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PubMed2000

Sub-chronic inhibition of nitric-oxide synthesis modifies haloperidol-induced catalepsy and the number of NADPH-diaphorase neurons in mice.

RATIONALE: NG-nitro-L-arginine (L-NOARG), an inhibitor of nitric-oxide synthase (NOS), induces catalepsy in mice. This effect undergoes rapid tolerance, showing a significant decrease after 2 days of sub-chronic L-NOARG treatment. Nitric oxide (NO) has been shown to influence dopaminergic neurotransmission in the striatum. Neuroleptic drugs such as haloperidol, which block dopamine receptors, also cause catalepsy in rodents. OBJECTIVES: To investigate the effects of subchronic L-NOARG treatment in haloperidol-induced catalepsy and the number of NOS neurons in areas related to motor control. METHODS: Male albino Swiss mice were treated sub-chronically (twice a day for 4 days) with L-NOARG (40 mg/kg i.p.) or haloperidol (1 mg/kg i.p.). Catalepsy was evaluated at the beginning and the end of the treatments. Reduced nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry was also employed to visualize NOS as an index of enzyme expression in mice brain regions related to motor control. RESULTS: L-NOARG sub-chronic administration produced tolerance of L-NOARG and of haloperidol-induced catalepsy. It also induced an increase in the number of NADPH-d-positive cells in the dorsal part of the caudate and accumbens nuclei compared with haloperidol and in the pedunculopontine tegmental nucleus compared with saline. In contrast, there was a decrease in NADPH-d neuron number in the substantia nigra, pars compacta in both haloperidol-treated and L-NOARG-treated animals. CONCLUSIONS: The results give further support to the hypothesis that NO plays a role in motor behavior control and suggest that it may take part in the synaptic changes produced by antipsychotic treatment.

Animals↗

PubMed1997

The relationship between D2 receptor occupancy and plasma levels on low dose oral haloperidol: a PET study.

The purpose of this study was to determine the relationship between dopamine D2 receptor occupancy and plasma haloperidol. Twelve patients treated with 1-5 mg/day of haloperidol had their D2 occupancy measured using [11C]-raclopride and positron emission tomography and haloperidol plasma levels measured using gas chromatograph mass spectrophotometer. The patients exhibited haloperidol plasma levels ranging from 0.5 to 5.8 ng/ml and D2 occupancy from 53 to 88%. The D2 occupancy was related to the plasma level as a saturating rectangular hyperbola relationship (r2 = 0.84) and it showed that, on average, 50% D2 occupancy was achieved with 0.51 ng/ml and 80% D2 occupancy with 2.0 ng/ml. Our findings demonstrate that 2-5 mg/day of haloperidol, which usually leads to plasma levels of 1-2 ng/ml, would be expected to induce 60-80% dopamine D2 receptor occupancy. If, as has been claimed, 70% D2 occupancy is adequate for typical neuroleptic response, then the conventional use of > 10 mg/day may have been too high, since 70% occupancy can be achieved in most patients by 2-5 mg/day. On the other hand, if as others have suggested, 8-12 ng/ml of haloperidol is the correct therapeutic window for plasma levels, then the required therapeutic D2 occupancy is closer to 90%, not 70%. The implications of the D2 occupancy findings for the optimal dosing of neuroleptics are discussed.

Administration, Oral↗

PubMed1997

Repeated REM sleep deprivation after chronic haloperidol administration in the rat.

