Effects of sulpiride and oxypertine on the dopaminergic system in the rat striatum.

We have examined the effects of sulpiride, oxypertine and haloperidol on the behavioral and biochemical dopamine receptor function in the rat striatum. Although acute treatment with haloperidol or oxypertine induced catalepsy, tolerance to catalepsy developed following chronic treatment with haloperidol but not with oxypertine. Rats treated with acute or chronic sulpiride did not show signs of catalepsy. Intracerebroventricular administration of sulpiride, however, induced catalepsy and tolerance developed after chronic treatment. After chronic treatment with either of these three drugs, dopamine D2 receptors were up-regulated in the striatum. While acute administration of haloperidol, sulpiride or oxypertine increased the concentration of homovanillic acid in the striatum, the rate of increases was attenuated following chronic treatment with haloperidol or sulpiride, but not with oxypertine. While acute administration of sulpiride or oxypertine decreased dopamine, the decrease was attenuated following repeated administration of sulpiride but not of oxypertine. These results suggest that the unique pharmacological profile of oxypertine may be related to its therapeutic effect of activating apathetic patients, and that both sulpiride and oxypertine may cause tardive dyskinesia, as haloperidol does.     

Enhancement of dopamine metabolism in rat brain frontal cortex: a common effect of chronically administered antipsychotic drugs

Administration of 4 antipsychotic drugs, haloperidol, chlorpromazine, thioridazine and clozapine, for 21 days elicited increased dopamine metabolism in frontal cortex of rat brain. Only clozapine failed to decrease the apparent firing rate of dopamine neurons in the striatum, as indexed by [homovanillic acid]/[dopamine]. These data support the hypotheses that frontal cortex dopamine neurons may be a common site for antipsychotic action while decreased release of dopamine in the striatum may be associated with the development of extrapyramidal side effects.     

Effects of intraplantar injection of carrageenan on central dopamine release

The present study examined the changes of extracellular concentration of dopamine and its metabolite homovanillic acid in the striatum, the periaqueductal gray and the dorsal horn of lumbar spinal cord following intraplantar injection of carrageenan. In vivo microdialysis and high-performance liquid chromatography with electrochemical detection were performed. The results showed that intraplantar injection of carrageenan significantly increased dopamine or homovanillic acid levels in the different central regions. The present study suggested that the central dopamine system (at least including ascending nigrostrialtal pathway and descending A11--the dorsal horn fibers) be activated following the carrageenan, while the activation probably mediated antinociception.     

Apomorphine-haloperidol interactions: Different types of antagonism in cortical and subcortical brain regions

Apomorphine, a dopamine (DA) receptor stimulant induced a dose-dependent decrease in the content of the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the olfactory tubercle and striatum of rats, but it was ineffective in the frontal cortex. Apomorphine also antagonized the haloperidol-induced accumulation of DOPAC and HVA in the olfactory tubercle and striatum, whereas in the frontal cortex it antagonized the effects of haloperidol on DOPAC but not on HVA. The total (free and conjugated) content of DA metabolites was measured in these experiments.     

Uric acid levels and dopamine transmission in rat striatum: diurnal changes and effects of drugs

Carbon paste disc electrodes were used to detect voltammetrically changes in the extracellular concentration of the purine metabolite, uric acid, and the dopamine metabolite, homovanillic acid (HVA), in the striatum of unanaesthetized, unrestrained rats under a variety of conditions. The motor activity level for each rat was recorded between the electrochemical scans. In totally unperturbed animals, there was a significant correlation between the levels of the two metabolites during the bright, relatively inactive, period of the diurnal cycle. During much of the dark (active) phase of the cycle, however, the uric acid signal showed no significant change compared with the light-on period, in contrast to the HVA signal which showed a marked increase. Significant variations in the concentration of striatal uric acid were observed during the switch-over from light to dark and dark to light conditions. The unilateral infusion of gamma-aminobutyric acid, taurine and haloperidol into the substantia nigra caused increases in the height of both the uric acid and HVA peak in the ipsilateral striatum; the size of these changes showed a significant correlation. Variable changes occurred on the contralateral side where no correlation was observed. Intraperitoneal administration of the mixed dopamine-receptor agonist, apomorphine, and the mixed antagonist, haloperidol, did not affect striatal uric acid levels significantly. These results suggest that, although there are conditions where parallel changes in dopamine release/receptor-activation and uric acid levels do occur in the striatum, neither the release of dopamine nor activation of dopamine receptors need necessarily lead to changes in the extracellular concentration of uric acid.     

