Extrastriatal dopamine D(2) receptor binding in Huntington's disease

Huntington's disease (HD) is a neurodegenerative disorder, primarily affecting medium spiny neurones in the striatum. The density of striatal dopamine D(2) receptors is reduced in HD but there is little known about this biomarker in brain regions outside the striatum. The primary objective of this study was to compare extrastriatal dopamine D(2) receptor binding, in age-matched control subjects and patients with HD. All subjects were examined using a high-resolution positron emission tomography system and the high-affinity dopamine D(2) receptor radioligand [(11) C]FLB 457. A ROI based analysis was used with an atrophy correction method. Dopamine D(2) receptor binding potential was reduced in the striatum of patients with HD. Unlike the striatum, dopamine D(2) receptor binding in thalamic and cortical subregions was not significantly different from that in control subjects. A partial least square regression analysis which included binding potential values from all investigated cortical and subcortical regions revealed a significant model separating patients from controls, conclusively dependent on differences in striatal binding of the radioligand. Some clinical assessments correlated with striatal dopamine D(2) receptor binding, including severity of chorea and cognitive test performance. Hence, the present study demonstrates that dopamine D(2) receptors extrinsic to the striatum are well preserved in early to mid stage patients with HD. This observation may have implication for the development of therapy for HD.     

Developmental and age-related changes of dopamine transporter, and dopamine D1 and D2 receptors in human basal ganglia

The developmental and age-related changes of the dopamine transporter (DAT), and the dopamine D1 and D2 receptor (D1R and D2R) subtypes were investigated in basal ganglia (BG) of human brain. DAT immunostaining was mainly observed in the neuropil, neurons, and glia of the striatum. The DAT-positive neuropil was detectable at 32 GW, a peak being reached at 9–10 years of age, with a decrease to 50–63 years of age. The developmental pattern of DAT immunoreactivity in neuron was similar to that of the neuropil. DAT-positive glia were observed in the BG at 32 GW, which increased slightly at 38–40 GW, and then did not obviously change until 6–8 months after birth. D2R-positive neurons were clearly observed at 19 GW, a peak being reached at 32 GW and 1–3 months of age in the globus pallidus and striatum, respectively, with a decrease after 9–10 years of age. D1R was expressed as early as D2R, but decreased after 6–8 months. Our results suggest that D1R and D2R expression is an intrinsic property of striatal neurons and is independent of dopaminergic innervation. D1R may play a more important role in neuronal maturation of the BG than D2R. D2R may be closely correlated with late neuronal development. The higher expression of DAT during adolescence may be related to function of the BG which learns complex behavioral patterns. The significance of the age-related decreases in DAT, D1R and D2R in the BG remains to be further investigated.     

多巴胺D2受体基因的TaqI A多态性与迟发性运动障碍的关联分析

目的　研究多巴胺D2受体 (DRD2 )基因TaqIA多态性与精神分裂症伴迟发性运动障碍 (TD)的相关性。方法　使用异常不自主运动量表 (AIMS)评定精神分裂症患者有无TD及TD严重程度 ,并采用简明精神病评定量表 (BPRS)评定患者精神症状 ;应用聚合酶链反应 (PCR)—限制性片段长度多态性 (RFLP)法分析TD组和非TD组的DRD2基因的TaqIA等位基因频率和基因型分布。结果　DRD2基因TaqIA的等位基因频率和基因型分布在TD组与非TD组之间均无显著性差异 ,且不同基因型间的AIMS总分值也无显著性差异。结论　在中国汉族男性精神分裂症患者中DRD2基因的TaqIA多态性可能不是影响TD发生的主要危险因素。     

Expression of D4 dopamine receptors in striatonigral and striatopallidal neurons in the rat striatum

Recent studies have reported the regional distribution of D(4) dopamine receptors in the rat striatum at the cellular and subcellular levels. However, the precise identity of the striatal neurons that express these receptors remains unknown. We have studied the expression of D(4) receptors in the striatal interneurons as well as in the output regions of the striatum using immunohistochemistry. Furthermore, we have evaluated the contribution of the striatum to D(4) receptor immunoreactivity in these areas by means of ibotenic acid lesion of the striatum. D(4) receptors were observed in the substantia nigra pars reticulata (SNr), the entopeduncular nucleus (EP) and the globus pallidus (GP), and they were found, using electron microscopy, to be located presynaptically. D(4) immunoreactivity in the striatal output nuclei was observed to dramatically decrease following lesion of the striatum with ibotenic acid. Striatal interneurons were not found to express D(4) receptors. These results demonstrate that D(4) receptors are located almost exclusively in striatal projection neurons, in both striatonigral and striatopallidal neurons.     

