Homovanillic acid in caudate and pre-frontal cortex following neuroleptics

Homovanillic acid (HVA) was measured in rat caudate and pre-frontal cortex 3 h following a single dose of a variety of neuroleptics. Thioridazine, haloperidol, fluphenazine, and metoclopramide increased HVA levels in caudate more than in pre-frontal cortex; whereas sulpiride and clozapine produced greater increases in HVA in pre-frontal cortex. These results are consistent with the proposal that rat pre-frontal cortex is relatively deficient in dopamine autoreceptors.     

Homovanillic acid in caudate and pre-frontal cortex following acute and chronic neuroleptic administration

Homovanillic acid (HVA) was measured in rat caudate and pre-frontal cortex after single and repeated doses of several types of neuroleptic drugs. Twice daily administration of low or high doses of haloperidol, fluphenazine, or (-) sulpiride resulted in greater tolerance to the initial HVA increase in caudate compared to prefrontal cortex.     

Brain homovanillic acid: regional changes over time with antipsychotic drugs.

Acute administration of equivalent doses of either chlorpromazine, thioridazine, or clozapine, respectively, produced progressively smaller increases in brain homovanillic acid (HVA) in the rabbit; however, changes in HVA in three brain regions were of equal magnitude for a single dose of a given drug. Chronic administration of fluphenazine enanthate resulted in a decrease in HVA relative to acute treatment in caudate more than limbic regions. No differences between caudate and limbic regions were observed during daily chlorpromazine administration for 3 ro 8 days. Tolerance appeared to develop in approximately 1 week. Chronic treatment with clozapine produced no tolerance at one week but suggestive evidence of tolerance in caudate and limbic regions at two weeks. No tolerance was observed in the hypothalamus during chronic treatment with any drug used. Cisternal CSF HVA paralleled caudate HVA during acute and chronic treatments.     

Tolerance to the increase of striatal homovanillic acid elicited by several anorectic drugs

Several anoretic drugs affect dopamine metabolism in the rat striatum, increasing the concentration of homovanillic acid (HVA). However l- and d-amphetamine and mazindol develop a tolerance to increase. On the contrary, the effect of fenfluramine and S 992 is not reduced by sub-chronic treatments. Moreover, a cross-tolerance to this biochemical effect develops between amphetamine and mazindol, but pretreatment with fenfluramine or with S 992 does not induced cross-tolerance to amphetamine.     

Induction of Fos protein by antipsychotic drugs in rat brain following kainic acid-induced limbic-cortical neuronal loss

Antipsychotic drugs increase expression of the immediate early gene, c-fos, in the striatum, nucleus accumbens and prefrontal cortex of rat brain. Since intracerebro-ventricular (ICV) infusion of kainic acid (KA) produces loss of limbic-cortical neurons that project to these brain areas, we postulated that the c-fos responses to antipsychotics in these brain areas would be altered following ICV KA administration. To produce limbic-cortical lesions, rats received ICV infusions of either KA (4.5 nmol) or vehicle. Then, 25–28 days later, rats received 0.13, 0.35, or 1.5 mg/kg haloperidol, 6.3, 17.5, or 30.0 mg/kg clozapine, or saline. In both KA-lesioned and control animals, haloperidol produced greater increases in Fos protein immunoreactivity in the striatum than in limbic-cortical areas, while clozapine produced greater increases in Fos protein immunoreactivity in limbic-cortical areas than in the striatum. In both KA-lesioned and control animals, haloperidol and clozapine administration also produced similar dose-dependent increases in Fos protein immunoreactivity in the striatum and nucleus accumbens. However, the ability of clozapine to increase Fos protein immunoreactivity in the infralimbic prefrontal cortex was significantly enhanced in KA-lesioned rats compared to controls. Since limbic-cortical pathology has been implicated in the negative symptoms of schizophrenia, the enhanced effect of clozapine on limbic-cortical expression of c-fos in KA-lesioned rats may be relevant to understanding clozapine’s unusual therapeutic actions in patients with schizophrenia. Received: 27 May 1997/Final version: 18 November 1997     

Effect of antipsychotic drugs on homovanillic acid levels in striatum and olfactory turbercle of the rat

Dose-response curves for the elevation of homovanillic acid levels in corpus striatum and olfactory tubercle of rats were determined by mass fragmentography after treatment with antipsychotic drugs. The order of potency in both regions was: haloperidol > chlorpromazine > thioridazine and clozapine. The relative elevation of the content of homovanillic acid was significantly greater in the striatum than in the olfactory tubercle for all drugs except thioridazine. The antipsychotic effect of the drugs tested may be related to the interference with dopaminergic mechanisms in striatal and/or limbic areas.     

