Haloperidol-induced Effects Research Articles

Effect of 5-HT6 Receptor Ligands Combined with Haloperidol or Risperidone on Antidepressant-/Anxiolytic-Like Behavior and BDNF Regulation in Hippocampus and Prefrontal Cortex of Rats.

BackgroundThe presence of depressive and anxiety symptoms in patients with schizophrenia may have an important impact on treatment and compliance. Hence, interventions addressing such comorbidity in schizophrenia should be explored. One target may be a serotonergic 5-HT6 receptor (5-HT6R) since its ligands displayed antidepressant- and anxiolytic-like activities in preclinical experiments.MethodsAcute and chronic (21 days) administration of haloperidol or risperidone in combination with a selective 5-HT6R agonist (WAY-181187) or antagonist (SB-742457) to rats was performed for detecting antidepressant- and anxiolytic-like behaviors. In addition, the level of brain-derived neurotrophic factor (BDNF) protein and its gene expression in hippocampus and prefrontal cortex were determined.ResultsBoth single and chronic administration of WAY-181187 with haloperidol produced antidepressant- and anxiolytic-like activities. SB-742457 did not provide full benefits in terms of improvement of haloperidol-induced adverse mood effects. However, the administration of SB-742457 with risperidone triggered its anxiolytic-like activity. Both 5-HT6R ligands evoked no changes in haloperidol-induced effects on BDNF level. WAY-181187 induced repression of the BDNF gene while SB-742457 increased its expression in both structures. 5-HT6R ligands, when combined with risperidone, did not change BDNF protein level and increased gene expression in the hippocampus, while they elevated BDNF level and potentiated gene expression in the prefrontal cortex.ConclusionThe combined administration of WAY-181187 and haloperidol provided the greatest benefits, which were manifested by antidepressant-like effects and suppression of the anxiogenic-like properties. The combined administration of risperidone with both agonist and antagonist resulted only in an anxiolytic-like effect. It seems that the anxiolytic-like effects induced by haloperidol or risperidone with the addition of 5-HT6R ligands are task-specific. The data on BDNF protein and gene expression did not fully correspond with the behavioral outcomes, and thus it appears that other factors/mechanisms are involved in the observed antidepressant- and/or anxiolytic-like effects.

Repeated treatment with haloperidol, but not olanzapine, alters synaptic NMDA receptor composition in rat striatum

We here show that repeated administration of the first generation antipsychotic haloperidol, but not of the second generation olanzapine, significantly reduced the expression of NMDA subunit NR2A at striatal synapses, whereas both drugs decreased αCaMKII protein levels and autophosphorylation degree. Given that alterations in the localization of NMDA receptor regulatory subunits at synapses have been described in experimental parkinsonism, the haloperidol-induced effect on NMDA subunit localization might contribute to drug-induced parkinsonism induced by haloperidol.

Ritanserin counteracts both rat vacuous chewing movements and nigro-striatal tyrosine hydroxylase-immunostaining alterations induced by haloperidol

The effect of subchronic co-administration of ritanserin (1.5 mg/kg, i.p., twice a day) and haloperidol (1 mg/kg, i.p., twice a day) on rat vacuous chewing movements and on tyrosine hydroxylase-immunostaining was investigated. Ritanserin significantly reduced rat vacuous chewing movements observed following 2, 3 and 4 weeks of haloperidol administration and after 5 days of haloperidol withdrawal. Furthermore, ritanserin prevented the reduction of striatal tyrosine hydroxylase-immunostaining and the shrinkage of nigral dopaminergic cell bodies induced by haloperidol. The present results indicate that ritanserin may possess protective properties on both dopaminergic nigro-striatal neuron alterations and vacuous chewing movements induced by haloperidol, and provide further evidence indicating a possible association between these two haloperidol-induced effects.

