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At least 811 records · Page 45Linked to original sources

PubMed1978

Effects of amphetamine and haloperidol on avoidance behavior and exploratory activity.

The effect of graded doses of D-amphetamine and haloperidol were tested on retention of a one trial learning passive avoidance response, on extinction of pole-jumping active avoidance behavior and on open-field activity. Low doses of amphetamine (10 microgram/animal) increased passive avoidance latency when given s.c. 1 h prior to the retention test. Higher doses (20 and 1000 microgram/animal) caused a bimodal distribution of avoidance latencies. Haloperidol (0.03 or 1.0 microgram/animal) significantly attenuated passive avoidance behavior. Amphetamine caused a delay of extinction of pole-jumping avoidance behavior in a dose-dependent manner (10, 30 or 90 microgram per rat). Conversely, haloperidol induced a dose-dependent facilitation of extinction (0.03 or 0.1 microgram per rat). Open-field activity was not significantly affected by 30 microgram amphetamine or 0.03 microgram haloperidol; 90 microgram amphetamine significantly increased rearing activity and 0.1 microgram haloperidol decreased ambulation. The data show that passive and active avoidance behavior are sensitive measures to test the activity of psychomotor stimulant and neuroleptic drugs. Exploratory behavior allows more specific behavioral effects to be dissociated from locomotor influences.

Animals↗

PubMed1981

Haloperidol-induced supersensitivity to the discrimination of apomorphine.

Rats were trained to discriminate between the stimulus properties of intraperitoneal 0.16 mg/kg apomorphine and saline in a two-lever, food-motivated operant task. Once trained, the rats were tested with the ED50 of apomorphine (0.02 mg/kg) or saline before and 1-22 days after a ten-day regimen of daily 2.0 mg/kg administrations of haloperidol. Chronic haloperidol treatment produced increased discrimination of, and lever selection perseverance to, the low dose of apomorphine when rats were tested at 12 days after the withdrawal of haloperidol and this increased discrimination returned to pre-haloperidol levels by the sixteenth day. The results suggest the development of supersensitivity by prolonged pharmacologic blockade of central dopaminergic receptors with haloperidol and indicate the peak and duration of this effect.

Animals↗

PubMed1982

Dopamine metabolites and catalepsy after lithium and haloperidol.

Lithium administered in chow produced a small increase in DA metabolites (DOPAC and HVA) in rat caudate but not cortex and augmented the increase in DA metabolites in both regions produced by haloperidol administration for 2 days. Given for 10 days with haloperidol, lithium attenuated the tolerance to an increase in DA metabolites in caudate. When administered with haloperidol for 22 days, lithium prevented the tolerance to catalepsy produced by daily administration of haloperidol alone. Lithium can augment and prolong the increase in regional DA metabolites and extend the duration of catalepsy produced by chronic haloperidol.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1983

Differential effect of acute and chronic haloperidol administration on dopamine turnover in rat nigrostriatal and retinal dopaminergic neurons.

Haloperidol-induced increases in DOPAC and HVA declined in the striatum but remained unchanged in the retina after chronic pretreatment with haloperidol (1-4 weeks). DA concentrations were unaffected in the striatum but decreased in the retina after acute or chronic haloperidol administration. Light stimulation increased both retinal DA and DOPAC. The findings indicate that acute and chronic haloperidol affect nigrostriatal and retinal DA neurons differentially. In addition, DA neurons in retina respond differently to activations by haloperidol and light.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1988

Repeated administration of HA-966 and haloperidol to rats: similar tolerance to striatal dopamine accumulation after HA-966 challenge, but dissimilar effects on striatal [3H]spiperone binding.

Repeated administration of 1-hydroxy-3-amino-pyrrolidone-2 (HA-966) to rats induces tolerance, as shown by a decreased, drug-stimulated accumulation of dopamine (DA) in the striatum. In the present study we compared the adaptive response of the striatal dopaminergic system to repeated administration of HA-966 with the adaptive response observed after repeated haloperidol. These treatments deprive dopamine (DA) receptors from their agonist and cause a blockade of DA receptors, respectively. Tolerance to HA-966 was not accompanied by a change in the specific binding of [3H]spiperone to striatal membranes. This is in contrast to the well-documented up-regulation of DA receptors that occurs with tolerance to haloperidol. Repeated haloperidol pretreatment also diminished DA accumulation following a challenge dose of HA-966, to a similar extent as that caused by repeated pretreatment with HA-966. These similar effects of pretreatment with HA-966 or haloperidol on the response to the HA-966 challenge are in line with, and strengthen, the idea that an increased sensitivity of presynaptic DA receptors is responsible for the decreasing effect of HA-966 after its repeated administration. Haloperidol and HA-966 clearly have different effects on postsynaptic DA receptors, as is shown by their differential effects on striatal [3H]spiperone binding.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1990

Clozapine fails to prevent the development of haloperidol-induced behavioral hypersensitivity in a cotreatment paradigm.

