Ketamine does not decrease striatal dopamine D2 receptor binding in man

Abstract Rationale. A glutamate–dopamine interaction has been implicated in the psychosis-like effects of glutamate N-methyl-D-aspartate (NMDA) receptor antagonists, such as phencyclidine and ketamine. However, recent imaging studies addressing striatal glutamate–dopamine interaction directly in vivo in man have been controversial. Objectives. To examine whether the NMDA receptor antagonist ketamine in high subanesthetic concentrations decreases striatal [¹¹C]raclopride binding potential in man. To further evaluate whether changes in striatal [¹¹C]raclopride binding are associated with ketamine-induced behavioral effects. Methods. The effect of computer-driven subanesthetic ketamine infusion on striatal dopamine release was studied in healthy male subjects using a controlled study design. Dopamine release was studied using positron emission tomography and the [¹¹C]raclopride displacement paradigm. A conventional region of interest-based analysis and voxel-based analysis were applied to the positron emission tomography data. Results. The average plasma ketamine concentration was 293±29 ng/ml. Ketamine did not alter striatal [¹¹C]raclopride binding. Ketamine induced typical behavioral effects, such as hallucinations but there was no correlation between these effects and displacement of [¹¹C]raclopride binding. Conclusions. This controlled study indicates that ketamine does not decrease striatal [¹¹C]raclopride binding. Striatal dopamine release is of minor importance in the psychosis-like effects of ketamine. Electronic Publication     

Preferential involvement of D3 versus D2 dopamine receptors in the effects of dopamine receptor ligands on oral ethanol self-administration in rats

There is evidence that dopamine transmission is involved in reinforcement processes and the present study investigated the relative involvement of D₃ versus D₂ dopamine receptors in the effects of dopamine ligands on the reinforcing action of ethanol. Rats were trained to self-administer ethanol (10% v/v) orally in a free-choice two-lever operant task using a saccharin-fading procedure. When preference in responding for ethanol over water had developed the rats were tested with several dopamine agonists and antagonists. Pretreatment with the non-selective dopamine agonist, apomorphine (0.01–0.1 mg/kg), the preferential D₂ agonist, bromocriptine (1–10 mg/kg) and the selective D₃ agonists, 7-OH-DPAT (0.003–0.1 mg/kg), PD 128907 (0.1–3 mg/kg), (+)3PPP (0.3–3 mg/kg), quinelorane (0.0001–0.003 mg/kg) and quinpirole (0.003–0.03 mg/kg), resulted in dose-dependent decreases in responding for ethanol. The relative potencies of the dopamine agonists to decrease ethanol self-administration were highly correlated with their published potencies to produce in vitro functional D₃ but not D₂ responses. Active doses could be considered as those selectively stimulating receptors involved in the control of dopamine release, suggesting that reduction of dopamine transmission was associated with a decrease in ethanol-reinforced responding. This conclusion was further supported by the finding that pretreatment with the D₂/D₃ dopamine antagonists, haloperidol (0.1–0.4 mg/kg) and tiapride (10–60 mg/ kg), decreased responding for ethanol at doses which have been shown previously to block dopamine transmission. Received: 25 January 1998/Final version: 24 April 1998     

A PET study of D1-like dopamine receptor ligand binding

Rationale: Several positron emission tomography (PET) studies have shown that radioligand binding to D₂-like dopamine receptors competes with endogenous dopamine. Objective: The purpose of this PET study was to examine the effect of amphetamine and reserpine on D₁-like dopamine receptor binding. Methods: Three Cynomolgus monkeys were examined with the radioligands [¹¹C]SCH 23390 or [¹¹C]NNC 112 at baseline condition and after pretreatment with amphetamine (2 mg/kg IV). The B/F values (binding potential) in the striatum and the neocortex were calculated at transient equilibrium. In two monkeys, the effect of the long-lasting dopamine depletion after reserpine (1 mg/kg IV) was followed by a repeated Scatchard procedure in up to 77 days after drug administration. The Scatchard analysis was based on two PET measurements with high and low specific radioactivity and allowed the calculation of D₁-like dopamine receptor density (B_max) and apparent affinity (K_D ^app). Results: The effect of amphetamine on the B/F values was between –14 and 6%. These changes can be considered as within the range of the test-retest reliability. Thus, there was no evident effect of amphetamine-induced dopamine release on D₁-like dopamine receptor binding. Five hours after reserpine administration, there was no change in B_max or K_D ^app. At 3, 23, and 28 days after reserpine administration, the Scatchard analyses indicated a 13–20% reduction in B_max without any evident change in K_D ^app in both the striatum and the neocortex. Conclusions: The lack of evident effects of amphetamine and reserpine on D₁-like dopamine receptor binding is markedly different from the 20% amphetamine-induced decrease and 50% reserpine-induced increase that has been consistently reported for D₂-like dopamine receptor binding. The data indicated that D₁-like dopamine receptor occupancy of endogenous dopamine is low at physiological condition. It is thus unlikely that D₁-like dopamine receptor radioligands can be used to measure changes in the concentration of endogenous dopamine. Received: 8 March 1999 / Final version: 12 May 1999     