Repeated haloperidol administration produces up-regulation of dopamine (DA) receptors. REM sleep deprivation (REMSD) does also, but in addition, has been shown to produce REM sleep rebound. Should DA receptor up-regulation play a role in REM sleep rebound, haloperidol could conceivably have effects similar to those observed following REMSD. This is the central question investigated in this study. Male Wistar rats were prepared for sleep recordings. They were randomly assigned to the following groups: group 1, REMSD by small platforms (40 h REMSD + 8 h recording); group 2, was the large platform control group (40 h in large platforms + 8 h of recording); group 3, received 2-week daily administration of haloperidol (3 mg/kg, i.p.) plus REMSD (40 h REMSD + 8 h of recording); group 4, 2-week administration of haloperidol (3 mg/kg) without sleep manipulation and at the end 40 h were allowed to elapse, following which 8 h of sleep recordings was carried out. In each group the sleep manipulation and/or sleep recordings were repeated five consecutive times. Repeated REMSD produced increases of REM sleep time after each recovery in group 1. Large platforms did not produce increases of REM sleep during the recovery trials. The 2-week administration of haloperidol plus REMSD prevented REM sleep rebound (group 3). The 2-week administration of haloperidol without sleep manipulation (group 4) produced a REM sleep reduction. Dopamine modulation seems not to be important for REM sleep rebound. Hypersensitivity of DA receptors developed after REMSD may be an epiphenomenon associated with this sleep manipulation, but seems not to participate in REM sleep enhancement after REMSD.

Animals↗

PubMed1997

Haloperidol enhances latent inhibition in visual tasks in healthy people.

We have previously shown that 0.5 mg haloperidol (i.v.) increased latent inhibition in one of two visual tasks. The present study analysed the effects of a higher dose of haloperidol (1.0 mg, i.v.) on latent inhibition in these two visual tasks in healthy volunteers in a randomised controlled trial. In the task where 0.5 mg haloperidol had enhanced latent inhibition, 1.0 mg had the same effect, thus replicating the previous result. In the task where 0.5 mg haloperidol had been ineffective, 1.0 mg haloperidol enhanced latent inhibition in high schizotypal subjects only. This indicates that subjects with higher schizotypy scores are more sensitive to dopamine blockade. A comparison of the results from the studies at the two different doses suggests a dose dependence of haloperidol's effects on latent inhibition that parallels results from animal work.

Adult↗

PubMed1999

L-701,324, a selective antagonist at the glycine site of the NMDA receptor, counteracts haloperidol-induced muscle rigidity in rats.

RATIONALE: It has recently been suggested that the overactivity of glutamatergic neurotransmission may contribute to the pathophysiology of Parkinson's disease. Therefore, a search for new compounds which block glutamatergic receptors and show antiparkinsonian properties in animal models of this disease seems to be justified. OBJECTIVE: The aim of this study was to determine whether L-701,324 [7-chloro-4-hydroxy-3(3-phenoxy) phenylquinoline-2-(H)-one], a selective and full antagonist at the glycine site of the NMDA receptor, counteracts parkinsonian-like muscle rigidity and catalepsy induced by haloperidol in rats. METHODS: The muscle tone was measured as the resistance developed to passive flexion and extension of the hind limb. Electromyographic (EMG) activity was additionally recorded in the gastrocnemius and tibialis anterior muscles. RESULTS: L-701,324 (2.5-40 mg/kg IP) dose-dependently decreased the muscle tone enhanced by haloperidol (1-5 mg/kg IP). Likewise, the haloperidol-enhanced resting EMG activity and the EMG reflex response to passive movements were diminished by lower and almost abolished by higher doses of L-701,324. However, up to a dose of 20 mg/kg IP, L-701,324 did not influence haloperidol (0.5 mg/kg IP)-induced catalepsy. Moreover, L-701,324 (1.25-5 mg/kg IP) given alone or together with haloperidol (0.5-1 mg/kg IP) disturbed rotarod performance. Gross observation of behaviour indicated that rats injected with L-701,324 in doses equal to or higher than 5 mg/kg, alone or in combination with haloperidol, were markedly ataxic, i.e. rats showed signs of disturbed balance and loss of control over their hind limbs. CONCLUSIONS: The present study suggests that L-701,324 exhibits a beneficial action in the animal model of parkinsonian rigidity, but not that of parkinsonian akinesia. Nonetheless, this compound is not devoid of motor side-effects.

Animals↗

PubMed1999

The effects of subchronic haloperidol on intact and dizocilpine-disrupted sensorimotor gating.