Homovanillic acid in rat caudate and prefrontal cortex following phencyclidine and amphetamine

Phencyclidine (PCP) and d-amphetamine (AMP) had different effects upon homovanillic acid (HVA) levels in rat prefrontal cortex as compared to caudate. Lower doses of PCP increased HVA in prefrontal cortex only while lower doses of AMP decreased HVA in caudate alone. Higher doses of both drugs produced a decreased HVA in caudate and an increase in prefrontal cortex. At some doses PCP may selectively activate mesocortical dopaminergic neurons.     

精神分裂症患者血浆高香草酸浓度与临床症状、性别和药物治疗的关系

目的：通过分析精神分裂症患者中枢多巴胺代谢产物－血浆高香草酸浓度（ｐＨＶＡ）与临床指征的关系,进一步探讨多巴胺神经递质及其药物治疗在精神分裂症的作用。方法在４６例长期药物治疗、５８例未治疗精神分裂症患者中,采用高液相色谱连接电化学分析仪测定ＰＨＶＡ;测前评定阳性症状量表（ＳＡＰＳ）和阴性症状量表（ＳＡＮＳ）。结果（１）与６２例健康对照组比,治疗组ＰＨ－ＶＡ显著减低,未治疗组显著增高,以阴性症状组为     

Correlation between antiavoidance activities of antipsychotic drugs in rats and daily clinical doses

Effects of oral antipsychotic drugs, 12 phenothiazines, 3 thioxanthenes, 5 butyrophenones and 8 other derivatives on Sidman and discriminated avoidance responses in rats were investigated and compared to their clinical doses routinely used PO. Almost all drugs except sulpiride and clozapine suppressed the avoidance responses with a dose-dependent decrease in the response rate (lever-pressing) and increase in the shock rate in the Sidman avoidance performance or a decrease in both the response and avoidance rates in the discriminated one. Sulpiride (80-640 mg/kg) produced no marked change in the avoidance responses. Clozapine (2.5-10 mg/kg) increased the shock rate or decreased the avoidance rate without eliciting any change in the response rate. The avoidance-suppressing activities of the antipsychotic drugs were well correlated with their clinical daily doses. However, the avoidance-suppressing effects of carpipramine, clocapramine, thiothixene and sulpiride were relatively less potent, while that of clotiapine was more potent than in the clinical activities. The potencies of the avoidance-suppressing effects of each drug on the Sidman and the discriminated avoidance responses were almost identical except for triflupromazine, pimozide, thioridazine, spiclomazine and propericiazine. The former two drugs suppressed the Sidman avoidance response more than the discriminated avoidance response. However, the latter three drugs suppressed the discriminated avoidance response more markedly than the Sidman avoidance response. The present results suggest that the avoidance response in rats is applicable in evaluating the clinical efficacies of antipsychotic drugs.     

Regional rat brain levels of 3,4-dihydroxyphenylacetic acid and homovanillic acid: concurrent fluorometric measurement and influence of drugs

A concurrent semi-automatic fluorometric assay technique for 3, 4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), is described. The method is based on a rapid manually performed isolation of DOPAC and HVA on small columns of Sephadex G-10 followed by an automated fluorometric detection with a continuous flow system. DOPAC and HVA were measured in the corpus striatum, nucleus accumbens and olfactory tubercle of the rat, under normal conditions and after treatment with amphetamine, apomorphine, clozapine, haloperidol, morphine, oxotremorine, pargyline, probenecid, sulpiride and thioridazine. Clozapine, morphine, sulpiride and oxotremorine induced the most pronounced rise of DA metabolites in the nucleus accumbens. Probenecid produced a DOPAC accumulation in the nucleus accumbens. Striking differences were observed between the DOPAC/HVA ratios in the different structures of control animals. The concurrent assay enables a rapid screening of the action of drugs in regional DA metabolism.     

Regional homovanillic acid levels and oral movements in rats following chronic haloperidol treatment

Rats with more severe orofacial movements after 51 days of haloperidol administration showed lower levels of the dopamine metabolite homovanillic acid (HVA) in the caudate compared to animals who did not develop significant mouth movements. This effect was not observed in other brain regions sampled. This finding is consistent with the hypothesis that dopaminergic receptor supersensitivity in neostriatal structures plays some role in the development of orofacial movements in rats, in association with chronic neuroleptic administration.     

