CB1 receptor antibody, staining was observed in striatal and cortical neurons, but not in striatal and cortical astrocytes. Taken together, these results suggest that glial cells possess G-protein-coupled receptors activated by cannabinoids distinct from the neuronal CB1 receptor, and that glial cells responses must be taken into account when assessing central effects of cannabinoids.     

Neuroprotective cannabinoid receptor antagonist SR141716A prevents downregulation of excitotoxic NMDA receptors in the ischemic penumbra

Whether cannabinoids act as neuroprotectants or, on the contrary, even worsen neuronal damage after cerebral ischemia is currently under discussion. We have previously shown that treatment with the cannabinoid (CB1) receptor antagonist SR141716A reduces infarct volume by ∼40% after experimental stroke. Since it is suggested that SR141716A may exert neuroprotection besides its cannabinoid receptor-blocking effect, we addressed the question whether SR141716A may act via modulation of postischemic ligand binding to excitatory NMDA and/or α-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA) receptors. For this purpose, rats (n = 12) were treated with either intravenous saline (control) or CB1 receptor antagonist SR141716A (1 mg/kg) 30 min after permanent middle cerebral artery occlusion. Five hours after ischemia, quantitative receptor autoradiography was performed using [³H]CP 55,940, [³H]MK-801, and [³H]AMPA for labeling of CB1, NMDA, and AMPA receptors, respectively. Ligand binding was analyzed within the infarct core, cortical penumbra, and corresponding areas of the contralateral hemisphere and compared to that of sham-operated rats (n = 5). Both in ischemic controls and SR141716A-treated rats [³H]CP 55,940 ligand binding was not specifically regulated in the cortical penumbra or contralateral cortex. Importantly, reduced infarct volumes in SR141716A-treated rats were associated with maintained [³H]MK-801 binding to excitotoxic NMDA receptors in the penumbra, compared to a decrease in the control group. In summary, our data suggest that SR141716A may possess additional intrinsic neuroprotective properties independent of receptor-coupled pathways or due to action as a partial agonist.     

Decreased density of serotonin 2A receptors in the superior temporal gyrus in schizophrenia-a postmortem study

The superior temporal gyrus (STG) is strongly implicated in the pathophysiology of schizophrenia, particularly with regards to auditory hallucinations. In this study, using in situ quantitative autoradiography in postmortem tissue, we investigated the binding of the [³H]ketanserin to 5-HT_2A receptors and [³H]mesulergine to 5-HT_2C receptors in the left STG of 8 male schizophrenic patients compared to 8 control subjects. A strong [³H]ketanserin binding was observed in the STG, however there was a very weak [³H]mesulergine binding in the STG. A significant decrease in binding of [³H]ketanserin was clearly observed in schizophrenia patients in comparison with control subjects. There were no significant correlations between 5-HT_2A binding density and age, postmortem intervals, or brain pH. These results suggest that the alterations of the 5-HT_2A receptors contribute to the pathophysiology of the STG in schizophrenia. Furthermore, there is a clear tendency for a positive correlation between 5-HT_2A and muscarinic M1 receptor bindings, and for negative correlations between 5-HT_2A and GABA_A receptor bindings and between muscarinic M1 and GABA_A receptor bindings. This provides a possible mechanism of auditory hallucinations through interactions between 5-HT_2A, acetylcholine muscarinic and GABA transmissions in the STG in schizophrenia.     

Decreased density of muscarinic receptors in the superior temporal gyrusin schizophrenia

Recent studies have indicated that muscarinic receptors are involved in the pathophysiology in schizophrenia, particularly in cognitive deficits. The superior temporal gyrus (STG) is an area that has also been strongly implicated in the pathophysiology of schizophrenia. Therefore, in this study, we investigated the binding density of two muscarinic antagonists, [(3)H]pirenzepine and [(3)H]AF-DX 384, in the STG of schizophrenia patients compared with controls. A significant decrease (44% in the superficial layers and 48% in the deep layers, P<0.01) in binding density of [(3)H]pirenzepine was observed in schizophrenia patients, which suggested a reduction of muscarinic M1 and M4 receptor densities in the STG of schizophrenia patients. A tendency toward decreased [(3)H]AF-DX 384 binding density (34%, P=0.09) was also observed in schizophrenia patients compared with controls. Because of the positive correlation between [(3)H]pirenzepine and [(3)H]AF-DX 384 binding, and, insofar as both ligands have high affinities for the M4 receptor, the involvement of M4 receptor alteration is also suggested in the STG in schizophrenia. These results suggest that changes of the muscarinic receptors M1 and M4 might contribute to the STG pathology in schizophrenia.     

Role of CB1 and CB2 receptors in the inhibitory effects of cannabinoids on lipopolysaccharide-induced nitric oxide release in astrocyte cultures

The purpose of this study was to investigate the role of the central cannabinoid receptor (CB(1)) in mediating the actions of the endogenous cannabinoid agonist anandamide and the synthetic cannabinoid CP-55940. Activation of primary mouse astrocyte cultures by exposure to bacterial lipopolysaccharide (LPS) caused a marked (approximately tenfold) increase in nitric oxide (NO) release. Coincubation with the cannabinoid agonists anandamide or CP-55940 markedly inhibited release of NO (-12% to -55%). This effect was abolished by SR-141716A (1 microM), a CB1 receptor antagonist. SR-141716A alone also significantly increased NO release in response to LPS, suggesting that endogenous cannabinoids modify inflammatory responses. In contrast, coincubation with the CB2 receptor antagonist SR-144528 (1 microM) abolished the inhibitory effects of the endogenous cannabinoid anandamide on LPS-induced NO release, although this may reflect nonspecific effects of this ligand or cannabinoid actions through atypical receptors of anandamide. We also showed that endogenous or synthetic cannabinoids inhibit LPS-induced inducible NO synthase expression (mRNA and protein) in astrocyte cultures. These results indicate that CB1 receptors may promote antiinflammatory responses in astrocytes.     