Loss of striatal histamine H2 receptors in Huntington's: Chorea but not in Parkinson's disease: Comparison with animal models

Autoradiographic techniques were used to study the distribution of histamine H₂-receptors as labeled with [¹²⁵I]iodoaminopotentidine in the brains of patients affected by human neurodegenerative pathologies, as compared with control cases. The highest levels of histamine H₂ binding sites in control cases were found in the caudate, putamen, and accumbens nuclei. In Huntington's chorea, the levels of histamine H₂ receptor binding sites were found to be markedly decreased in virtually all regions examined, particularly in the putamen and globus pallidus lateralis. The loss of binding sites was related to the grade of the disease. Losses were more marked in grade III disease cases. The possible influence of neuroleptic treatment, commonly used in Huntington's patients, was studied by including samples from clinically treated schizophrenic patients. A moderate increase in the densities of [¹²⁵I]iodoaminopotentidine was found in the globus pallidus of these patients. In Parkinson's disease, the levels of histamine H₂-receptor binding sites were found not to be significantly different from those of control cases. These results were comparable with those obtained from unilaterally neurotoxin-lesioned guinea pigs. Similar losses of binding sites were observed in the quinolinic acid lesioned striatal intrinsic neurons in the guinea pig, whereas lesioning dopaminergic cell bodies in the substantia nigra with 6-hydroxydopamine did not produce any significant change. These results strongly suggest that histamine H₂-receptors are expressed by striatal neurons, which degenerate in Huntington's chorea, but not by nigral dopaminergic neurons and may play a role in the regulation of the intact striato-nigral pathway. © 1993 Wiley-Liss, Inc.     

Association study of three polymorphisms in the dopamine D2 receptor gene and schizophrenia in the Russian population

Polymorphisms in the dopamine D2 receptor gene (DRD2) have repeatedly been associated with schizophrenia. Recently, the C957T polymorphism (rs6277), which alters mRNA stability and dopamine-induced upregulation of DRD2 expression in cell cultures and DRD2 mRNA translation in vitro, was tested for an association with the disease. Frequency of the C allele, corresponding to a normal wild-type level of expression, was higher in patients compared to controls, and that of the T allele was lower. To replicate and extend previous findings, we conducted an association study of the C957T polymorphism and two additional SNPs (C939T and TaqIA) in 311 patients with a DSM-IV diagnosis of schizophrenia and 364 mentally healthy people from the Russian population as controls. The results of our study confirmed the association between the C957T polymorphism and schizophrenia. Consistent with previous findings, frequency of the C allele and the CC genotype were higher in patients compared to the control group (p = 0.002). Meta-analysis of total 5 samples also suggests significant allelic association. The distribution of C939T genotypes in the case sample was significantly different from that of the controls: in the case sample, the TT genotype frequency was higher compared to the combined frequency of CT and CC genotypes (p = 0.002). Though no association was found between the TaqIA polymorphism and schizophrenia, a haplotype-wise analysis revealed a lower frequency of the T–C (C957T–TaqIA) haplotype in patients (p = 0.02). In conclusion, our findings provide additional evidence for an association between the C957T polymorphism and schizophrenia.     

D1 dopamine receptor--the search for a function: a critical evaluation of the D1/D2 dopamine receptor classification and its functional implications

The present review focuses on the hypothesized D1/D2 dopamine (DA) receptor classification, originally based on the form of receptor coupling to adenylate cyclase activity. The pharmacological effects of compounds exhibiting putative selective agonist or antagonist profiles at those DA receptors positively coupled to adenylate cyclase activity (D1 DA receptors) are extensively reviewed. Comparisons are made with the effects of putative selective D2 DA receptor agonists and antagonists, and on the basis of this work, the DA receptor classification is critically evaluated. A variety of biochemical, behavioral, and electrophysiological evidence is presented which supports the view that D1 and D2 DA receptors can interact in both an opposing and synergistic fashion. Particular attention is focused on the possibility that D1 receptor stimulation is required to enable the expression of certain D2 receptor-mediated effects, and the functional consequences of this form of interaction are considered. A hypothetical model is presented which considers how both the opposing and enabling forms of interaction between D1 and D2 DA receptors can control behavioral expression. Finally, the clinical relevance of this work is discussed and the potential use of selective D1 receptor agonists and antagonists in the treatment of psychotic states and Parkinson's disease is considered.     