多巴胺D3受体基因多态性与帕金森病

目的：探讨多巴胺Ｄ３受体（ＤＲ Ｄ３）基因多态性与帕金森病（ｐａｒｋｉｎｓｏｎ ｄｉｓｅａｅ，ＰＤ）遗传易感性的关系。方法：采用聚合酶链反应－限制性片段长度多态性（ＰＣＲ－ＲＦＬＰ）技术分析比较了１３０例ＰＤ病人和１２０名正常对照者的ＤＲＤ３基因第１号外显子ＢａｌＩ多态性和第５号内含子ＭｓｐＩ多态性。结果：ＤＲ Ｄ３基因ＢａｌＩ多态位点和ＭｓｐＩ多态位点各基因型的分布和等位基因频率在ＰＤ组和对照     

卡利拉嗪:抗精神分裂症新药、多巴胺D3/D2受体部分激动剂

多巴胺D3受体(D3R)是一种G蛋白偶联的D2样受体,多表达于与认知、情绪等脑机能密切相关的边缘区域。以D3R为靶标治疗帕金森病、精神分裂症及药物成瘾等中枢神经系统疾病具有潜在的应用价值,因此高选择性及亲和性的D3R配体的设计合成、结构优化及活性筛选成为研究热点。阿特维斯公司和匈牙利吉瑞大药厂开发的口服新药卡利拉嗪于2015年9月被FDA批准上市,作为一种对D3受体表现出更高亲和力的多巴胺D3/D2受体部分激动剂,用于治疗精神分裂症及双向躁郁症。介绍卡利拉嗪的研发背景、合成方法、临床药理学、临床评价、安全性和耐受性等研究概况。     

Long-term effects of postnatal amphetamine treatment on striatal protein kinase A activity, dopamine D(1)-like and D(2)-like binding sites, and dopamine content

The purpose of the present study was to determine whether exposure to amphetamine during the preweanling period would alter dopaminergic functioning in the dorsal striatum of adult rats. In three experiments, we assessed the effects of repeated amphetamine treatment on striatal protein kinase A (PKA) activity, dopamine (DA) D₁-like and D₂-like binding sites, and DA content. Rats were pretreated with saline or amphetamine (2.5 mg/kg, ip) for 7 consecutive days starting on postnatal day (PD) 11. At PD 90, rats were killed and their dorsal striata (i.e., caudate–putamen) were removed and frozen until time of assay. Amphetamine pretreatment produced long-term reductions in both striatal PKA activity and DA content. Early amphetamine exposure also resulted in an upregulation of D₂-like binding sites, while leaving D₁-like binding sites unaffected. It is likely that the upregulation of D₂-like binding sites was stimulated by the persistent decline in striatal DA levels. Although speculative, it is possible that excess striatal D₂-like receptors were responsible for inhibiting PKA activity through actions on the cAMP signal transduction pathway. The behavioral relevance of these amphetamine-induced neurochemical changes has not yet be determined.     