Biochemical and molecular effects of chronic haloperidol administration on brain and muscle mitochondria of rats

The objectives of the current study were to evaluate (1) the respiratory rates and enzyme activities of brain and muscle mitochondria from rats chronically treated with haloperidol, (2) the protective role of dopamine (DA) D-1 (SKF38393) and D-2 (quinpirole) receptor agonists, and (3) the effect of haloperidol on the mitochondrial DNA (mtDNA) and protein synthesis. Thirty male Sprague-Dawley rats were subdivided into the following five groups: controls, haloperidol, haloperidol plus SKF38393, haloperidol plus quinpirole, and haloperidol plus SKF38393 and quinpirole. We compared the respiratory rates and enzymatic activities of brain and muscle mitochondria from controls with other groups. We finally analyzed the mitochondrial protein synthesis and mtDNA alterations (deletions, point mutations, and depletion) in two rats from each group. In brain but not in muscle from haloperidol-treated rats, we found a decrease of oxygen consumption rates using glutamate plus malate (−68 ± 35%, P < 0.05) and succinate (−78 ± 20%, P < 0.05) as substrates as well as low complex I, II, and V activities (−35 ± 15%, P < 0.05; −54 ± 13%, P < 0.05; and −60 ± 33%, P < 0.01; respectively). The administration of SKF38393 alone or together with quinpirole prevented most of haloperidol-induced effects, whereas the protective effects of quinpirole alone were lower. Brain mitochondrial protein synthesis was decreased in haloperidol-treated rats and was not prevented by SKF38393, quinpirole, or both. We did not find mtDNA abnormalities in brain or muscle mitochondria from haloperidol-treated rats. Chronic administration of haloperidol in rats is associated with a nonspecific deleterious effect in the activity of electron transport chain of brain, and this effect is only partially prevented by DA D-1 agonists. These results suggest that other mechanisms different from DA receptors pathway can contribute to the expression of behavioral supersensitivity. J. Neurosci. Res. 53:475–481, 1998. © 1998 Wiley-Liss, Inc.

Biochemical and molecular effects of chronic haloperidol administration on brain and muscle mitochondria of rats.

The objectives of the current study were to evaluate (1) the respiratory rates and enzyme activities of brain and muscle mitochondria from rats chronically treated with haloperidol, (2) the protective role of dopamine (DA) D-1 (SKF38393) and D-2 (quinpirole) receptor agonists, and (3) the effect of haloperidol on the mitochondrial DNA (mtDNA) and protein synthesis. Thirty male Sprague-Dawley rats were subdivided into the following five groups: controls, haloperidol, haloperidol plus SKF38393, haloperidol plus quinpirole, and haloperidol plus SKF38393 and quinpirole. We compared the respiratory rates and enzymatic activities of brain and muscle mitochondria from controls with other groups. We finally analyzed the mitochondrial protein synthesis and mtDNA alterations (deletions, point mutations, and depletion) in two rats from each group. In brain but not in muscle from haloperidol-treated rats, we found a decrease of oxygen consumption rates using glutamate plus malate (-68 +/- 35%, P < 0.05) and succinate (-78 +/- 20%, P < 0.05) as substrates as well as low complex I, II, and V activities (-35 +/- 15%, P < 0.05; -54 +/- 13%, P < 0.05; and -60 +/- 33%, P < 0.01; respectively). The administration of SKF38393 alone or together with quinpirole prevented most of haloperidol-induced effects, whereas the protective effects of quinpirole alone were lower. Brain mitochondrial protein synthesis was decreased in haloperidol-treated rats and was not prevented by SKF38393, quinpirole, or both. We did not find mtDNA abnormalities in brain or muscle mitochondria from haloperidol-treated rats. Chronic administration of haloperidol in rats is associated with a nonspecific deleterious effect in the activity of electron transport chain of brain, and this effect is only partially prevented by DA D-1 agonists. These results suggest that other mechanisms different from DA receptors pathway can contribute to the expression of behavioral supersensitivity.