RATIONALE: Reversal of deficits in prepulse inhibition (PPI) of the startle reflex in rats is considered a preclinical screen for potential antipsychotics. Whereas acutely administered antipsychotics consistently reverse apomorphine-induced deficits in PPI, some antipsychotics, including haloperidol, are unable to reverse deficits in PPI produced by non-competitive NMDA antagonists such as phencyclidine or dizocilpine (MK-801). Acute administration of antipsychotics tends to facilitate baseline PPI. However, the effect is generally not large enough in magnitude nor reliable enough to be considered a useful preclinical screen for antipsychotic activity. OBJECTIVE: Because the clinical effects of antipsychotics typically require subchronic administration, this study tested the hypothesis that reversal of NMDA antagonist-induced deficits in PPI by antipsychotics require subchronic administration. A second aim of this study was to determine if subchronic administration of an antipsychotic produces a more potent facilitation of baseline PPI than acute administration. METHODS: Rats received a subcutaneous injection of 0, 0.025, 0.1 or 0.5 mg/kg haloperidol for 16 consecutive days. On day 16, half the rats in each haloperidol dose group received a second subcutaneous injection consisting of either dizocilpine (0.1 mg/kg) or saline. RESULTS: None of the haloperidol doses tested had a significant effect on baseline PPI. The 0.1 mg/kg dose of haloperidol diminished but did not completely reverse dizocilpine-induced disruption of PPI. The other doses had no significant effect. CONCLUSIONS: These results suggest that time course factors may partially modify the effects of haloperidol on dizocilpine-induced disruption of PPI but not its effect on baseline PPI.

Animals↗

PubMed1986

Hypophysectomy may non-selectively alter pharmacokinetic parameters to enhance the ability of haloperidol to increase striatal dopamine receptor density in the rat.

We have investigated the effect of a range of doses of haloperidol (0.625-5.0 mg/kg/day) or saline, administered for 14 days, followed by a 3 day drug washout period, to sham operated or hypophysectomized rats. Haloperidol increased the number of specific striatal 3H-spiperone binding sites (Bmax) in sham-operated animals at doses of 2.5 and 5.0 mg/kg/day, and in hypophysectomized animals at all doses used (0.625-5.0 mg/kg/day). The inhibition of locomotor activity produced by haloperidol was greater in hypophysectomized than sham-operated animals. Plasma and striatal haloperidol levels after equivalent doses were greater in hypophysectomized than in sham-operated animals. We conclude that hypophysectomy may enhance the ability of haloperidol to induce striatal dopamine receptor supersensitivity in the rat, and that this may be due to differences in the pharmacokinetic handling of haloperidol between sham-operated and hypophysectomized animals.

Animals↗

PubMed1986

Acute and chronic effects of haloperidol on plasma and brain homovanillic acid in the rat.

The effects of acute and chronic administration of haloperidol on homovanillic acid (HVA) in plasma and the brain were examined in the rat. Acute haloperidol treatment (1 mg/kg) resulted in highly significant elevations in HVA within 30 min and produced a maximal increase of HVA in 3-6 hr in both plasma and the whole brain. The response of brain HVA to increasing doses (0.05-30 mg/kg) of haloperidol showed an inverted U pattern. Plasma HVA showed a very flat response to lower doses (less than or equal to 5 mg/kg) of haloperidol and a dramatically elevated one to higher doses (greater than or equal to 10 mg/kg). Haloperidol produced a parallel increase in plasma and brain HVA at lower doses (less than or equal to 2 mg/kg) only. After chronic administration of haloperidol for up to 28 days, the response of HVA in plasma correlated mainly with, but tolerated later than, those in the whole brain and the olfactory tubercle.

Animals↗

PubMed1992

Scopolamine attenuates haloperidol-induced c-fos expression in the striatum.

Haloperidol increases the expression of Fos, the protein product of the proto-oncogene c-fos, in some parts of the central nervous system. Haloperidol also produces catalepsy in rodents and extrapyramidal side effects in humans, both of which are reduced by muscarinic receptor antagonists. In order to gain insight into the neurochemical and neuroanatomical substrates of haloperidol-induced catalepsy we examined the effects of the muscarinic receptor antagonist scopolamine on haloperidol-induced Fos expression in the striatum, nucleus accumbens and lateral septal nucleus. At a dose that reduced the cataleptic effect of haloperidol, scopolamine decreased the neuroleptic-induced Fos expression in the striatum and lateral septal nucleus but not the nucleus accumbens. These results indicate that haloperidol may increase c-fos expression in medium spiny striatal neurons indirectly by enhancing striatal acetylcholine release. They are also consistent with the hypothesis that neuroleptic-induced increases in striatal c-fos expression are predictive of extrapyramidal side effects produced by these compounds.