Evidence for the sensitivity of operant timing behaviour to stimulation of D1 dopamine receptors

Rationale Temporal differentiation of operant behaviour is sensitive to dopaminergic manipulations. Previous studies using the fixed-interval peak procedure implicated D₂-like dopamine receptors in these effects. However, recent findings suggest that d-amphetamine alters timing performance on the free-operant psychophysical procedure via D₁-like receptors. It is not known whether this effect of d-amphetamine is mimicked by direct D₁-like receptor stimulation. Objective The effects of a D₁-like receptor agonist 6-chloro-2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepine (SKF-81297) on performance on the free-operant psychophysical procedure and the interaction between SKF-81297 and a D₁-like receptor antagonist 8-bromo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol (SKF-83566) and a D₂-like receptor antagonist haloperidol, were examined. Materials and methods Rats were trained to respond on two levers (A and B) under a free-operant psychophysical schedule, in which sucrose reinforcement was provided intermittently for responding on A during the first half and on B during the second half of 50-s trials. Logistic psychometric functions were fitted to the relative response rate data (percent responding on B [%B] vs time from trial onset [t]) under each treatment condition, and quantitative indices of timing (T₅₀ [value of t corresponding to %B = 50] and the Weber fraction [(T₇₅-T₂₅)/2T₅₀; T₂₅ and T₇₅ are values of t corresponding to %B = 25 and %B = 75] were compared among treatments. Results SKF-81297 (0.8 mg kg⁻¹) reduced T₅₀; this effect was antagonized by SKF-83566 (0.03 mg kg⁻¹) but not by haloperidol (0.05, 0.1 mg kg⁻¹). Conclusions Stimulation of D₁-like dopamine receptors affects performance in the free-operant psychophysical procedure.     

Antagonism of the discriminative stimulus effects of cocaine at two training doses by dopamine D2-like receptor antagonists

RATIONALE: The relative contributions of different dopamine receptor subtypes to the discriminative stimulus effects of cocaine may be influenced by the training dose of cocaine. Substitution tests with dopamine receptor agonists have suggested that the role of dopamine D2-like receptors is diminished relative to that of D1-like receptors at a training dose of 3 mg/kg cocaine compared with a training dose of 10 mg/kg. OBJECTIVES: To test whether dopamine D2-like receptor antagonists were differentially effective at attenuating cocaine's discriminative stimulus effects at different training doses, and to test for the first time an antagonist that is selective for the dopamine D2 receptor within the D2-like receptor subfamily. METHODS: Rats were trained to press one lever after receiving cocaine and another after receiving saline (maintaining >95% drug-appropriate responding). Three dopamine D2-like receptor antagonists (haloperidol, raclopride and L-741,626) were tested in rats trained at 3 mg/kg or 10 mg/kg cocaine. At the lower training dose, the D1-like receptor antagonist SCH 39166 was also tested. RESULTS: The antagonists were not differentially effective between training groups: they all produced parallel, rightward shifts in cocaine's dose-effect function, indicating surmountable antagonism. CONCLUSIONS: The results demonstrate that D2-like receptor antagonists with different affinities for the various D2-like receptors can antagonise the discriminative stimulus effects of cocaine at two training doses. Importantly, antagonism by L-741,626 implies that stimulation of D2 receptors alone (not D3 or D4 receptors) is sufficient to mediate cocaine's discriminative stimulus effects. Finally, the claim that D1-like receptors are preferentially involved at low training doses of cocaine is only consistent with the current findings if indirect stimulation of D2 receptors by low doses of cocaine remains necessary for the expression of the D1-like receptor-mediated effect.     

Endurance training effects on striatal D2 dopamine receptor binding and striatal dopamine metabolites in presenescent older rats

Endurance training is associated with higher binding of 3H-spiperone to striatal D2 dopamine receptors of rats sacrificed 48 h following the last exercise bout (Gilliam et al. 1984). In the present study we investigated the effects of endurance training in presenescent older rats on the relationship between steady-state levels of DA and its metabolites in striatum versus the affinity and density of striatal D2 DA receptors. Citrate synthase activity of the gastrocnemius-plantaris muscle was 29.06±2.27 mole/g wet wt in 21-month-old trained rats versus 22.88±1.13 mole/g wet wt in 21-month-old untrained animals.DOPAC levels and DOPAC/DA ratios were greater in the old controls. Endurance training was associated with lower DOPAC levels in the 21-month-old animals. Thus, endurance training may postpone selectively changes in DA metabolism over a portion of the lifespan.As expected, the number of D2 DA binding sites was reduced with age (6 months B _max:429±21 fmoles/mg protein; 21 months:355±20) with no change in affinity. The B_max of old runners was significantly higher (457 ± 38 fmoles/mg protein) than that of old controls. Thus, endurance training appears to exert a protective effect on D2 dopamine receptors during the lifespan. Taken together, the present results suggest that there may be a possible reciprocal relationship between changes in DA metabolites and DA binding as a function of exercise in presenescent older rats, and that endurance training may decelerate the effects of age both on nigrostriatal dopamine neurons and on striatal D2 dopamine receptors during a portion of the lifespan.     