Kynurenate blocks the acute effects of haloperidol on midbrain dopamine neurons recorded in vivo

The acute effect of systemic administration of the antipsychotic drug haloperidol on the activity of midbrain dopamine (DA) neurons was investigated with extracellular single cell recording in the chloral hydrate anaesthetized male rat. DA cells in the zona compacta-substantia nigra (SN) and ventral tegmental area (VTA) were excited by low doses of haloperidol. This excitation, which included increased firing rate and burst firing, was no longer present after treatment with the excitatory amino acid (EAA) antagonist kynurenate (1 mumol ICV). Kynurenate alone profoundly regularized the activity and abolished burst firing in VTA-DA neurons, while SN-DA neuronal activity was unaffected by this treatment. Thus, VTA-DA neurons, but not SN neurons, appear to be dependent on a tonic EAA input for their normal varied, burst-firing activity. The antagonism of haloperidol-induced effects by kynurenate suggests that the acute excitatory action of haloperidol on midbrain DA neurons is executed via EAA neurons, in the case of the VTA probably via a corticofugal EAA pathway from the medial prefrontal cortex.

Acutely Administered Haloperidol-Induced Widespread Reduction of Regional Cerebral Blood Flow Observed from Subtraction of Brain Imaging with Single Photon Emission Computed Tomography Using Technetium-99m Hexamethyl-Propyleneamine Oxime

Changes in brain images with single photon emission computed tomography (SPECT) using technetium-99m hexamethyl-propyleneamine oxime (99mTc HMPAO) before and after intramuscular injection of haloperidol (0.08 mg/kg) were studied in 2 unmedicated schizophrenic patients and 2 normal controls by a new technique, i.e. subtraction of brain images. The haloperidol injection reduced regional cerebral blood flow extensively in the bilateral cerebral hemispheres in one of the schizophrenics and one of the normal controls, with little or no haloperidol-induced effects in the remaining 2 subjects. The widespread cortical reduction is considered to be due to a nonspecific or indirect effect of haloperidol in view of the broad action sites inconsistent with the known anatomy of the mesocortical dopaminergic system.

Effect of intracaudate haloperidol and apomorphine on switching motor patterns upon current behaviour of cats

Previous studies using various experimental set-ups, have shown that the dopaminergic activity in the caudate nucleus (CN) is involved in the organism's ability to switch from one motor or behavioural program to another without the help of external stimuli (switching arbitrarily). The main purpose of the present study was to investigate how arbitrarily switching motor patterns manifests itself in an ‘open field situation’. Therefore, the effects of CN application of haloperidol ( 12.5 μ g 5 μ l ) and apomorphine ( 0.6 μ g 5 μ l ) were analyzed on the ability to switch from one motor program to any other program in cats habituated to an observation cage. Application of haloperidol decreased switching. In addition the number of distinct motor patterns declined after injecting haloperidol into the CN. The haloperidol-induced effect, however, was not selectively restricted to any particular motor pattern. Switching from one motor pattern to another increased after CN injection of apomorphine. Moreover, the number of distinct motor patterns increased after CN injection of apomorphine. However, the effect of CN application of apomorphine was not selectively restricted to any particular motor pattern. Since previous studies have demonstrated that various expressions of dopaminergic CN activity are funnelled through the deeper layers of the superior colliculus (dl-SC), it was hypothesized that switching induced by CN application of apomorphine may also be channelled through the dl-SC. Therefore the effect of dl-SC-injected muscimol ( 75 ng 1 μ l ) was analyzed on the ability to switch motor programs in cats pretreated with apomorphine. Injection of muscimol into the dl-SC reduced both the number of distinct motor patterns and the number of switchings in cats pretreated with apomorphine.

Repeated testing of rats markedly enhances the duration of effects induced by haloperidol on treadmill locomotion, catalepsy, and a conditioned avoidance response