Cannabinoid CB2 receptor agonists protect the striatum against malonate toxicity: Relevance for Huntington's disease

Cannabinoid agonists might serve as neuroprotective agents in neurodegenerative disorders. Here, we examined this hypothesis in a rat model of Huntington's disease (HD) generated by intrastriatal injection of the mitochondrial complex II inhibitor malonate. Our results showed that only compounds able to activate CB₂ receptors were capable of protecting striatal projection neurons from malonate‐induced death. That CB₂ receptor agonists are neuroprotective was confirmed by using the selective CB₂ receptor antagonist, SR144528, and by the observation that mice deficient in CB₂ receptor were more sensitive to malonate than wild‐type animals. CB₂ receptors are scarce in the striatum in healthy conditions, but they are markedly upregulated after the lesion with malonate. Studies of double immunostaining revealed a significant presence of CB₂ receptors in cells labeled with the marker of reactive microglia OX‐42, and also in cells labeled with GFAP (a marker of astrocytes). We further showed that the activation of CB₂ receptors significantly reduced the levels of tumor necrosis factor‐α (TNF‐α) that had been increased by the lesion with malonate. In summary, our results demonstrate that stimulation of CB₂ receptors protect the striatum against malonate toxicity, likely through a mechanism involving glial cells, in particular reactive microglial cells in which CB₂ receptors would be upregulated in response to the lesion. Activation of these receptors would reduce the generation of proinflammatory molecules like TNF‐α. Altogether, our results support the hypothesis that CB₂ receptors could constitute a therapeutic target to slowdown neurodegeneration in HD. © 2008 Wiley‐Liss, Inc.     

帕金森病大鼠模型尾壳核多巴胺D2受体活性变化研究

目的：探讨帕金森病病程中多巴胺D2受体的活性变化及其规律。方法：在建立6－羟基多巴胺毁损的帕金森病大鼠模型基础上，应用放射配基结合分析法结合Scanchard作图，测定不同时间点模型大鼠及对照大鼠尾壳核多巴胺D2受体的最大结合容量（Bmax)和平衡解离常数（KD）。结果：大鼠模型毁损侧尾壳核多巴胺D2受体Bmax显著升高，而KD值显著降低，在1个月时达到高峰，受体的亲合力显著增高。结论：帕金森病大鼠模型毁损侧尾壳核存在D2受体上行调节，D2受体明显超敏。     

多巴胺D2受体基因rs1800497多态性与精神分裂症的关联分析

目的 探讨中国汉族人群多巴胺D2受体（DRD2）基因rs1800497多态性与精神分裂症发病的关系及其与性别的关联性.方法 采用TaqMan法检测200例精神分裂症患者（患者组）和219名健康对照（对照组）DRD2基因rs1800497单核苷酸多态性（SNP）,并对等位基因、基因型频率进行比较.结果 患者组与对照组rs1800497等位基因分布和基因型分布差异均无统计学意义（P＞0.05）.患者组或对照组不同性别rs1800497等位基因分布和基因型分布差异均无统计学意义（P＞0.05）.男性患者组与对照组相比或女性患者组与对照组相比,rs1800497等位基因分布和基因型分布差异均无统计学意义（P＞0.05）.结论 中国汉族人群DRD2 rs1800497位点可能不是精神分裂症的易感位点.     

强啡肽原基因和多巴胺D2受体基因与精神分裂症的关系研究

目的探讨甘肃省汉族人群强啡肽原（Prodynorphin,PDYN）基因和多巴胺D2受体（dopamine D2 receptor,DRD2）基因与精神分裂症遗传易感性的关系及其相互作用对精神分裂症的影响。方法采用聚合酶链反应-限制性片段长度多态性〈PCR—RFLP）技术检测128例精神分裂症患者和124例健康对照者PDYN基因启动子区68bp可变串联重复序列（variable number tandem repeat,VNTR）多态性及DRD2基因启动子区-141位胞嘧啶插入／缺失（-141C Ins／Del）多态性的基因型和等位基因的频率。结果精神分裂症患者PDYN等位基因和基因型频率与健康对照者没有显著不同;精神分裂症患者DRD2-141C Del等位基因的频率则显著低于健康对照者;在携带DRD2-141C Del等位基因的精神分裂症患者和健康对照者中,精神分裂症患者PDYN等位基因3的频率显著高于健康对照者。结论DRD2-141C Del等位基因的降低可能与精神分裂症的遗传易感性相关,单独的PDYN基因多态性不会改变精神分裂症的危险度,但是通过与DRD2—141C Del等位基因的上位相互作用可能与这种疾病的易感性相关。     