The potential role of dopamine D3 receptor neurotransmission in cognition

Currently available treatments have limited pro-cognitive effects for neuropsychiatric disorders, such as schizophrenia, Parkinson's disease and Alzheimer's disease. The primary objective of this work is to review the literature on the role of dopamine D₃ receptors in cognition, and propose dopamine D₃ receptor antagonists as possible cognitive enhancers for neuropsychiatric disorders. A literature search was performed to identify animal and human studies on D₃ receptors and cognition using PubMed, MEDLINE and EMBASE. The search terms included “dopamine D₃ receptor” and “cognition”. The literature search identified 164 articles. The results revealed: (1) D₃ receptors are associated with cognitive functioning in both healthy individuals and those with neuropsychiatric disorders; (2) D₃ receptor blockade appears to enhance while D₃ receptor agonism seems to impair cognitive function, including memory, attention, learning, processing speed, social recognition and executive function independent of age; and (3) D₃ receptor antagonists may exert their pro-cognitive effect by enhancing the release of acetylcholine in the prefrontal cortex, disinhibiting the activity of dopamine neurons projecting to the nucleus accumbens or prefrontal cortex, or activating CREB signaling in the hippocampus. These findings suggest that D₃ receptor blockade may enhance cognitive performance in healthy individuals and treat cognitive dysfunction in individuals with a neuropsychiatric disorder. Clinical trials are needed to confirm these effects.     

Evidence that the enhancement of dopamine function by repeated electroconvulsive shock requires concomitant activation of D1-like and D2-like dopamine receptors

In this study, the behavioural response to dopamine D₁-like receptor agonists (SKF 38393, SKF 81297 and SKF 77434) and D₂-like receptor agonists (quinpirole and RU 24213), administered alone and in combination to rats treated repeatedly with electroconvulsive shock (five ECS over 10 days) or sham, was tested. Agonist-induced behaviour was monitored by automated activity meters and direct observation using a checklist scoring method. Repeated ECS (compared to sham controls) had no significant effect on the behavioural response to SKF 38393 (7.5 mg/kg SC), SKF 81297 (0.2 mg/kg SC), SKF 77434 (0.1 mg/kg SC), quinpirole (0.1 and 0.25 mg/kg SC) or RU 24213 (0.3 mg/kg SC), when administered alone. In contrast, repeated ECS markedly increased locomotion (activity counts and scores) induced by the non-selective dopamine agonist apomorphine (0.5 mg/kg SC) and by co-administration of a D₁-like agonist plus a D₂-like agonist [SKF 38393 (7.5 mg/kg SC) plus quinpirole (0.25 mg/kg SC), SKF 81297 (0.2 mg/kg SC) plus quinpirole (0.1 mg/kg SC), and SKF 77434 (0.1 mg/ kg SC) plus RU 24213 (0.3 mg/kg SC)]. This ECS-induced enhancement of dopamine-mediated behaviour was observed for up to 3 weeks after cessation of ECS treatment. In addition, ECS also enhanced the locomotor response to intra-accumbens SKF 38393 plus quinpirole (0.4 and 1.0 μg/side, respectively). These results provide evidence that the enhancement of dopamine function by repeated ECS requires concomitant stimulation of both D₁-like and D₂-like receptors, and that this effect is long-lasting. Received: 24 January 1997 /Final version: 5 March 1997     

多巴胺D_3受体选择性配体治疗药物依赖的新进展

药物依赖是一种以复吸为特征的慢性脑病,迄今为止尚缺乏有效的防复吸药物。随着药物依赖及复吸神经生物学机制的研究不断深入,发现了一些潜在的药物干预靶点。靶向多巴胺D3受体(DAD3R)防复吸药物研究受到了广泛关注,DAD3R选择性分布在啮齿类动物及人脑内与药物依赖相关的中脑边缘多巴胺系统,在药物依赖发生发展过程中发挥着重要作用。本文重点介绍DAD3R在药物依赖中的作用及选择性配体治疗药物依赖研究的进展。     

Similar binding of 3H-ADTN and 3H-apomorphine to calf brain dopamine receptors.