Effects of zonisamide on extracellular levels of monoamine and its metabolite, and on Ca2+ dependent dopamine release.

The effects of zonisamide (3-sulfamoylmethyl-1,2-benzisoxazole), a novel anticonvulsant, on extracellular levels of monoamine and its metabolite in the striatum and hippocampus, and Ca2+ dependent monoamine release in the striatum of freely moving rats were studied by microdialysis. Zonisamide increased dopamine, homovanillic acid and 5-hydroxyindoleacetic acid, and decreased 3,4-dihydroxyphenylacetic acid in the rat striatum. However, zonisamide showed no effect on Ca2+ dependent dopamine release in the rat striatum. In the hippocampus, zonisamide increased dopamine, homovanillic acid, serotonin and 5-hydroxyindoleacetic acid and decreased 3,4-dihydroxyphenylacetic acid. The present results suggest that zonisamide facilitates dopaminergic and serotoninergic neurotransmission but does not affect Ca2+ dependent dopamine release within therapeutic plasma concentrations.     

Cobalt injections into the substantia nigra of the rat: effects on behavior and dopamine metabolism in the striatum

Small amounts of cobalt unilaterally injected into the substantia nigra of rats caused a strong, spontaneous contralateral turning which was suppressed by haloperidol. One to 2 days after intranigral cobalt microinjection, d-amphetamine decreased the intensity of the contralateral turning; 5 days after cobalt application, d-amphetamine changed the direction of the turning to the ipsilateral side. Intranigral cobalt microinjection initially caused a significant increase in the concentration of dopamine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid in the ipsilateral striatum. Thereafter, dopamine and its metabolites declined progressively to values significantly below control values. Similar biochemical changes in the striatum were also seen after partial electrolytic lesions of the substantia nigra. However, such lesions produced only mild contralateral turning. Frontal hemisection did not result in any increase of striatal metabolite values, and produced mild ipsilateral turning. Thus, there was no parallelism between the intensity and time course of the turning behavior induced by the different techniques and the changes in dopamine metabolism in the striatum. Within the cobalt-injected substantia nigra, γ-aminobutyric acid (GABA) and glutamic acid decarboxylase were decreased to less than 60% of the contralateral control values. The possibility is considered that the depression of a GABA-mediated inhibitory influence on the nigrostriatal or mesolimbic dopamine neurons may play a role in the cobalt-induced contralateral turning and altered striatal dopamine metabolism.     

Diazepam potentiates the effect of neuroleptics on behavioural activity as well as dopamine and norepinephrine turnover: Do benzodiazepines have antipsychotic potency?

A single injection of diazepam (10 mg/kg, s.c.), haloperidol (2 mg/kg, i.p.) or chlorpromazine (10 mg/kg, i.p.) decreased the ambulatory as well as sniffing behaviour of rats. These behavioural responses were further decreased when diazepam was administered concurrently with the neuroleptic. Acute haloperidol or chlorpromazine treatment increased striatal dopamine as well as cerebro-cortical norepinephrine turnover. In contrast, diazepam diminished the release of both of these catecholamines. When diazepam was administered together with haloperidol or chlorpromazine, a further decrease particularly in dopamine release was seen in striatum. This effect of diazepam on norepinephrine and dopamine turnover persisted even after 21 days of daily treatment, Similarly, the sedative effect of diazepam elicited in the form of depressed locomotor activity was also apparent after long-term administration of this benzodiazepine. However, chronic administration of neuroleptics enhanced the spontaneous locomotor activity and sniffing behaviour by about 25%. Furthermore, repeated neuroleptic treatment decreased the synthesis and turnover of dopamine and norepinephrine. This was reflected in decreased tyrosine hydroxylase and homovanillic acid level in striatum as well as by low concentration of 3-methoxy-4-hydroxyphenylethylene glycol in the cerebral cortex. When diazepam was administered together with haloperidol or chlorpromazine for 21 days, behavioural activity remained elevated and was comparable to groups of rats receiving neuroleptics alone. The cocomitant injection of diazepam and neuroleptics for 21 days elicited a synergistic effect on decreased synthesis and release of dopamine as well as norepinephrine. These data provide neurochemical evidence for potentiation of the neuroleptic effects by a benzodiazepine.     

