The human dopamine D2Longer receptor has a high-affinity state and inhibits adenylyl cyclase

Liu, Ivy S.C; George, Susan R.; Seeman, Philip

doi:10.1016/s0169-328x(00)00064-4

Cited by 31 publications

(23 citation statements)

References 16 publications

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“…We used the human cloned dopamine D2 Long receptor (in Chinese hamster ovary (CHO) cells 18 ) . The cells were harvested by gently scraping the cells off the bottom of the Petri dish, centrifuged, resuspended in phosphate-buffered saline (0.9% NaCl), recentrifuged and the pellet frozen at À701.…”

Section: Methodsmentioning

confidence: 99%

Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics

2005

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Although phencyclidine and ketamine are used to model a hypoglutamate theory of schizophrenia, their selectivity for NMDA receptors has been questioned. To determine the affinities of phencyclidine, ketamine, dizocilpine and LSD for the functional high-affinity state of the dopamine D2 receptor, D2 High , their dissociation constants (K i ) were obtained on [ 3 H]domperidone binding to human cloned dopamine D2 receptors. Phencyclidine had a high affinity for D2 High with a K i of 2.7 nM, in contrast to its low affinity for the NMDA receptor, with a K i of 313 nM, as labeled by [ 3 H]dizocilpine on rat striatal tissue. Ketamine also had a high affinity for D2 High with a K i of 55 nM, an affinity higher than its 3100 nM K i for the NMDA sites. Dizocilpine had a K i of 0.3 nM at D2 High , but a K d of 1.8 nM at the NMDA receptor. LSD had a K i of 2 nM at D2 High . Because the psychotomimetics had higher potency at D2 High than at the NMDA site, the psychotomimetic action of these drugs must have a major contribution from D2 agonism. Because these drugs have a combined action on both dopamine receptors and NMDA receptors, these drugs, when given in vivo, test a combined hyperdopamine and hypoglutamate theory of psychosis. Keywords: dopamine receptor; phencyclidine; domperidone; ketamine; NMDA receptors; psychotomimetics While the clinical anti-dopaminergic actions of antipsychotic drugs are compatible with the hyperdopamine hypothesis of psychosis and schizophrenia, 1,2 the psychoses caused by glutamate antagonists such as phencyclidine or ketamine suggest a hypo-glutamate component in psychosis. [3][4][5] However, phencyclidine also lowers plasma prolactin 6 and elicits rotation, 7 suggesting a direct or indirect dopaminemimetic action of phencyclidine.Although phencyclidine and ketamine are not selective for glutamate NMDA receptors, 8 the precise affinities of these drugs for dopamine D2 receptors need to be clarified in order to determine their dopaminergic and non-dopaminergic components of action. More specifically, although phencyclidine had a dissociation constant of 37 000 nM at the D2 receptor in rat striatal homogenate, 8 phencyclidine had a dissociation constant of 1.3 nM for the functional high-affinity site of the cloned D2 receptor, or the D2 High receptor. 9 This apparent discrepancy may be resolved by the recent finding that dopamine itself has a dissociation constant of 3000 nM when competing vs [ 3 H]raclopride at striatal D2 receptors, but has a dissociation constant of 1.5 nM at the D2 High receptor when the link between dopamine D1 and D2 receptors is blocked by the D1 antagonist SCH23390. 10 The link between D1 and D2 receptors arises from several sources, including the colocalization of dopamine D1 and D2 receptors in at least 50% of the medium spiny neurons in the striatum, the cooperation and mutual potentiation of D1 and D2 agonists on various behaviors, and the biochemical conversion of D2 receptors from their functional high-affinity state, D2 High , into their low-affinity state, D2 Lo...

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Section: Methodsmentioning

confidence: 99%

Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics

2005

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“…17 For affinity studies involving cloned receptors we used the cloned dopamine D 2 long (human) receptor expressed in Chinese Hamster Ovary cell line (CHO), grown and treated as described previously. 18 The cells were suspended at 200 g protein ml −1 and the suspension was homogenized for 5 s (Polytron, setting 5). The rest of the procedures for cloned tissue were similar to that for brain tissue.…”

Section: Tissuementioning

confidence: 99%

“…D2 long receptors were expressed in CHO cells as described before. 18 The ability of ketamine and PCP to stimulate […”

Section: S]gtp-␥-s Incorporationmentioning

confidence: 99%

NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D2 and serotonin 5-HT2 receptors—implications for models of schizophrenia

2002

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“…However, quantification of the D2 receptor family has limitations, because as antagonists these ligands bind with equal affinity to both the high (DRD2 HIGH ) and the low (DRD2 LOW ) affinity states of the DRD2. The DRD2 HIGH primarily mediate the effects of dopamine (George et al, 1985;Leff, 1995;Liu et al, 2000). In addition, the PET/SPECT signal from these radioligands consists of a mix of DRD2 and DRD3 binding (Halldin et al, 1995;Mukherjee et al, 1999;Narendran et al, 2006;Strange, 2001;Videbaek et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

In Vivo Imaging of Cerebral Dopamine D3 Receptors in Alcoholism

Erritzoe

Tziortzi

Bargiela

et al. 2014

Neuropsychopharmacol

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Animal studies support the role of the dopamine D3 receptor (DRD3) in alcohol reinforcement or liking. Sustained voluntary alcohol drinking in rats has been associated with an upregulation of striatal DRD3 gene expression and selective blockade of DRD3 reduces ethanol preference, consumption, and cue-induced reinstatement. In vivo measurement of DRD3 in the living human brain has not been possible until recently owing to a lack of suitable tools. In this study, DRD3 status was assessed for the first time in human alcohol addiction. Brain DRD3 availability was compared between 16 male abstinent alcohol-dependent patients and 13 healthy non-dependent age-matched males using the DRD3-preferring agonist positron emission tomography (PET) radioligand [ 11 C]PHNO with and without blockade with a selective DRD3 antagonist (GSK598809 60 mg p.o.). In striatal regions of interest, where the [ 11 C]PHNO PET signal represents primarily DRD2 binding, no differences were seen in [ 11 C]PHNO binding between the groups at baseline. However, baseline [ 11 C]PHNO binding was higher in alcohol-dependent patients in hypothalamus (V T : 16.5±4 vs 13.7±2.9, p ¼ 0.040), a region in which the [ 11 C]PHNO signal almost entirely reflects DRD3 availability. The reductions in regional receptor binding (V T ) following a single oral dose of GSK598809 (60 mg) were consistent with those observed in previous studies across all regions. There were no differences in regional changes in V T following DRD3 blockade between the two groups, indicating that the regional fractions of DRD3 are similar in the two groups, and the increased [ 11 C]PHNO binding in the hypothalamus in alcohol-dependent patients is explained by elevated DRD3 in this group. Although we found no difference between alcohol-dependent patients and controls in striatal DRD3 levels, increased DRD3 binding in the hypothalamus of alcohol-dependent patients was observed. This may be relevant to the development of future therapeutic strategies to treat alcohol abuse.

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The human dopamine D2Longer receptor has a high-affinity state and inhibits adenylyl cyclase

Cited by 31 publications

References 16 publications

Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics

Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics

NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D2 and serotonin 5-HT2 receptors—implications for models of schizophrenia

In Vivo Imaging of Cerebral Dopamine D3 Receptors in Alcoholism

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