The involvement of dopamine in nociception: the role of D1 and D2 receptors in the dorsolateral striatum

Determination of the neuroanatomical and neurochemical factors that contribute to nociception is an essential element in the study and treatment of pain. Several lines of evidence have implicated nuclei and neurotransmitters within the basal ganglia in nociception. For example, previous studies have shown that dopamine receptors in the striatum are involved in acute nociception, however, it remains to be determined if dopamine receptors in the dorsolateral striatum are involved in persistent nociception. The purpose of the present study was therefore to determine whether activation or antagonism of dopamine receptors in the dorsolateral striatum influences the nociceptive responses of rats in the formalin test, a model of persistent pain. It was found that micro-injection of the non-selective dopamine antagonist haloperidol into the dorsolateral striatum increases formalin-induced nociception whereas injection of the non-selective dopamine agonist apomorphine reduces formalin-induced nociception. Injection of the D₁ antagonist SCH23390 or the D₁ agonist SKF38393 does not affect formalin-induced nociception. In contrast, injection of the D₂ antagonist eticlopride enhances formalin-induced nociception, whereas injection of the D₂ agonist quinpirole reduces formalin-induced nociception. These results provide additional evidence that dopamine receptors in the striatum are involved in nociception. Furthermore, this study strongly suggests that D₂, but not D₁, dopamine receptors in the dorsolateral striatum are involved in modulation of persistent nociception.     

Huntington's disease like-2 neuropathology.

Huntington's disease like-2 (HDL-2) neurodegeneration is a recently described autosomal dominant disorder with features similar to Huntington's disease (HD). Only one case report has described neuropathology from an affected patient. We describe the clinical presentation and illustrate the pathology in two additional molecularly confirmed patients, compare these with the previously published case, and contrast them with HD. We examined two patients with HDL-2. Their charts were reviewed, their brains were examined using standard neuropathology techniques, including immunoperoxidase stains, and their diagnoses were confirmed with a PCR-based assay for repeat length. The first patient presented with obsessive suspiciousness, while the second had depression and decreased visual acuity. Both patients developed increased tone and cogwheel rigidity, but neither developed choreoathetosis. Extensive degeneration affected the caudate nucleus and putamen, especially dorsally and laterally. In addition, the first patient showed lateral temporal, lateral frontal, and orbitofrontal cortical atrophy, while the second patient displayed marked degeneration in the occipital and parietal cortices. Neither patient showed significant changes in the cerebellum or brainstem. Both cases had ubiquitin-immunoreactive neuronal intranuclear inclusions (NII). The patients with of HDL-2 reviewed here were remarkable for significant frontal inhibition with parkinsonism, a lack of choreiform movements, and African ancestry. Pathologically, HDL-2 is similar to HD in its effect on the neostriatum but may differ, at least in some cases, in its degree of focal cortical involvement, including the occipital lobe.     

Alterations in striatal and extrastriatal D-1 and D-2 dopamine receptors in the MPTP-treated common marmoset: An autoradiographic study

In adult common marmosets (Callithrix jacchus), MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) treatment induced almost total depletion of cells in the substantia nigra pars compacts (SNc) but partial cell loss in the ventral tegmental area (VTA). There was severe depletion of [³H]-mazindol binding to dopamine (DA) uptake sites in the caudate, putamen, and SNc. The loss of [³H]-mazindol binding in the nucleus accumbens (NAc) and olfactory tubercle (OT) was less marked. [³H]-mazindol binding in the body of caudate nucleus showed a small but significant recovery with increasing post-lesion survival times. The specific binding of [³H]-SCH 23390 to D-1 DA receptor sites was increased after MPTP treatment in all subregions of both caudate and putamen but was unaltered in the NAc and OT. Substantia nigra pars reticulata (SNr), frontal cortex, and medial segment of globus pallidus (GPm) all demonstrated moderate levels of [³H]-SCH 23390 binding in control animals, which were unaffected by MPTP treatment. Specific [³H]-spiperone binding to D-2 DA receptor sites was not altered by MPTP treatment in the subregions of caudate-putamen. Moderate levels of [³H]-spiperone binding were observed in control animals in the NAc, OT, SNc, and the lateral segment of globus pallidus (GPl). [³H]-spiperone binding in the SNc and OT was partially decreased in MPTP-treated animals. The changes in specific [³H]-spiperone and [³H]-SCH 23390 binding induced by MPTP-treatment did not alter with post-lesion survival times. These results demonstrate that MPTP treatment causes greater dopaminergic denervation of the caudate-putamen than in NAc/OT. This resulted in an increase in postsynaptic D-1 DA receptor sites in the caudate-putamen but not in the NAc/OT. Also, there appeared to be loss of presynaptic D-2 DA receptic sites in the SNc and OT. In the caudate-putamen, the loss of presynaptic D-2 DA receptor sites may have masked postsynaptic D-2 DA receptor upregulation. © 1993 Wiley-Liss, Inc.     

