Dopamine displaces [3H]domperidone from high‐affinity sites of the dopamine D2 receptor, but not [3H]raclopride or [3H]spiperone in isotonic medium: Implications for human positron emission tomography

Seeman, Philip; Tallerico, Teresa; Ko, Françoise

doi:10.1002/syn.10232

Cited by 123 publications

(100 citation statements)

References 36 publications

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“…13,17,20 In addition, because receptor agonists accelerate the exchange of receptor-bound GDP for GTP, the stimulation of [ 35 S]GTP-g-S incorporation is a useful index of agonist action. Phencyclidine and ketamine also increased the incorporation of [ 35 S]GTP-g-S into cloned D2-containing cells 8 (Figure 2).…”

Section: Discussionmentioning

confidence: 99%

“…[ 17 Although early experiments did not reveal the D1-D2 link in any rat striatum or in every human striatum, 11 recent work, using a competition method, has consistently revealed the D1-D2 link in rat and human striata. 10 This recent work showed that the block of D1 receptors unveiled the presence of a highaffinity state for D2 in a dopamine/[ 3 H]raclopride competition-type experiment, with a dopamine dissociation constant of 1.5 nM.…”

Section: Discussionmentioning

confidence: 99%

“…8 17 Therefore, using the more readily displaceable [ 3 H]domperidone, phencyclidine had a dissociation constant at D2 High of 2.770.8 nM (n ¼ 9) (Figure 1, top) for the human cloned D2 receptor and 4.370.8 nM for the rat striatal tissue (Figure 1, middle). These K i values were essentially unchanged when phencyclidine was tested in the presence of 100 nM SCH23390 to occlude other receptors such as dopamine D1 receptors and serotonin-2 receptors that may interact with the D2 receptor.…”

Section: Methodsmentioning

confidence: 99%

“…[ 3 H]Domperidone, however, is a selective ligand for D2 that readily detects D2 High receptors without the addition of SCH23390. 17 Therefore, in order to obtain the potencies of phencyclidine, ketamine, dizocilpine and LSD at the functional D2 High receptor, the present study used [ 3 H]domperidone to label D2 receptors. The results indicate that the potencies of the psychotomimetics were greater at D2 High than at the NMDA receptor.…”

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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: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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

2005

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“…Because the Kd of [ 3 H]domperidone is 0.47 nM at D2 receptors in rat striatum, the final concentration of 2 nM occupied 81% of the D2 receptors, using the equation f = C/(C + Kd), where f is the fraction of receptors occupied by [ 3 H]domperidone, and C is 2 nM (Seeman, et al, 2003).…”

Section: Tissue Collectionmentioning

confidence: 99%

Cocaine self-administration produces a persistent increase in dopamine D2High receptors

Briand

Flagel

Seeman

et al. 2008

European Neuropsychopharmacology

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Cocaine addicts are reported to have decreased numbers of striatal dopamine D2 receptors. However, in rodents, repeated cocaine administration consistently produces hypersensitivity to the psychomotor activating effects of both indirect dopamine agonists, such as cocaine itself, and importantly, to direct-acting D2 receptor agonists. The current study reports a possible resolution to this long-standing paradox. The dopamine D2 receptor exists in both a low and a high affinity state, and dopamine exerts its effects via the more functionally relevant high-affinity D2 receptor (D2 High ). We report here that cocaine self-administration experience produces a large (approximately 150%) increase in the proportion of D2 High receptors in the striatum with no change in the total number of D2 receptors, and this effect is evident both 3 and 30 days after the discontinuation of cocaine self-administration. Changes in D2 High receptors would not be evident with the probes used in human (and non-human primate) imaging studies. We suggest, therefore, that cocaine addicts and animals previously treated with cocaine may be hyper-responsive to dopaminergic drugs in part because an increase in D2 High receptors results in dopamine supersensitivity. This may also help explain why stimuli that increase dopamine neurotransmission, including drugs themselves, are so effective in producing relapse in individuals with a history of exposure to cocaine.

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Addictive Processes

Torregrossa¹,

Halligan²

2009

Handbook of Neuroscience for the Behavioral Sciences

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Dopamine displaces [³H]domperidone from high‐affinity sites of the dopamine D2 receptor, but not [³H]raclopride or [³H]spiperone in isotonic medium: Implications for human positron emission tomography

Cited by 123 publications

References 36 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

Cocaine self-administration produces a persistent increase in dopamine D2High receptors

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