Chronic haloperidol affects striatal D2-dopamine receptor reappearance after irreversible receptor blockade

Pich, Emilio Merlo; Benfenati, Fabio; Farabegoli, C.; Fuxé, Kjell; Meller, Emanuel; Aronsson, M.; Goldstein, Menek; Agnati, Luigi F.

doi:10.1016/0006-8993(87)91595-2

Cited by 45 publications

(8 citation statements)

References 19 publications

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“…The protein-modifying reagent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) has been used to antagonize a number of CNS receptors, including cholinergic , dopaminergic (Meller et al, 1985;Hess et al, 1987Hess et al, , 1988Pich et al, 1987;Saller et al, 1989), adrenergic (Neve and Moli-no& 1986;Pilc et al, 1989), and serotonergic receptors (Battaglia et al, 1986. It is likely that this compound has irreversible effects, because reductions in receptor density are observed after extensive washing to remove EEDQ.…”

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confidence: 99%

Modification of γ‐Aminobutyric Acid_A Receptor Binding and Function by N‐Ethoxycarbonyl‐2‐Ethoxy‐1,2‐Dihydroquinoline In Vitro and In Vivo: Effects of Aging

Miller

Lumpkin

Galpern

et al. 1991

Journal of Neurochemistry

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The irreversible protein-modifying reagent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was used to investigate binding site characteristics on the gamma-aminobutyric acidA (GABAA) receptor complex. In vitro, preincubation with EEDQ led to a concentration-dependent decrease in receptor number for benzodiazepine, t-butylbicyclophosphorothionate (TBPS), and GABA binding sites in cerebral cortex. The effect was maximal at the highest concentration of EEDQ used (10(-4) M) and was greatest for the benzodiazepine site. Pretreatment of membranes with the benzodiazepine antagonist Ro 15-1788, 1 or 10 microM, or the agonist lorazepam, 10 microM, largely prevented the effects of EEDQ. Scatchard analysis indicated no effect of EEDQ, 10(-4) M, on apparent affinity, but a decrease in receptor density for each site. Administration of EEDQ to mice, 12.5 mg/kg i.p., led to a substantial (55-65%) decrease in number of benzodiazepine binding sites in cortex after 4 h. Slightly smaller changes were observed for TBPS and GABA binding. No changes were observed in apparent affinity at any site. Prior administration of Ro 15-1788, 5 mg/kg, prevented the effect of EEDQ on benzodiazepine binding. Density of benzodiazepine binding sites gradually recovered over time, and receptor density returned to control values by 96 h after EEDQ injection. Number of binding sites in cortex for TBPS and GABA also increased over time after EEDQ. Benzodiazepine sites in cerebellum were decreased proportionally to cortex after EEDQ, and increased over a similar time course. Function of the GABAA receptor in chloride uptake in cortex was markedly reduced (65%) by EEDQ.(ABSTRACT TRUNCATED AT 250 WORDS)

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confidence: 99%

Modification of γ‐Aminobutyric Acid_A Receptor Binding and Function by N‐Ethoxycarbonyl‐2‐Ethoxy‐1,2‐Dihydroquinoline In Vitro and In Vivo: Effects of Aging

Miller

Lumpkin

Galpern

et al. 1991

Journal of Neurochemistry

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“…An increase in D2 receptor biosynthesis, as indirectly revealed by measurement of the rate of recovery of [3H]spiperone binding following inactivation by EEDQ, was suggested to occur in reserpine-treated rats (Norman et al, 1987). However, Pich et al (1987) found that after irreversible blockade of D2 receptors by EEDQ, chronic treatment by haloperidol decreased the receptor degradation. Alternatively, the larger increase in content of striatal D2 receptor mRNA, as compared with D2 receptor number measured with radioligands, might be attributable to the fact that radioligands could have labeled other dopamine receptor subtypes or D2 receptors synthesized by neurons extrinsic to the striatum.…”

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confidence: 99%

Effects of Dopaminergic Transmission Interruption on the D₂ Receptor Isoforms in Various Cerebral Tissues

