On the significance of the increase in homovanillic acid (HVA) caused by antipsychotic drugs in corpus striatum and limbic forebrain

Stawarz, Robert J.; Hill, Harlan F.; Robinson, Susan E.; Setler, Paulette E.; Dingell, James V.; Sulser, Fridolin

doi:10.1007/bf00421014

Cited by 72 publications

(12 citation statements)

References 18 publications

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“…This is consistent with the results of in vitro binding studies, showing that the affinity of neuroleptics, including clozapine and haloperidol, for D2 receptors of different brain areas is nearly identical (Burt et al 1976;Seeman and Ulpian 1983). Furthermore, the orignial observation that clozapine exerts a stronger effect on the limbic DA system than on the striatal DA system (Anden and Stock 1973;Bartholini 1976) could not be confirmed in other studies (Stawarz et al 1975;Westerink and Korf 1975;Waldmeier and Maitre 1976;Wilk et al 1975). …”

Section: Discussionsupporting

confidence: 76%

Effects of fluperlapine on dopaminergic systems in rat brain

Bürki¹

1986

Psychopharmacology

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Fluperlapine has been reported to possess antischizophrenic and antidepressant properties, with low incidence of extrapyramidal side-effects. In order to get more information about the interactions of fluperlapine with rat brain dopaminergic systems, its binding to striatal D2 receptors, measured ex vivo, and its effects on DA metabolism in different brain areas were investigated. Clozapine and haloperidol served as reference compounds in these investigations. It was found that all three agents blocked D2 receptors and increased DA metabolism. Clozapine and fluperlapine differed from haloperidol in that their potency was much lower. Although occupation of striatal D2 receptors by the two dibenzo-epines developed rapidly, the duration was considerably shorter than that of haloperidol. There was no indication that the two dibenzo-epines had a stronger or longer-lasting effect on limbic or cortical DA metabolism compared to that on the striatum. Both drugs caused a weak increase in striatal DA, whereas haloperidol decreased it. It was concluded that the low incidence of extrapyramidal side-effects of fluperlapine, and also of clozapine, is probably due to their weak and relatively brief action on brain DA systems and not due to a selective action on A10 neurotransmission. The anticholinergic properties of the dibenzo-epines might even further reduce the consequences of their already weak effects on DA systems.

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Section: Discussionsupporting

confidence: 76%

Effects of fluperlapine on dopaminergic systems in rat brain

Bürki¹

1986

Psychopharmacology

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“…The in hibitory potencies of short-acting neuroleptics in ex vivo 3H-spiroperidol binding correlated well with their reported clinical antipsychotic efficacy and also with their increasing potencies of homovanillic acid in the striatum (4). Among the neuroleptics tested, however, haloperidol showed a weak inhibitory effect on ex vivo 3H-spiroperidol binding in com parison with its clinical potency or its in vivo pharmacological activity.…”

Section: Discussionsupporting

confidence: 55%

Ex vivo 3H-spiroperidol binding to rat striatum and the inhibitory effects of neuroleptics.

Nakajima¹,

Egawa²,

Kuruma³

1981

Jpn.J.Pharmacol

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Abstract-Neuroleptic drugs were given to rats and at different time intervals the animals were decapitated and 3H-spiroperidol binding to the striatal homogenates was determined in vitro. Two hours after an intraperitoneal administration of spiroperidol, perphenazine, haloperidol, chlorpromazine or thioridazine in doses of 0.03-30 mg/kg, 3H-spiroperidol binding to the striatal homogenates was inhibited dose-dependently with an ID50 value of 0.11, 0.23, 1.1, 3.7 or 9.4 mg/kg, respectively. After a single intra muscular administration of fluphenazine enanthate (10 mg/kg), a long acting neuroleptic drug, long-lasting inhibitory effect (over 4 weeks) on the binding was also observed. These results indicate that ex vivo 3H spiroperidol binding method may be useful to measure the duration and the potency of anti-dopaminergic activities of drugs. receptors, and phar macokinetic characteristics can be elucidated. The present study was carried out to demon strate the validity of the ex vivo 3H spiroperidol binding method. MATERIALS AND METHODS Pilot experimentsto select the tissue preparation and the optimun ligand concen tration for ex vivo study: Male Sprague Dawley rats (180-250 g) were given saline or 3 mg/kg chlorpromazine (CPZ i.p.). Two hr later, the rats were decapitated and the striata homogenized in 35 volumes of ice-cold water. Aliquots (3 ml) of the striatal homogenates were further centrifuged at 20,000xg for 20 min at 40, and the pellets resuspended in 3 ml of ice-cold water. To assess the degree of CPZ incorporation among these fractions, striatal homogenates (0.5 ml, obtained from rat treated with CPZ), membrane fraction (0.5 ml, CPZ) or supernatant fraction (0.5 ml, CPZ) plus membrane fraction (0.5 ml, control) were incubated for 15 min at 370 with 62.5 pM 3H-spiroperidol , according to the method of Fields et al. (2) with slight modification. In the kinetic study, high affinity 3H spiroperidol binding to striatal homogenates was determined at five different ligand concentrations -0.031, 0.0625, 0.125, 0.25 and 0.5 nM. The incubation mixture (in triplicate) with a total volume of 10 ml

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“…For example, it is known that neuroleptic drugs inhibit dopamine-sensitive adenylate cyclase (5-7), increase the firing rate of dopamine neurons (8), decrease the stimulated release of dopamine from dopaminergic neurons (9), accelerate the turnover of dopamine (10,11), and block the effects of such dopamine-mimetic drugs as amphetamine and apomorphine (11,12). The potency of the drugs in these tests is not correlated 1:1 with their potencies in controlling schizophrenia (13,5). For example, haloperidol and spiroperidol are 20-100 times more potent clinically than chlorpromazine, yet they are equal to or weaker than chlorpromazine in blocking the dopamine-sensitive adenylate cyclase (5-7).…”

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confidence: 99%