Distinct differences in the cannabinoid receptor binding in the brain of C57BL/6 and DBA/2 mice, selected for their differences in voluntary ethanol consumption

The two inbred strains of mice C57BL/6 and DBA/2 mice have been shown to differ significantly in their preference for alcohol (EtOH). These strains of mice have been employed to study various aspects of pharmacological and behavioral effects of EtOH. We have previously demonstrated that chronic EtOH exposure down-regulated cannabinoid receptors (CB1) in mouse synaptic plasma membranes and enhanced the synthesis of endogenous cannabimimetic compound anandamide (AnNH) in human neuroblastoma cells. The purpose of the present study was to investigate whether there were differences in the density and the affinity of CB1 receptors in the brains of the two inbred C57BL/6 (alcohol-preferring) and DBA/2 (alcohol avoiding) mice. The results indicate the presence of specific CB1 receptors in the brain membranes of both the strains. It was also found that the CB1 receptor densities (B(max)) were 25% lower in C57BL/6 (0.66 +/- 0.15 pmol/mg protein) compared with that of DBA/2 (0.88 +/- 0.08 pmol/mg protein) mice. Significant differences in the affinity were also observed between the two lines (K(d), 0.68 +/- 0.15 nM for C57BL/6 and 2.21 +/- 0.56 nM for DBA/2). The competition studies with SR141716A, a CB1 receptor antagonist, and 2-arachidonylglycerol (2-AG) and anandamide (AnNH), known CB1 receptor agonists, all showed a substantial decrease in [(3)H]CP-55,940 binding in both strains of mice with a higher K(i) values in the DBA/2 mice. These results suggest that CB1 receptor signal transduction may play an important role in controlling the voluntary EtOH consumption by these strains of mice.     

Cannabinoids inhibit the release of [3H]glutamate from rodent hippocampal synaptosomes via a novel CB1 receptor-independent action

In this study we investigated the effect of cannabinoids on [3H]glutamate release from hippocampal synaptosomes of rat and CB1-null mutant mouse. In the rat, cannabinoid receptor agonists, i.e. CP55,940 (EC50, 0.84 microm), WIN55,212-2 (EC50, 3.47 microm), ACEA (EC50, 17.8 microm), and R-(+)-methanandamide (EC50, 19.8 microm) concentration-dependently inhibited the 25-mm-K+ depolarization-evoked release of [3H]glutamate and, among them, WIN55,212-2 displayed the greatest efficacy. The CB1 receptor antagonists SR141716A (1-5 microm) and AM251 (1 microm) and the VR1 vanilloid receptor antagonist capsazepine (10 microm) did not antagonize the effect of the agonists. SR141716A by itself attenuated the evoked [3H]glutamate release. WIN55,212-2 inhibited the release of [3H]glutamate in CB1 -/- mice as well. These data demonstrate that the action of cannabinoids on glutamate release in the hippocampus is pharmacologically distinct and independent from the cloned CB1 receptor.     

Evaluation of the in vivo receptor occupancy for the behavioral effects of cannabinoids using a radiolabeled cannabinoid receptor agonist, R-[125/131I]AM2233

G-protein coupled receptors exist in both high and low agonist affinity conformations, with tracer levels of agonist radioligands preferentially binding to the former. The goal of the present study was to characterize the in vivo binding of the aminoalkyindole-based, CB1 receptor agonist, R-[125/131I]AM2233 ((2-[125/131I]iodo-phenyl)-[1-(1-methyl-piperidin-2-yl-methyl)-1H-indol-3-yl]-methanone), and to use this radiotracer to selectively measure the receptor occupancy by the related CB1 receptor agonist, WIN55212-2, to the agonist-preferring affinity state of the receptor. In mouse locomotor assays, both WIN55212-2 and AM2233 (racemic) produced an approximately 60% reduction in activity at 1 mg/kg, (i.v.) and completely inhibited activity at 3 mg/kg, confirming their agonist nature. In ex vivo autoradiography, preferential uptake of R-[131I]AM2233 was apparent in CB1 receptor-rich areas, including globus pallidus, substantia nigra, striatum, cerebellum, and hippocampus. Overall brain uptake of R-[131I]AM2233 was 1.3% injected activity/g at 5 min in mice. Coinjection of 3 mg/kg (i.v.) SR141716A, a CB1 receptor antagonist, with R-[125I]AM2233 inhibited the radiotracer binding almost to nonspecific levels in the striatum, globus pallidus, and substantia nigra, although residual binding to a non-CB1 receptor remained in the hippocampus. In contrast to the effect of SR141716A, coinjection of 10 mg/kg (i.v.) WIN55212-2, a high dose that produced an immediate and profound immobility and catalepsy in the mice, reduced CB1 receptor-specific binding of R-[125I]AM2233 in CB1 receptor-rich areas by only 21-43%. These observations suggest that the behavioral effects of CB1 receptor agonists are manifested with a relatively small fraction of the agonist-preferring affinity state of the receptor occupied.