Martres

Sokoloff

Giros

et al. 1992

Journal of Neurochemistry

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We examined the effects of an interruption of dopamine neurotransmission, by either dopamine receptor blockade or degeneration of dopamine neurons by 6-hydroxydopamine, on the levels of D2 receptor mRNAs. In addition, we evaluated by the polymerase chain reaction (PCR) the relative abundance of the two D2 receptor isoform mRNAs generated by alternative splicing. Daily injections of 4 mg/kg of haloperidol to rats elicited in striatum a rapid and progressive increase in D2 receptor mRNA levels, which reached 70% after a 15-day treatment. By contrast, there was no apparent change in D2 receptor mRNA levels in cerebral cortex and pons-medulla, in spite of an increased density of D2 receptor in the former tissue. Using the PCR with primers flanking the alternative exon, we observed that the relative proportion of the shorter receptor isoform (D2S) mRNA was slightly but significantly enhanced in cerebral cortex (17%) and pons-medulla (18%) after a 15-day haloperidol treatment. Unilateral degeneration of dopamine neurons induced by local injection of 6-hydroxydopamine resulted in a marked decrease in levels of total D2 receptor mRNAs in substantia nigra (-79%) and ventral tegmental (-63%) area, two cell body areas. In the substantia nigra, the longer isoform (D2L) mRNA was significantly more decreased in content than the D2S isoform mRNA, so that there was a large enhancement in the relative abundance of the latter (81%).(ABSTRACT TRUNCATED AT 250 WORDS)

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“…This is a standard in all previous studies and is observed to make sure that the challenge drug, haloperidol in this study, has exited the system and is not directly competing with the ex vivo ligand. Since the receptors have been shown to recover with a half-rate of 95 hours (Pich et al 1987), 24 h may lead to recovery of about 10-20% of the receptors. While this recovery may lead to an error in occupancy determination, the direction of this error will lead to a false assumption of greater protection/occupancy with the EEDQ method.…”

Section: Discussionmentioning

confidence: 99%

Dopamine D2 Receptor Blockade by Haloperidol 3H-Raclopride Reveals Much Higher Occupancy than EEDQ

Kapur

Barsoum

Seeman

2000

Neuropsychopharmacology

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Chronic haloperidol affects striatal D2-dopamine receptor reappearance after irreversible receptor blockade

Cited by 45 publications

References 19 publications

Modification of γ‐Aminobutyric Acid_A Receptor Binding and Function by N‐Ethoxycarbonyl‐2‐Ethoxy‐1,2‐Dihydroquinoline In Vitro and In Vivo: Effects of Aging

Modification of γ‐Aminobutyric Acid_A Receptor Binding and Function by N‐Ethoxycarbonyl‐2‐Ethoxy‐1,2‐Dihydroquinoline In Vitro and In Vivo: Effects of Aging

Effects of Dopaminergic Transmission Interruption on the D₂ Receptor Isoforms in Various Cerebral Tissues

Dopamine D2 Receptor Blockade by Haloperidol 3H-Raclopride Reveals Much Higher Occupancy than EEDQ

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Chronic haloperidol affects striatal D2-dopamine receptor reappearance after irreversible receptor blockade

Cited by 45 publications

References 19 publications

Modification of γ‐Aminobutyric AcidA Receptor Binding and Function by N‐Ethoxycarbonyl‐2‐Ethoxy‐1,2‐Dihydroquinoline In Vitro and In Vivo: Effects of Aging

Modification of γ‐Aminobutyric AcidA Receptor Binding and Function by N‐Ethoxycarbonyl‐2‐Ethoxy‐1,2‐Dihydroquinoline In Vitro and In Vivo: Effects of Aging

Effects of Dopaminergic Transmission Interruption on the D2 Receptor Isoforms in Various Cerebral Tissues

Dopamine D2 Receptor Blockade by Haloperidol 3H-Raclopride Reveals Much Higher Occupancy than EEDQ

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Modification of γ‐Aminobutyric Acid_A Receptor Binding and Function by N‐Ethoxycarbonyl‐2‐Ethoxy‐1,2‐Dihydroquinoline In Vitro and In Vivo: Effects of Aging

Modification of γ‐Aminobutyric Acid_A Receptor Binding and Function by N‐Ethoxycarbonyl‐2‐Ethoxy‐1,2‐Dihydroquinoline In Vitro and In Vivo: Effects of Aging

Effects of Dopaminergic Transmission Interruption on the D₂ Receptor Isoforms in Various Cerebral Tissues