We have previously established that chronic cotreatments involving antimuscarinic agents and haloperidol attenuate the development of behavioral hypersensitivity without affecting dopamine receptor proliferation. The antipsychotic agent clozapine also has significant antimuscarinic activity and was coadministered with haloperidol in rats for 2 months to determine if it would similarly attenuate the development of hypersensitivity. Clozapine or chlorpromazine cotreatment, unlike thioridazine cotreatment, did not attenuate the development of haloperidol-induced behavioral hypersensitivity. Clozapine or thioridazine cotreatment also failed to prevent the development of haloperidol-induced D2 receptor proliferation, whereas chlorpromazine cotreatment enhanced D2 receptor proliferation relative to haloperidol-treated animals. Alterations in dopamine biochemistry in the striatum or nucleus accumbens could not explain this dissociation between behavioral hypersensitivity and dopamine receptor proliferation. It is therefore hypothesized that dopamine receptor proliferation is permissive for behavioral hypersensitivity and that factors in addition to alterations in dopamine function contribute to the expression of dopamine hypersensitivity states.

Animals↗

PubMed1990

Neurochemical effects of chronic co-administration of ritanserin and haloperidol: comparison with clozapine effects.

The effects of chronic treatment with clozapine (20 mg/kg per day), ritanserin (0.5 mg/kg per day), haloperidol (0.5 mg/kg per day), or the combination of haloperidol and ritanserin, on dopamine (DA) and serotonin (5-HT) metabolism were studied. Chronic haloperidol treatment decreased DA metabolism in nucleus caudatus. Chronic ritanserin treatment failed to alter striatal or mesolimbic DA metabolism but decreased the concentrations of 5-HT and 5-hydroxyindoleacetic acid in the nucleus raphe dorsalis. The effects of chronic haloperidol were not altered by concomitant ritanserin administration. In comparison, chronic clozapine treatment affected neither DA nor 5-HT metabolism. These results show that the biochemical effects of chronic haloperidol treatment on the major ascending DA neurons cannot be modulated by concomitant 5-HT2 receptor blockade.

Animals↗

PubMed1991

Striatal N-methyl-D-aspartate receptors in haloperidol-induced catalepsy.

Bilateral ablation of the frontal cortex of rats markedly reduced the catalepsy induced by haloperidol (1 mg/kg i.p.). Similarly, the selective antagonist of N-methyl-D-aspartate (NMDA) receptors, D(-)-2-amino-5-phosphonopentanoic acid (10 micrograms/side), injected bilaterally into the rostral part of the caudate-putamen (CP) reduced haloperidol-induced catalepsy whereas its injection into the intermediate part of the CP was ineffective. The quisqualate receptor antagonist, L-glutamic acid diethyl ester (100 micrograms/side), did not affect haloperidol-induced catalepsy when injected into the rostral part of the CP. On the other hand, NMDA (1 micrograms/side) injected bilaterally into the rostral part of the CP was able to restore haloperidol-induced catalepsy in frontally decorticated rats without any notable cataleptic effect of its own. These findings suggest that a certain degree of tonic stimulatory effect of corticostriatal glutamatergic pathways on NMDA receptors within the rostral part of the CP is a prerequisite for the expression of the cataleptogenic action of haloperidol.

Animals↗

PubMed1992

Co-administration of progabide inhibits haloperidol-induced oral dyskinesias in rats.

Vacuous chewing movements in rats may be an animal analogue of the human motor disorder, tardive dyskinesia. The movements are phenomenologically and pharmacologically similar to tardive dyskinesia. The pathophysiology of these involuntary oral movements, and perhaps of tardive dyskinesia, are likely to include both dopamine receptor changes, and alterations in GABA (gamma-aminobutyric acid) system function. In an attempt to test the involvement of GABA system dysfunction in these movements, we treated rats chronically with water alone, haloperidol alone, the GABA agonist progabide alone, and haloperidol plus progabide. Sprague-Dawley rats received haloperidol (1.5 mg/kg per day) in their drinking water and progabide (100 mg/kg per day) in their food for 12 months. After 12 months of treatment, haloperidol had induced vacuous chewing movements when administered alone, but the prevalence of the movements was decreased by 40% with the coadministration of progabide. Moreover, the haloperidol-progabide-treated animals did not merely demonstrate movement suppression but actual inhibition of movement onset, as determined by an additional progabide-withdrawal experiment. These data would suggest that progabide and perhaps other GABAmimetic compounds can prevent the development of tardive dyskinesia in man.

Administration, Oral↗

PubMed1992

Haloperidol-induced vacuous chewing in rats: suppression by alpha-methyl-tyrosine.