In the present experiments we have investigated the duration of haloperidol-induced effects in rats tested repeatedly, and in rats tested on a single occasion after drug administration. The behavioral test situations used include treadmill locomotion (speed 4 m/min), inclined grid catalepsy, two-way conditioned avoidance behavior and open field spontaneous locomotor activity. It was found that the duration of haloperidol-induced effects on treadmill locomotion, spontaneous locomotor activity, catalepsy and a conditioned avoidance response (doses: 0.32, 0.32, 1.25 and 0.2 mg/kg IP, respectively) was about 2 hr or less in animals observed once only (“independent procedure”). With the possible exception for locomotor activity, the duration of haloperidol-induced effects was considerably prolonged, up to 8 hr depending on the test situation, in animals observed repeatedly after the administration of haloperidol in the same doses (“dependent procedure”). The enhanced duration by the dependent procedure is probably not caused by handling stress since the enhanced duration of haloperidol-induced effects in some of the behavioral tests were only noted in animals tested repeatedly in one particular test, and not in animals given the repeated pretests in another situation. Furthermore, it was not possible to relate the enhanced duration of haloperidol-induced effects by repeated testing to changes in striatal DA metabolism as evaluated by measurements of DOPAC, HVA and DA. It was found that the treadmill test 2–4 hr after haloperidol (0.12–0.32 mg/kg IP), at certain doses and time intervals produced an increase in DA turnover [(DOPAC + HVA)/DA], but this increase was the same in both procedures (dependent and independent). Our findings that the time-course of action of haloperidol is dependent on the test procedures used may be of importance when interpreting interaction studies and the relationship between pharmacokinetics and behavioral effects of this, and possible other, psychotropic drugs.

Caudate nucleus and programming behaviour in cats: Role of dopamine in switching motor patterns

Cats were trained to walk on a specially designed treadmill: the cats were able to collect food pellets by switching motor patterns with or without the help of exteroceptive stimuli inherent to the treadmill. To study the involvement of the caudate nucleus in switching motor patterns cats received intracaudate bilateral injections of haloperidol. In addition, in a final series of experiments, EMG recordings of two antagonistic muscles, together with recordings of characteristic changes in the length of one muscle, were made before and after the haloperidol treatment. Haloperidol treatment resulted in a decreased number of motor patterns which were not directed by exteroceptive stimuli (non-exteroceptively directed motor patterns). This haloperidol-induced effect was dose-dependently counteracted by the additional intracaudate injections of apomorphine which per se remained ineffective. Haloperidol neither altered the number of food collecting attempts nor reduced the number of exteroceptively directed motor patterns. Furthermore, haloperidol did not affect the capacity to switch to proprioceptively directed motor patterns. Finally, haloperidol did not produce abnormalities in EMG and length signals recorded from hindlimb muscles. It is concluded that haloperidol selectively reduced the animal's capacity to ‘programme non-stimulus directed motor behaviour’. The data are discussed in view of their significance for therapy of patients with basal ganglia disorders, such as patients suffering from Parkinson's disease.

Apomorphine and haloperidol-induced effects on male rat sexual behavior: No evidence for actions due to stimulation of central dopamine autoreceptors

The administration of apomorphine (0.2-0.8 mg/kg IP) or (+)3-PPP(4-8 mg/kg IP) produced a facilitation of the male rat sexual behavior. Apomorphine in lower doses, as well as the selective DA autoreceptor agonist (-)3-PPP were ineffective. Except for a decrease in number of intromissions and an increase in the postejaculatory interval at the highest dose (0.32 mg/kg IP) there were no effects after administration of haloperidol. These data indicate that activation or inhibition of the presynaptic dopamine receptor does not affect male rat sexual behavior.

Effect of anaesthetic agents on the synthesis and disappearance of brain dopamine normally and after haloperidol, Kcl or axotomy.

The synthesis of dopamine was determined as the accumulation of Dopa after Dopa decarboxylase inhibition. The release of dopamine was determined as the disappearance of the amine after treatment with the tyrosine hydroxylase inhibitor α-methyltyrosine. These processes were not significantly changed in the rat brain by pentobarbital sodium anaesthesia or by 10 min halothane anaesthesia. The accelerations of the dopamine synthesis and release after treatment with haloperidol were markedly reduced during pentobarbital, but not halothane anaesthesia. Anaesthesia with pentobarbital did not affect the increased synthesis and release of dopamine observed when the dopaminergic nerve terminals were depolarized by local treatment with KCl. The increases in dopamine synthesis and concentration after axotomy were similar whether the operation was performed during pentobarbital or halothane anaesthesia. It is suggested that the selective reduction of the haloperidol-induced effects by pentobarbital may be due to interference with a neuronal feedback loop.