Insular dopamine D2 receptors and novelty seeking personality in Parkinson's disease.

Novelty seeking is a temperament trait characterized by impulsiveness and exploratory behavior. Dopamine has been suggested to be the primary neurotransmitter modulator of novelty seeking, and in young healthy subjects, a correlation between increased novelty seeking and decreased insular cortical dopamine D2 receptor availability has been reported. The proposed link between dopamine deficiency and reduction in novelty seeking in Parkinson's disease is controversial. The present study examined whether a link between insular D2 receptor availability and novelty seeking can be replicated in Parkinson's disease patients. [11C]FLB 457 positron emission tomography imaging was carried out in 28 patients with Parkinson's disease, and the data were analyzed using voxel-based statistical analysis. The results demonstrated a negative correlation between the novelty seeking score and the dopamine D2 availability bilaterally in the insular cortex (corrected P=0.001; r=-0.74 [right hemisphere]; r=-0.66 [left hemisphere]). The results provide further support for a relationship between novelty seeking and insular D2 receptors. They indicate that the association is cross-cultural, independent of age, and unaffected by dopaminergic degeneration.     

The effect of Parkinson's disease and Huntington's disease on human visuomotor learning

Visuomotor adaptation is often driven by error‐based (EB) learning in which signed errors update motor commands. There are, however, visuomotor tasks where signed errors are unavailable or cannot be mapped onto appropriate motor command changes, rendering EB learning ineffective; and yet, healthy subjects can learn in these EB learning‐free conditions. While EB learning depends on cerebellar integrity, the neural bases of EB‐independent learning are poorly understood. As basal ganglia are involved in learning mechanisms that are independent of signed error feedback, here we tested whether patients with basal ganglia lesions, including those with Huntington's disease and Parkinson's disease, would show impairments in a visuomotor learning task that prevents the use of EB learning. We employed two visuomotor throwing tasks that were similar, but were profoundly different in the resulting visual feedback. This difference was implemented through the introduction of either a lateral displacement of the visual field via a wedge prism (EB learning) or a horizontal reversal of the visual field via a dove prism (non‐EB learning). Our results show that patients with basal ganglia degeneration had normal EB learning in the wedge prism task, but were profoundly impaired in the reversing prism task that does not depend on the signed error signal feedback. These results represent the first evidence that human visuomotor learning in the absence of EB feedback depends on the integrity of the basal ganglia.     

Seizures in juvenile Huntington's disease: Frequency and characterization in a multicenter cohort

Little is known about the epilepsy that often occurs in the juvenile form of Huntington's disease (HD), but is absent from the adult‐onset form. The primary aim of this study was to characterize the seizures in juvenile HD (JHD) subjects with regard to frequency, semiology, defining EEG characteristics, and response to antiepileptic agents. A multicenter, retrospective cohort was identified by database query and/or chart review. Data on age of HD onset, primary HD manifestations, number of CAG repeats, the presence or absence of seizures, seizure type(s), antiepileptic drugs used, subjects' response to antiepileptic drugs (AEDs), and EEG results were assembled, where available. Ninety subjects with genetically confirmed JHD were included. Seizures were present in 38% of subjects and were more likely to occur with younger ages of HD onset. Generalized tonic‐clonic seizures were the most common seizure type, followed by tonic, myoclonic, and staring spells. Multiple seizure types commonly occurred within the same individual. Data on EEG findings and AED usage are presented. Seizure risk in JHD increases with younger age of HD onset. Our ability to draw firm conclusions about defining EEG characteristics and response to AEDs was limited by the retrospective nature of the study. Future prospective studies are required. © 2012 Movement Disorder Society     