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

The effect of various antipsychotic drugs on the blockade of dopaminergic receptors in striatum and limbic forebrain was examined by establishing dose-response curves for the increase in HVA and for the antagonism of d-amphetamine-induced rotation in rats with unilateral lesions of the substantia nigra. A good quantitative correlation was found between dopaminergic blockade in the striatum as reflected by the ED₁₀₀ for striatal HVA increase and the ED₅₀ for rotational antagonism and the occurrence of extrapyramidal side effects in man. The ED₁₀₀ for the increase in HVA in the limbic forebrain showed the same rank order of potency as those in the striatum: Haloperidol > pimozide > chlorpromazine > thioridazine > clozapine. The results thus demonstrate a very good correlation between the degree of dopaminergic blockade and the increase of extrapyramidal side effects in man, but suggest the possibility of a dissociation between dopaminergic blockade and antipsychotic activity.     

Influence of drugs on striatal and limbic homovanillic acid concentration in the rat brain.

Homovanillic acid (HVA) was measured in the corpus striatum aan the limbic structures nucleus accumbens and olfactory tubercle of the rat, under normal conditions and after different drug treatments. Clozapine, thioridazine, morphine and physostigmine induced a similar percentage HVA increase in the three brain structures studied. Haloperidol and pimozide induced a higher percentage increase of HVA in the corpus striatum and nucleus accumbens when compared with the olfactory tubercle. Oxotremorine induced the highest HVA levels in the nucleus accumbens. Probenecid induced a significantly higher percentage accumulation of HVA in the limbic structures, especially in the olfactory tubercle. The HVA rise seen after haloperidol was suppressed by pretreatment with p-chlorophenylalanine or amino-oxyacetic acid in all structures studied. After atropine or trihexylphenidyl treatment the HVA rise induced by haloperidol was slightly suppressed in the limbic structures only. Our results suggest that not only under normal conditions but also after treatment with various types of drugs, dopamine metabolism as reflected by the HVA levels, is closely related in the different rat brain structures.     

Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding

Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). An ex vivo autoradiography technique was applied to determine the receptor occupancy by the drugs administered in vivo. Of particular interest are the central 5HT_2A receptors and D₂-type receptors. Predominant 5HT_2A receptor antagonism is supposed to add to an atypical profile of the antipsychotics (treatment of the negative symptoms, low incidence of extrapyramidal side effects). D₂ antagonism is required for the treatment of positive symptoms. A contribution of the new dopamine receptor subtypes D₃ and in particular D₄ receptors has been proposed.In vitro, all compounds, except the typical antipsychotics haloperidol and fluspirilene, showed higher affinity for 5HT_2A than for D₂ receptors. Subnanomolar affinity for human 5HT_2A receptors was observed for ORG-5222, sertindole, resperidone, 9-OH-risperidone and ziprasidone. Fluspirilene, ORG-5222, haloperidol, ziprasidone, risperidone, 9-OH-risperidone and zotepine displayed nanomolar affinity for human D₂ receptors. Sertindole and olanzapine were slightly less potent. Pipamperone, clozapine and seroquel showed 2 orders of magnitude lower D₂ affinity in vitro. Clozapine, but even more so pipamperone, displayed higher affinity for D₄ than for D₂ receptors. For most other compounds, D₄ affinity was only slightly lower than their D₂ affinity. Seroquel was totally devoid of D₄ affinity. None of the compounds had nanomolar affinity for D₁ receptors; their affinity for D₃ receptors was usually slightly lower than for D₂ receptors.In vivo, ORG-5222, risperidone, pipamperone, 9-OH-risperidone, sertindole, olanzapine, zotepine and clozapine maintained a higher potency for occupying 5HT_2A than D₂ receptors. Risperidone and ORG-5222 had 5HT_2A versus D₂ potency ratio of about 20. Highest potency for 5HT_2A receptor occupancy was observed for ORG-5222 followed by risperidone and olanzapine. Ziprasidone exclusively occupied 5HT_2A receptors. ORG-5222, haloperidol, fluspirilene and olanzapine showed the highest potency for occupying D₂ receptors. No regional selectivity for D₂ receptor occupancy in mesolimbic versus nigrostriatal areas was detected for any of the test compounds. Risperidone was conspicuous because of its more gradual occupancy of D₂ receptors; none of the other compounds showed this property. The various compounds also displayed high to moderate occupancy of adrenergic ₁ receptors, except fluspirilene and ziprasidone. Clozapine, zotepine, ORG-5222 and sertindole occupied even more ₁ than D₂ receptors. Clozapine showed predominant occupancy of H₁ receptors and occupied cholinergic receptors with equivalent potency to D₂ receptors. A stronger predominance of 5HT_2A versus D₂ receptor occupancy combined with a more gradual occupancy of D₂ receptors differentiates risperidone and its 9-OH-metabolite from the other antipsychotic compounds in this study. The predominant 5HT_2A receptor occupancy probably plays a role in the beneficial action of risperidone on the negative symptoms of schizophrenia, whereas maintenance of a moderate occupancy of D₂ receptors seems adequate for treating the positive symptoms of schizophrenia. A combined 5HT_2A and D₂ occupancy and the avoidance of D₂ receptor overblockade are believed to reduce the risk for extrapyramidal symptoms.     