Cobalt infections into the substantia nigra of the rat: Effects on behavior and dopamine metabolism in the striatum

Small amounts of cobalt unilaterally injected into the substantia nigra of rats caused a strong, spontaneous contralateral turning which was suppressed by haloperidol. One to 2 days after intranigral cobalt microinjection, d-amphetamine decreased the intensity of the contralateral turning; 5 days after cobalt application, d-amphetamine changed the direction of the turning to the ipsilateral side. Intranigral cobalt microinjection initially caused a significant increase in the concentration of dopamine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid in the ipsilateral striatum. Thereafter, dopamine and its metabolites declined progressively to values significantly below control values. Similar biochemical changes in the striatum were also seen after partial electrolytic lesions of the substantia nigra. However, such lesions produced only mild contralateral turning. Frontal hemisection did not result in any increase of striatal metabolite values, and produced mild ipsilateral turning. Thus, there was no parallelism between the intensity and time course of the turning behavior induced by the different techniques and the changes in dopamine metabolism in the striatum. Within the cobalt-injected substantia nigra, γ-aminobutyric acid (GABA) and glutamic acid decarboxylase were decreased to less than 60% of the contralateral control values. The possibility is considered that the depression of a GABA-mediated inhibitory influence on the nigrostriatal or mesolimbic dopamine neurons may play a role in the cobalt-induced contralateral turning and altered striatal dopamine metabolism.     

Somatodendritic and postsynaptic serotonin-1A receptors in the attenuation of haloperidol-induced catalepsy

The mechanism by which stimulation of somatodendritic and/or postsynaptic 5-hydroxytryptamine (5-HT, serotonin)-1A receptor could attenuate acute Parkinsonian-like effects of typical antipsychotics is investigated by comparing the anticataleptic and neurochemical effects of 8-hydroxy-2-di-n-propylaminotetralin (8-OH-DPAT) and buspirone in rats injected with haloperidol. Cataleptic effects of a submaximal dose (1 mg/kg) of haloperidol were attenuated more by prior administration of 8-OH-DPAT (0.25 mg/kg) than buspirone (1 mg/kg). Striatal 5-HT metabolism decreased more in buspirone- than 8-OH-DPAT-injected animals. Administration of haloperidol did not alter 5-HT metabolism in saline-, 8-OH-DPAT- or buspirone-injected animals. Dopamine decreased and its metabolite homovanillic acid (HVA) increased in the striatum of rats injected with buspirone. Effects of 8-OH-DPAT on dopamine metabolism were not significant. Haloperidol-induced increases of dopamine metabolites were attenuated by prior administration of 8-OH-DPAT, but not buspirone. The mechanism by which stimulation of somatodendritic as well as postsynaptic 5-HT-1A receptors could attenuate haloperidol-induced catalepsy is discussed. The findings have potential implications in the treatment of schizophrenia and motor behavior.     

Evidence for, and nature of, the tonic inhibitory influence of habenulointerpeduncular pathways upon cerebral dopaminergic transmission in the rat