The binding of 3H(+/-)-ADTN (of high specific activity; 7.6 Ci/mmole) to homogenates of calf striatum was investigated. The dissociation constant (KD) for the specific, saturable binding of 3H-(+/-)-ADTN was 1 nM and the density of specific sites was 100 fmoles/mg protein. The IC50 values (nM concentrations inhibiting specific binding by 50%) were 0.9 for (+/-)-N-propyl-norapomorphine, 3.0 for dopamine, 7 for (--)-adrenaline, 60 for (--)-noradrenaline and 4000 for isoproterenol, a series of potencies compatible with properties for a dopaminergic site. The (+)-enantiomer of ADTN was 10 times more potent than (--)-ADTN in competing for 3H-(+/-)-ADTN, while the (--)-enantiomer of 5-OH-dipropyl-ATN was 40 times more potent than the (+)-isomer. The IC50 values for various agonists against 3H-(+/-)-ADTN were similar to those against 3H-apomorphine or 3H-dopamine in the calf striatum. A comparison of these 3H-(+/-)-ADTN data to those for 3H-spiperone suggests that the two 3H-ligands label different receptor sites.     

新型多巴胺D2类受体部分激动剂brexpiprazole

在多巴胺D2类受体中,D2受体部分激动剂对中脑边缘通路可产生功能性拮抗作用,能有效的改善精神分裂症因D2过度活动引起的阳性症状;对中脑皮层通路可产生功能性激动作用,可改善D2功能低下所引起的阴性症状、认知损害。brexpiprazole是一种新型多靶点作用机制的用于精神障碍疾病的治疗药物,除主要具备多巴胺D2受体部分激动作用之外,还具备D3受体部分激动作用、5-HT1A部分受体激动作用和5-HT2A部分受体拮抗作用,是针对单胺类神经递质多靶点开发的同时具有抗精神分裂和抗抑郁作用的新药,目前正在进行Ⅲ期临床试验。     

多巴胺D2受体基因多态性与利培酮致高泌乳素血症的相关性

目的:探讨多巴胺D2受体基因多态性与利培酮致高泌乳素血症的相关性.方法:纳入115例接受单一利培酮治疗的精神分裂症患者为研究对象,于治疗前后测定血清泌乳素水平,根据泌乳素水平＞25 ng·mL-1和≤25 ng· mL-1,分为高泌乳素血症(hyperprolactinemia,HPRL)组和泌乳素水平正常(norma...     

In vivo assessment of release and metabolism of dopamine in the ventrolateral striatum of awake rats following administration of dopamine D1 and D2 receptor agonists and antagonists

The ability of specific dopamine (DA) receptor agonists and antagonists to modify the release and metabolism of DA in the ventrolateral striatum of awake rats was assessed using in vivo microdialysis. The specific DA D₂ receptor antagonist, raclopride (0.1, 0.5 and 2.0mg/kg, i.p.), dose-dependently increased release of DA and levels of the metabolites DOPAC and HVA, while the D₂ receptor agonist, quinpirole (0.03, 0.1 and 0.3 mg/kg), decreased levels of DA, DOPAC and HVA. The DA D₁ receptor antagonist, SCH23390 ([R + (+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-o]) (0.01, 0.05 and 0.25 mg/kg), produced an increase in DA, DOPAC and HVA but of a lesser magnitude than raclopride. The D₁ agonist SKF38393 (1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol) (1.0, 3.0 and 10.0 mg/kg) failed to affect the release of metabolism of DA at any dose. These results support previous findings that activation of D₂ receptors has greater control over in vivo DA function, than drugs specifically affecting D₁ receptors.     