Animals↗

PubMed1995

Phase-dependent phase shift of methamphetamine-induced circadian rhythm by haloperidol in SCN-lesioned rats.

Haloperidol, a non-selective dopamine receptor antagonist, was injected intraperitoneally in to suprachiasmatic nucleus (SCN)-lesioned rats at various phases of the locomotor activity rhythm induced by methamphetamine (MAP) treatment. A single injection of haloperidol shifted the phase of MAP-induced locomotor rhythm phase dependently, while saline injection had no effect on the phase. A phase-response curve of MAP-induced rhythm for haloperidol had a small phase-advancing area at CT 13 to 15, a large phase-delaying area at CT 3 to 7 and a dead zone at CT 17 to 1. Although the day-to-day variation of MAP-induced locomotor rhythm was about 2.5-times as great as that of light entrainable circadian rhythm, the phase shifts of both directions were statistically significant. Phase delay shifts at CT 5 depended on the dose of haloperidol. In addition to the phase-shifting effect, haloperidol suppressed the MAP-induced locomotor activity for activity for about 10 h regardless of the phase of the injection. Pentobarbital also suppressed ther locomotor activity for a similar duration. However, significant phase shift was not detected with pentobarbital injected at CT 5 or CT 13, at the phase where haloperidol induced the maximal phase delay or advance, respectively. Present findings suggest that the dopaminergic mechanism is involved in the entrainment and/or oscillatory mechanism of the MAP-induced rhythm.

Animals↗

PubMed1996

Effect of long-term haloperidol treatment on striatal neuropeptides: relation to stereotyped behavior.

Behavioral and biochemical responses to D1 and D2 dopamine (DA) agonists were used to evaluate the participation of striatal peptidergic mechanisms in the motor function alterations that attend chronic neuroleptic treatment. Rats, given haloperidol (1 mg/kg, i.c.) for 21 consecutive days, were randomly allocated to one of the following treatments: the D1 agonist SKF 38393, the D2 agonist quinpirole, their combination or saline. Stereotyped behavior and neuropeptide levels were evaluated after 5 days treatment and 4 days washout. Haloperidol increased most oral behaviors including licking, chewing and biting as well as striatal enkephalin and somatostatin levels. Subsequent treatment with SKF 38393 diminished the haloperidol-induced increase in licking and chewing; quinpirole reduced chewing behavior. The administration of both agonists together decreased chewing and biting. Neither DA agonist alone, nor their combination, reduced the haloperidol-induced increase in enkephalin levels. Both SKF 38393 and quinpirole, when given alone, tended to decrease the haloperidol-induced increase in somatostatin levels; when both D1 and D2 agonists were administered together, somatostatin levels declined significantly. These results suggest that somatostatin- but not enkephalin-containing striatal neurons contribute to the expression of haloperidol-induced stereotypies.

Animals↗

PubMed1983

Differential effects of acute and chronic administration of haloperidol on homovanillic acid levels in discrete dopaminergic areas of rat brain.

After acute administration of haloperidol, homovanillic acid (HVA) levels were increased in the prefrontal cortex, anterior cingulate cortex, discrete limbic areas and A14 dopamine (DA) neurons. The maximal effect of haloperidol was attained more slowly in the prefrontal cortex and amygdala than in the other regions. The ED50 of haloperidol was 0.03 mg/kg in the prefrontal cortex, but was 0.06-0.07 mg/kg in other areas examined. After repeated administration of haloperidol, tolerance to the HVA increase was observed in the striatum and all limbic areas examined, the amygdala being the most susceptible to this tolerance. In contrast, no tolerance was found in the anteromedial and suprarhinal DA neurons of the prefrontal cortex and A14 DA neurons. These results suggest that the prefrontal cortex may be a possible site for the antipsychotic action of haloperidol. On the other hand, no change of HVA levels in the A12 and A13 DA neurons of the hypothalamus was observed after haloperidol treatments, suggesting a lack of neuronal feedback mechanism in the A12 and A13 DA neurons.