The potential role of the habenula in the transsynaptic regulation of the activity of ascending dopaminergic systems has been investigated in the rat by studying the effect of an acute interruption of impulse traffic in the diencephalic conduction system (stria medullaris-habenula-fasciculus retroflexus) and of pharmacological manipulation of various neurotransmitter systems in the interpeduncular nucleus on dopamine metabolism in several dopaminergic projection fields. The bilateral infusion of tetrodotoxin into the fasciculus retroflexus (which conveys the habenulointerpeduncular tract) of conscious rats markedly increased homovanillic acid levels and dopamine synthesis and utilization in the medial prefrontal cortex, nucleus accumbens, olfactory tubercle and striatum. Similar changes in dopamine metabolism were observed in these areas after bilateral infusion of tetrodotoxin into the stria medullaris (which conveys most of the afferents to the habenula). Infusion of atropine (0.4-1 micrograms) into the interpeduncular nucleus increased homovanillic acid concentrations and dopamine utilization in the medial prefrontal cortex and nucleus accumbens but not in the olfactory tubercle and striatum. Moreover, intra-interpeduncular injection of oxotremorine (17 micrograms) antagonized the increase in dopamine utilization in the nucleus accumbens (but not in the olfactory tubercle) induced by an intrafasciculus retroflexus infusion of tetrodotoxin. Local infusion of naloxone (20 micrograms) into the interpeduncular nucleus increased homovanillic acid concentrations in the nucleus accumbens and olfactory tubercle but not in the medial prefrontal cortex and striatum. In contrast, intra-interpeduncular nucleus infusion of the substance P antagonist D-Arg1, D-Pro2, D-Trp7,9, Leu11-substance P or of substance P antiserum failed to alter homovanillic acid levels in the 4 dopamine-rich areas investigated. Finally, intraraphé medianus (but not intraraphé dorsalis) infusion of muscimol (25 ng) moderately increased dopamine synthesis in the nucleus accumbens and striatum. The present findings suggest that the habenulointerpeduncular pathways exert a tonic inhibitory influence on mesocortical, mesolimbic and mesostriatal dopaminergic neurons. Cholinergic and/or opioid peptidergic neurons coursing through the fasciculus retroflexus as well as ascending serotonergic neurons originating in the raphé medianus could take part in this inhibitory control of ascending dopaminergic neurons.     

Behavioral activation in rats increases striatal dopamine metabolism measured by dialysis perfusion

The dialysis perfusion method was used to study the effects of haloperidol, electrical brain stimulation, and behavioral activation on extracellular levels of dopamine metabolites in the rat striatum. Systemic administration of 0.2 mg/kg haloperidol increased extracellular levels of the metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) by 2-3-fold. Electrical stimulation of the medial forebrain bundle also increased HVA levels in dialysis perfusates. Rats pressing a lever for food reward showed 10-40% increases in HVA and DOPAC levels that reached a maximum 30-120 min after the behavioral session. The magnitude of the increases in HVA levels were correlated with the number of lever press responses. Presentation of a single 45-mg food pellet every 30 s to food-deprived rats produced a variety of motor activities and also increased the concentration of extracellular HVA. The results of the behavioral experiments indicate that striatal dopamine neurons are activated during conditions that increase motor activity.     

Lithium prevents adaptation of brain dopamine systems to haloperidol in schizophrenic patients

To evaluate the effect of lithium treatment on haloperidol-induced changes of brain dopamine systems, cerebrospinal fluid homovanillic acid (HVA) was assessed in nine patients during a sequential treatment protocol with placebo, lithium, lithium plus acute haloperidol, and lithium plus chronic haloperidol. None of the patients developed tolerance to the rise in HVA during treatment with haloperidol and lithium. Concurrent treatment with lithium appears to prevent the development of tolerance in dopamine metabolism during chronic haloperidol treatment. These data provide the first evidence in man that lithium may prevent neuroleptic-induced functional supersensitivity of brain dopamine systems.     

Effects of neuroleptic treatment on symptoms of schizophrenia and plasma homovanillic acid concentrations

Measurement of plasma concentrations of the dopamine metabolite, homovanillic acid, is an indirect tool to assess changes in dopamine turnover in schizophrenic patients. Plasma homovanillic acid concentrations have been reported to decrease during neuroleptic treatment, with the decrement correlating with symptomatic improvement in symptoms of schizophrenia. The present study tested the hypothesis that neuroleptic drugs decrease plasma homovanillic acid concentrations in those schizophrenic patients who improve with administration of neuroleptic drugs but not in patients who fail to display a treatment response. Twenty schizophrenic men who remained drug free for at least 2 weeks were treated with 20 mg/d of haloperidol for 5 weeks. Symptoms and plasma homovanillic acid concentrations were assessed on the last drug-free day and weekly for 5 weeks. Mean plasma homovanillic acid concentrations decreased in the group of patients who responded to neuroleptic treatment and did not change in the group of patients who did not improve. These findings suggest that there may be a qualitative distinction between responders and nonresponders to dopamine antagonists.     