Increased vulnerability to cocaine addiction in mice lacking dopamine D3 receptor

Neuroimaging studies using positron emission tomography suggest that reduced dopamine(DA) D2 receptor(D2R) availability in the striatum is associated with increased vulnerability to drug addiction in humans and experimental animals.However,the role of D3R in the neurobiology of addiction remains unclear.Here we report that D3R-knockout(D3-/-) mice display enhanced cocaine(and sucrose) taking observed during the acquisition and maintenance of cocaine self-administration and enhanced motivation for cocaine(and sucrose) seeking observed during progressive-ratio cocaine self-administration and extinction from cocaine self-administration.This increased vulnerability to cocaine was accompanied by decreased DA response to cocaine secondary to increased basal levels of extracellular DA in the nucleus accumbens,suggesting that enhanced cocaine-taking and cocaine-seeking behavior could be a compensatory response to decreased cocaine reward in D3-/-mice.In addition,D3-/-mice also displayed up-regulation of DA transporter in the striatum,suggesting that a neuroadaptative change occurred D3-/-mice to restore elevated basal levels of extracellular DA.These findings,for the first time,suggest that deletion of D3R increases vulnerability to cocaine-taking and cocaine-seeking behavior.Thus,reduced D3R availability in the brain constitutes an important risk factor for the development of cocaine addiction.     

Characterization of dopamine autoreceptor and [3H]spiperone binding sites in vitro with classical and novel dopamine receptor agonists

The specific D2 receptor agonist, LY 141865, but not the specific D1-receptor agonist, SK&F 38393, potently inhibited electrically evoked [3H]dopamine release from slices of the cat caudate. Similarly, LY 141865, but not SK&F 38393, inhibited [3H]spiperone binding to membranes of the cat caudate. The inhibition by dopamine receptor agonists of electrically evoked [3H]dopamine release was antagonized by the specific D2-receptor antagonist S-sulpiride. The inhibition of the electrically evoked release of [3H]dopamine by apomorphine was not, however, antagonized by the specific D1-receptor antagonist, bulbocapnine. Similarly, S-sulpiride but not bulbocapnine potently inhibited [3H]spiperone binding to membranes of the cat caudate. These results suggest that the dopamine autoreceptor modulating the depolarization-evoked release of [3H]dopamine, and the binding site of [3H]spiperone, are valid in vitro models for D2-dopamine receptors. Contrary to some previous reports, DPI was inactive in both in vitro dopamine receptor models. The IC50 values of a series of dopamine receptor agonists correlated very well in the two in vitro dopamine receptor models. One exception to this correlation was bromocriptine, which was more potent at [3H]spiperone binding sites than at the dopamine autoreceptor. With the exception of bromocriptine, all dopamine receptor agonists had one-hundred fold higher potency at the dopamine autoreceptor than at [3H]spiperone binding sites. [3H]Spiperone binding sites are localized primarily postsynaptic to dopamine terminals. Possible differences between the pharmacological properties of pre- and postsynaptic dopamine receptors should become apparent in the comparison of the two in vitro dopamine receptor models. However, the order of potency of dopamine receptor agonists with both in vitro models, dopamine autoreceptor and [3H]spiperone binding, was the same: N-n-propylnorapomorphine greater than TL-99 = 7-HAT greater than M-7 greater than Apomorphine greater than LY 141865.     

Synergistic effects of dopamine D2-like receptor antagonist sulpiride and beta-blocker propranolol on learning in the Carousel maze, a dry-land spatial navigation task

Spatial navigation attracts the attention of neuroscientists as an animal analogue of human declarative memory. The Carousel maze is a dry-land navigational paradigm, which proved to be useful in studying neurobiological substrates of learning. The task involves avoidance of a stable sector on a rotating arena and is highly dependent upon the hippocampus. The present study aims at testing hypothesis that sulpiride (a centrally-active dopamine D2-like receptor antagonist) and propranolol (a beta-blocker) impair spatial learning in the Carousel maze after combined systemic administration. These doses were previously shown to be subthreshold in this task. Results showed that both substances affected behavior and significantly potentiated their negative effects on spatial learning. This suggests central interaction of both types of receptors in influencing acquisition of this dynamic-environment task.