L-pyroglutamate: an alternate neurotoxin for a rodent model of Huntington's disease

Intrastriatal injections of L-Pyroglutamate (L-PGA) in mice produced behavioral and neuropathological effects that resemble in part the kainate-injected rat striatal model of Huntington's Disease (HD). The behavioral responses induced after unilateral injections of L-PGA included circling, postural asymmetry of head and trunk and possible dyskinesias. The neuropil in the injected striatum contained dilated profiles, degenerating neurons and oligodendroglia, and numerous phagocytic microglial-like cells. A dose response relation existed. The size of the lesion (expressed as a percent volume of the striatum destroyed) ranged from 1 +/- 0.18% at 0.02 mumoles to 20.2 +/- 3.97% at 200 mumoles L-PGA (pH = 7.3). L-PGA is a weak neurotoxin when compared to kainic acid. Several factors raise interest in the possible role of L-PGA in HD, including the recently reported elevated plasma levels of L-PGA in some HD patients, and these considered in the discussion.     

吡贝地尔对帕金森病模型大鼠脑多巴胺D2受体的影响

目的研究常用抗帕金森药多巴胺受体激动剂吡贝地尔对脑多巴胺D2受体的影响。方法立体定位右侧纹状体注射6-羟多巴胺制备偏侧帕金森病大鼠模型,模型成功后予吡贝地尔灌胃治疗[30mg/(kg·d)]5周。分4组(正常组、术后4周帕金森病模型大鼠组、术后9周帕金森病模型大鼠经吡贝地尔治疗组、术后9周帕金森病模型大鼠未治疗组)行125I-依匹必利(125I-epidepride)大鼠脑多巴胺D2受体放射自显影。图像分析得到纹状体与小脑的平均光密度值,计算并比较各组左、右两侧脑多巴胺D2受体的特异性放射性摄取比值(纹状体/小脑-1)的变化。结果正常大鼠脑多巴胺D2受体对依匹必利的特异性放射性摄取比值左、右两侧差异无统计学意义;成为帕金森病模型后,右侧(损毁侧)比值较正常稍升高,但差异无统计学意义;未治疗组帕金森病模型大鼠双侧比值较刚成模型时均明显降低,右侧(损毁侧)比值仍较左侧高;经吡贝地尔治疗后,双侧比值较未治疗组进一步降低,右侧(损毁侧)降低甚,比值较左侧低。结论长期吡贝地尔治疗可能会使帕金森病模型大鼠双侧脑多巴胺D2受体的数量减少,损毁侧减少为甚。     

Locomotor behavior of dopamine D1 receptor transgenic/D2 receptor deficient hybrid mice

Mice that incorporate the dopamine D1 receptor transgene controlled by the D1 receptor promoter exhibit a marked increase of D1 binding in several extra-striatal brain regions and show a paradoxical hypokinetic response to D1 agonist [Exp. Neurol. 157 (1999) 169]. The agonist-induced locomotor behavior of D1 receptor transgenic mice is similar to baseline locomotor activity manifested by D2 receptor deficient mice [J. Neurosci. 18 (1998) 3470]. The similarity between these two behavioral phenotypes raised the possibility that stimulation of the over-expressed D1 receptors in the transgenic mice could cause a suppression of D2 receptor responses that manifest in hypokinesia. Alternatively, the similar phenotypes could result from altered D1/D2 receptor balance in both animal models. Two different approaches were undertaken to test these alternative hypotheses. (1) The effects of pharmacological blockade of D2 receptors on D1 agonist-stimulated hypokinesia of the D1 over-expressing animals were investigated. (2) The behavioral phenotype of hybrid D1 receptor over-expressing/D2 receptor deficient mice generated by crossbreeding the D2 knockout mice and the D1 transgenic animals was studied. The results of these studies suggested that the hypomotor response of the D1 transgenic mice was not a result of an interaction of the over-expressed D1 receptors with the native D2 receptors and that over-expressed D1 receptors likely mediate hypokinesia in the D1 transgenic animals. Considering the significance of the D1 dopamine receptor as a therapeutic target for Parkinson's disease, this D1 receptor over-expressing model provides an important experimental system to probe the basis for altered behavioral responses following stimulation of transgenetically up-regulated receptors.