住院老年精神病患者用药调查与分析

目的了解本院住院老年精神病患者的药物使用情况及药物不良反应。方法采用一日调查法对本院住院老年精神病患者的用药进行调查。结果在参与调查的198例患者中,其中单一用药103例,两药联用68例。在老年精神病患者用药后监测的不良反应中,有110例（55．56％）患者发生不良反应。结论老年精神病患者抗精神病治疗以单一用药为主。     

Effect of piribedil and one of its metabolites on the concentration of homovanillic acid in the rat brain

Piribedil and its metabolite (pyrimidyl-2′)-1-(dihydroxy-3′,4′-benzyl)-4-piperazine dichlorhydrate (PdHBP), like apomorphine, decrease the level of HVa in the rat striatum. The effect appears rapidly and it lasts for about 2 hr. Piribedil antagonizes the rise of striatal HVA elicited by chlorpromazine, haloperidol and fenfluramine. Piribedil, PdHBP and apomorphine did not counteract the increase of striatal HVA induced by d-amphetamine.     

Effects of indomethacin on plasma homovanillic acid concentration in normal subjects: a study of prostaglandin-dopamine interactions

In laboratory animals, prostaglandins have been shown to act as endogenous neuromodulators of central dopamine (DA) activity. To examine the interaction between prostaglandins and DA in man, the effect of a prostaglandin synthesis inhibitor, indomethacin, was studied on plasma concentrations of the DA metabolite, homovanillic acid (pHVA). Indomethacin (150 mg PO) as compared to placebo significantly elevated mean pHVA concentrations in eight normal subjects. Results of this study support the hypothesis that, as in animals, inhibition of prostaglandin synthesis increases central DA turnover in man.     

5-Hydroxyindole acetic acid and homovanillic acid in cerebrospinal fluid in manic-depressive psychosis and the effect of probenecid treatment

Summary The increased concentrations of 5-hydroxyindole acetic acid and homovanillic acid produced in cerebrospinal fluid by probenecid has been investigated in 15 manic-depressive patients and 21 psychiatric control patients, and has been related to the concentrations of probenecid in the CSF. The pharmacokinetics of probenecid were the same in the manic-depressive patients and the controls, as judged by its concentrations in plasma (bound and free) and CSF after a standard oral dose p.o., and by measurements of half-life and volume of distribution after intravenous injection. — The manic-depressive patients had lower concentrations of 5-HIAA and HVA than controls at similar CSF concentrations of probenecid; this was concluded from results with pairs of patients matched with regard to probenecid in CSF, and from differences between the patients and controls in the slopes of the regression lines for probenecid in CSF against 5-HIAA/HVA. The differences in 5-HIAA/HVA between the diagnostic groups were greater with increasing concentrations of probenecid in CSF; and, with concentrations of probenecid in CSF>1.0 µg/ml, by using the 5HIAA concentrations it was possible to classify the patients correctly into their diagnostic groups in 92% of cases.     

Intracranial self-stimulation in orbitofrontal cortex and caudate nucleus of rhesus monkey: Effects of apomorphine,pimozide, and spiroperidol

Rhesus monkeys were prepared with stimulating electrodes implanted into the orbitofrontal cortex and head of the caudate nucleus under stereotaxic control. These regions of the brain contain high levels of dopamine, and intracranial self-stimulation was readily elicited from these loci in all animals tested using licking behavior as the operant response. Self-stimulation at both sites was significantly attenuated following peripheral injections of the dopamine receptor blocker spiroperidol (0.02 mg/kg). Similarly, pimozide (0.15 and 0.20 mg/kg) significantly reduced self-stimulation in the orbitofrontal cortex, but the suppression observed at caudate placements did not reach statistical signifcance. Licking for a reward of blackcurrant juice was unaffected by either drug. Apomorphine (0.2, 0.4 mg/kg) had a differential effect on self-stimulation. This drug significantly attenuated self-stimulation in the orbitofrontal cortex, while the same treatment tended to facilitate self-stimulation in the caudate. Apomorphine did not significantly affect responding for the fruit juice reward. The parallels between the effects of dopamine agonists and antagonists on self-stimulation in the monkey and rat suggest that dopamine influences self-stimulation of some sites in both the primate and the rat.