Animals↗

PubMed1984

Hypophysectomy fails to affect the supersensitivity of striatal dopamine target cells induced by prolonged haloperidol treatment.

The influence of hypophysectomy on biochemical indices of striatal dopamine target cell supersensitivity induced by prolonged haloperidol treatment was investigated in the rat. Hypophysectomy itself did not modify dihydroxyphenylacetic acid (DOPAC) levels but slightly enhanced acetylcholine concentrations in the striatum. Hypophysectomy failed to affect the ability of haloperidol, apomorphine and pergolide to alter these biochemical parameters after acute administration. Prolonged administration of haloperidol (by means of osmotic minipumps delivering 2.5 micrograms/h) for 14 days caused a decrease in DOPAC and an increase in acetylcholine levels in the striatum during withdrawal; these effects were of a similar magnitude in sham-operated and hypophysectomized rats. Moreover, there was a similar degree of tolerance to the elevation of DOPAC and to the diminution of acetylcholine concentrations in striatum in response to challenge with haloperidol during withdrawal in sham-operated and hypophysectomized animals. Finally, a similar supersensitive biochemical response to pergolide (decrease in DOPAC and increase in acetylcholine levels) was observed in both hypophysectomized and sham-operated animals after prolonged haloperidol treatment. These data suggest that hypophyseal factors do not affect the development of striatal dopamine target cell supersensitivity caused by prolonged haloperidol treatment.

Acetylcholine↗

PubMed1987

Tolerance to haloperidol-induced increases in dopamine metabolites: fact or artifact?

Haloperidol increased 3,4-dihydroxyphenylacetic acid and homovanillic acid concentrations in the striatum, nucleus accumbens and olfactory tubercle of both drug-naive rats and rats pretreated with haloperidol (10 injections). The increases in metabolite concentrations were greater in all brain regions of the naive rats, suggesting that haloperidol pretreatment resulted in a decreased responsiveness to the drug (tolerance). However, subchronic haloperidol injections also resulted in decreased basal metabolite concentrations in rats killed 48 h after the last injection. While the response of drug-experienced rats to haloperidol was attenuated relative to that of drug-naive rats, this difference could be accounted for entirely by the decreased basal metabolite concentrations that occur after repeated haloperidol injections.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1990

Chronic haloperidol and chlorpromazine treatment alters in vitro beta-endorphin metabolism in rat brain.

To determine if chronic haloperidol (3.0 mg/kg per day) or chlorpromazine (4.2 mg/kg per day) treatment alters central beta-endorphin metabolism, haloperidol and chlorpromazine were perfused via Alzet minipumps into male Sprague-Dawley rats for 8 days. Crude twice-washed membranes, purified synaptic plasma membranes and Golgi-enriched membranes, respectively, were isolated from rat brains and time course incubated with beta-endorphin. All samples were analyzed by high resolution, reversed-phase high performance liquid chromatography. The half-lives of beta-endorphin for animals treated with haloperidol or chlorpromazine were not statistically different from control animals at the crude washed membranes. At the purified synaptic plasma membranes, however, the half-lives of beta-endorphin from haloperidol (t 1/2 = 45.1 min)- and chlorpromazine (t1/2 = 47.0 min)-treated animals were significantly decreased as compared to the control animals (t1/2 = 78.0 min). The half-life of beta-endorphin at the Golgi-enriched membranes was increased for haloperidol (t1/2 = 112.3 min) and chlorpromazine (t1/2 = 103.0 min)-treated animals when compared to control animals (t1/2 = 80.2 min). The findings indicate a differential effect of the dopamine receptor antagonists haloperidol and chlorpromazine on the extracellular fate at the synaptic plasma membranes of beta-endorphin and the intracellular processing at the Golgi-enriched membranes in vitro.

Animals↗

PubMed1991

Alterations in dopamine release from striatal slices of rats after chronic treatment with haloperidol.