Aging-related changes in the nigrostriatal dopamine system and the response to MPTP in nonhuman primates: diminished compensatory mechanisms as a prelude to parkinsonism

Aging is the most prominent risk factor for Parkinson's disease. Yet, consensus of how advancing age may predispose the dopamine (DA) system to parkinsonism is lacking. Three age ranges of female rhesus monkeys, 8-9, 15-17, and 21-31 years, received unilateral DA depletion with intracarotid 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Morphological and biochemical analyses of DA-depleted and intact hemispheres revealed three primary findings: (1) The intact striatum exhibited age-related declines in dopamine (DA) and homovanillic acid (HVA) that were present by middle age; (2) In the MPTP-treated striatum, the compensatory increase in DA activity was absent in old monkeys; and (3) Age-associated morphological changes included declines in the density of tyrosine hydroxylase (TH) positive fibers in striatum, decreased nigral soma size, and optical density of TH, but no significant loss of neurons. These findings suggest that aging produces changes in the nigrostriatal DA system that approach the threshold for expression of parkinsonian features, and that progressive impairment of plasticity may be central to the role of aging in development of parkinsonism.     

Differential effects of amfonelic acid on the haloperidol- and clozapine-induced increase in extracellular DOPAC in the nucleus accumbens and the striatum.

This study compares the effects of the nonamphetamine stimulant amfonelic acid on the increase in extracellular 3,4-dihydroxyphenylacetic acid (DOPAC) induced by haloperidol and clozapine in the nucleus accumbens and the striatum of anaesthetized rats. DOPAC was simultaneously recorded in both regions using differential pulse voltammetry with electrically pretreated carbon fibre electrodes. Amfonelic acid (2.5 mg/kg s.c.) did not alter basal striatal DOPAC but produced a significant reduction in extracellular DOPAC in the nucleus accumbens. Haloperidol (1 mg/kg s.c.) increased extracellular DOPAC in both regions. When amfonelic acid was injected 5 min before haloperidol, the increase in DOPAC was potentiated in both the nucleus accumbens and the striatum but with a greater effect in the striatum. Clozapine (30 mg/kg i.p.) increased extracellular DOPAC in both regions, an effect partially attenuated by amfonelic acid in both regions but to a greater extent in the striatum. When ritanserin (5 mg/kg i.p.), a serotonergic antagonist (5-HT-2), was co-administered with haloperidol, the potentiation by amfonelic acid of the increase in extracellular DOPAC induced by haloperidol was attenuated in both the nucleus accumbens and the striatum. The present results confirm that amfonelic acid can be used to discriminate neurochemically between haloperidol and clozapine in vivo. The effects of amfonelic acid on the neuroleptic-induced changes in extracellular DOPAC were greater in the striatum than the nucleus accumbens. These results further demonstrate that both neuroleptics increase dopamine metabolism in the two brain regions but by different mechanisms, supporting the view that the regulation of dopamine metabolism differs in the two regions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Extrapontine myelinolysis with parkinsonism after rapid correction of hyponatremia: high cerebrospinal fluid level of homovanillic acid and successful dopaminergic treatment

Extrapontine myelinolysis (EPM) is a demyelinating process of the brain. We report the case of an 11-year-old girl who developed EPM with parkinsonism. Magnetic resonance imaging revealed demyelinating patterns in the basal ganglia without central pontine lesions. The cerebrospinal fluid levels of homovanillic acid and 5-hydroxyindoleacetic acid were high at the time of onset and normalized upon complete recovery from extrapyramidal symptoms after a dopaminergic treatment. We speculated that demyelination of nerve fibers containing dopamine receptors in the striatum might be a main cause of these symptoms.     

Regional changes of striatal dopamine receptors following denervation by 6-hydroxydopamine and fetal mesencephalic grafts in the rat.