The effects of chronic treatment with haloperidol on spontaneous and electrically evoked dopamine (DA) release from striatal slices of rats were investigated in vitro. DA was measured by high-performance liquid chromatography coupled to an electrochemical detector. The superfusion with haloperidol caused a dose-dependent (100 nM-100 microM) reduction in the electrically evoked DA release from striatal slices of rats, which was not antagonized by the superfusion with apomorphine. Chronic administration of haloperidol (1 mg/kg per day for 21 days) caused a significant reduction in electrically evoked DA release as well as in spontaneous DA release from striatal slices 24 h after the last injection. Moreover, pretreatment with haloperidol prevented the reduction of the DA release evoked in response to haloperidol superfusion (1 microM). These results indicated that chronic administration of haloperidol reduced DA release from striatal slices of rats, accompanied by tolerance for the inhibitory effect of drug superfusion on evoked DA release.

Animals↗

PubMed1995

Differential Fos-protein induction in rat forebrain regions after acute and long-term haloperidol and clozapine treatment.

Both acute and long-term effects of haloperidol and clozapine on Fos-like immunoreactive nuclei in several rat forebrain areas were quantified. Rats were treated with saline (1 ml/kg.day, control), haloperidol (1 mg/kg.day) and clozapine (20 mg/kg.day) i.p. for 21 days. Two hours before perfusion fixation a single (acute treatment) or last (long-term treatment) dose of the drug was given. Drug-induced catalepsy and gain in body weight were also measured. A single dose of haloperidol produced large increases in Fos-like immunoreactive nuclei in the striatum, the nucleus accumbens and central amygdala. Following long-term treatment these increases were reduced in all nuclei studied, except the lateral septum. Acute clozapine treatment had slight (if any) effects on the number of Fos-like immunoreactivity-expressing nuclei in the striatum, but the increases in the nucleus accumbens, the lateral septum, the paraventricular and supraoptic nuclei of the hypothalamus and the central amygdala were substantial. Long-term clozapine treatment reduced the acute response significantly in all the areas except the nucleus accumbens. Both haloperidol and clozapine treatment reduced the weight gain of the rats. Haloperidol, but not clozapine, induced catalepsy that remained maximal during the long-term haloperidol treatment. These results indicate that in most brain areas high Fos-protein levels are not necessary to maintain antipsychotic activity or side-effects. The persisting effect of clozapine in the nucleus accumbens may be of significance to the efficacy of this drug in treatment-refractory schizophrenia.

Animals↗

PubMed1992

Quantitative light microscopic demonstration of increased pallidal and striatal met5-enkephalin-like immunoreactivity in rats following chronic treatment with haloperidol but not with clozapine: implications for the pathogenesis of neuroleptic-induced movement disorders.

Acute and late onset movement disorders frequently complicate the treatment of psychosis with typical neuroleptic drugs like haloperidol, but not with atypical neuroleptic drugs like clozapine. Although the neural mechanisms underlying neuroleptic-induced movement disorders remain unknown, alterations in basal ganglia function are likely involved. A potential role for the endogenous opiate peptides in neuroleptic-induced movement disorders is suggested by the immunocytochemical localization of met5-enkephalin (ME) in the striatopallidal projection pathway, and by the increased levels of ME measured by radioimmunoassay in the rat caudate-putamen nuclei (CPN) following haloperidol treatment. We sought to determine whether met5-enkephalin-like immunoreactivity (MELI) in terminal fields within globus pallidus and in perikarya in CPN was differentially altered in rats chronically treated with haloperidol or clozapine. Acrolein-fixed forebrain sections were collected from cohorts of adult rats receiving 21-day oral administration of haloperidol, clozapine, or water. Sections from the three treatment groups were collectively processed for immunocytochemical labeling using varying dilutions of ME antiserum and the avidin-biotin peroxidase method. In globus pallidus, densitometry measures revealed significantly increased levels of immunoperoxidase labeling for ME in haloperidol-treated, but not in clozapine-treated animals. In CPN, optical densitometry as well as cell counting measurements also showed a significant increase in MELI only in the haloperidol-treated group. These results support the concept that alterations in endogenous opiate peptides in basal ganglia may contribute to movement disorders seen in patients receiving typical neuroleptic drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