Young adult female rats received a 6-hydroxydopamine lesion in the left substantia nigra and, 3 weeks later, some of them were grafted with a cell suspension from the ventral mesencephalon of rat embryos (14-15 days old). Six months after transplantation, some grafted rats, following injection of amphetamine, had switched to turning only toward the intact side (type 1), whereas others turned toward the intact side only during the first half of the test (type 2). Levels of dopamine, dihydroxyphenylacetic acid and homovanillic acid were, respectively, 2%, 15% and 35% of the intact side in the denervated striatum of 6-hydroxydopamine rats. Dopamine concentrations were restored to 13% and 10% of the intact side in the grafted striatum of type 1 and type 2 animals, respectively. Levels of homovanillic acid were unchanged following grafts whereas those of dihydroxyphenylacetic acid increased by 209% and 247% in the grafted striatum of type 1 and type 2 animals, respectively. The ratios of dihydroxyphenylacetic acid/dopamine as well as homovanillic acid/dopamine were low in the intact striatum whereas they increased in the denervated striatum with or without graft. The tyrosine hydroxylase immunoreactivity decreased by about 80% in the denervated striatum of 6-hydroxydopamine rats. In type 1 rats, tyrosine hydroxylase immunoreactivity revealed that the graft was localized in the dorsomedial part of the denervated striatum, whereas in type 2 animals, it was also in the medial striatum but it overlapped the dorsal and ventral parts of it equally. D1 as well as D2 dopamine receptors were measured throughout the striatum (9.0-7.6 rostral-caudal coordinates), by autoradiography, using [3H]SCH 23390 (D1 antagonist) and [3H]spiperone (D2 antagonist) binding. Supersensitive D2 receptors were normalized in the dorso- and ventromedial parts of the grafted striatum. D2 receptor density was higher in type 2 than in type 1 rats, more specifically at 8.6-8.2 rostral-caudal coordinates, where the graft was. D1 receptor supersensitivity was modest compared to D2 receptors in the striatum of 6-hydroxydopamine rats and decreased following grafts. DA receptors changes in the striatum, following fetal mesencephalic grafts, may explain the behavioral recovery seen in grafted rats.     

A comparison between the non-competitive NMDA antagonist dizocilpine (MK-801) and the competitive NMDA antagonist D-CPPene with regard to dopamine turnover and locomotor-stimulatory properties in mice

Summary Following intraperitoneal administration of the non-competitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801), levels of the dopamine (DA) metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) increased in mouse striatum and limbic forebrain. When dizocilpine was given to animals treated with NSD 1015, an inhibitor of 3,4-dihydroxyphenylalanine (DOPA) decarboxylase and monoamine oxidase, there was an increase in levels of DOPA and 3-methoxytyramine (3-MT). These findings suggest that dizocilpine stimulates DA synthesis and release in mouse brain. Following dizocilpine treatment a clear-cut increase in spontaneous locomotor activity was observed, probably partly due to enhanced dopaminergic tone. The competitive NMDA antagonist D-CPPene produced locomotor stimulation as well, but in contrast to following dizocilpine treatment levels of 3-MT decreased. Thus the stimulation of locomotor activity following D-CPPene treatment does not seem to be mediated through activation of central dopaminergic systems. However, haloperidol pretreatment antagonized this locomotor response, indicating that the dopaminergic system plays a permissive role in this context.     

Lesions of the superior colliculus in the rat differentiate between nigrostriatal and mesolimbic dopamine systems

Bilateral electrolytic lesions of the superior colliculus in rats increased spontaneous locomotor activity, enhanced amphetamine-induced hyperactivity and attenuated apomorphine-induced biting. These lesions were associated with an increased rate of turnover of dopamine in the nucleus accumbens, but not in the striatum. Similarly concentrations of the dopamine metabolites homovanillic acid and 3,4-dihydroxyphenylacetic acid were elevated in accumbens tissue but not in striatum in rats with bilateral collicular lesions. The results indicate that lesions of the superior colliculus cause differentiation between hyperactivity and stereotypy, and that this may be related to blockade of a nigrostriatal outflow, and relief of inhibition on mesolimbic systems.