Chronic treatment of rats with haloperidol (1 mg/kg twice daily for 4 weeks) induced repetitive vacuous chewing movements (VC), that persisted for over 72 h after haloperidol withdrawal. Haloperidol-induced VC were inhibited by the s.c. administration of the specific dopamine D1, receptor antagonist, SCH 23390 (0.025-0.100 mg/kg), in a dose-dependent manner, and were totally suppressed by an acute challenge with haloperidol (2 mg/kg i.p.) and by the dopamine synthesis inhibitor, alpha-methyl-tyrosine (AMT) (200 mg/kg i.p.). In AMT-treated rats, VC were reinstated by the administration of the selective D1 agonist, SKF 38393. The results support the hypothesis that chronic haloperidol-induced VC are mediated by dopamine acting selectively upon D1 receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1993

Haloperidol interacts with the strychnine-insensitive glycine site at the NMDA receptor in cultured mouse hippocampal neurones.

N-Methyl-D-aspartate (NMDA)-evoked responses in voltage-clamped hippocampal neurones in culture were reversibly, but not completely, attenuated on superfusion with micromolar concentrations (0.1-100 microM) of haloperidol with an IC50 (+/- S.E.M.) value of 1.9 +/- 0.2 microM (n = 7). In contrast, kainate- and (RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-evoked responses were relatively unaffected on application of 50 microM haloperidol. The NMDA receptor antagonist action of haloperidol was neither competitive in nature nor voltage-dependent but was reduced upon elevation of the extracellular concentration of glycine. Furthermore, in the absence of added glycine haloperidol (at 0.1 microM) frequently potentiated NMDA-evoked responses. Haloperidol thus appears to be a partial agonist for the strychnine-insensitive glycine site associated with the NMDA receptor-channel complex.

Animals↗

PubMed1993

The effects of haloperidol and raclopride in the paw test are influenced similarly by SCH 39166.

We investigated the role of dopamine D1 and D2 receptors in the paw test, an animal model used to assess both the antipsychotic potential and extrapyramidal side effects of drugs. The dopamine D1 receptor antagonist, SCH 39166, as well as the dopamine D2 receptor antagonist raclopride, increased the hindlimb retraction time (HRT), viz. a parameter that models antipsychotic potential, at doses that were lower than those that increased the forelimb retraction time (FRT), viz. a parameter that models extrapyramidal side effects. In contrast, the same dose of haloperidol enhanced both parameters. SCH 39166 enhanced the haloperidol- and raclopride-induced effects on FRT, whereas neither haloperidol nor raclopride enhanced the SCH 39166-induced effects upon this parameter. Except at very high doses, SCH 39166 did not alter the haloperidol- and raclopride-induced effects on HRT, and vice versa. No difference between haloperidol and raclopride was found in the interaction experiments. The clinical impact of these findings is discussed.

Animals↗

PubMed1993

Chronic treatment with haloperidol modifies the sensitivity of autoreceptors that modulate dopamine release in rat striatum.

The effects of apomorphine or sulpiride on electrically evoked dopamine release from striatal slices of rats pretreated with haloperidol were investigated. Chronic haloperidol treatment (1 mg/kg per day for 21 days) significantly reduced electrically evoked dopamine release from striatal slices until 72 h after the last injection. The apomorphine-induced reduction and the sulpiride-induced increase in evoked dopamine release were significantly enhanced by the chronic treatment with haloperidol at 72 h after the last injection. The enhancement of the sulpiride-induced increase in evoked dopamine release was inversely correlated with the dopamine release evoked by the first stimulation in striatal slices from haloperidol-treated (r = -0.85, n = 12, P < 0.01) but not from saline-treated rats. These results suggest that an increase in the sensitivity of dopamine autoreceptors due to chronic treatment with haloperidol could partially account for the reduction in dopamine release from striatal slices of rats.

Animals↗

PubMed1994

Persistent oral dyskinesias in haloperidol-withdrawn neonatal 6-hydroxydopamine-lesioned rats.

Because chronic haloperidol-treated rats demonstrate an increased incidence of spontaneous oral activity, while neonatal 6-hydroxydopamine-lesioned rats demonstrate an increased incidence of dopamine agonist-induced oral activity, we studied the influence of haloperidol in 6-hydroxydopamine-lesioned rats. At 3 days after birth rats received 6-hydroxydopamine hydrobromide (200 micrograms intracerebroventricularly; desipramine pretreatment, 20 mg/kg i.p., 1 h) or vehicle. Two months later haloperidol (1.5 mg/kg per day x 2 days per week, for 4 weeks; then 1.5 mg/kg per day, every day for 10 months) was added to the drinking water. After 15 weeks the level of spontaneous oral activity was stable. At 11 months there were 35.8 +/- 4.9 vs. 18.4 +/- 2.1 oral movements in 6-hydroxydopamine-lesioned vs. intact rats receiving haloperidol. This effect persisted unabated in lesioned rats for 4 months after haloperidol withdrawal. This stable high frequency of oral dyskinesias is an advantage for studying putative therapeutic drugs for tardive dyskinesia.

Animals↗

PubMed1995

The subsensitivity of striatal glutamate receptors induced by chronic haloperidol in rats.

The aim of the present study was to investigate the influence of chronic treatment with haloperidol on the contralateral head turns and rotations induced by intrastriatal agonists of NMDA and non-NMDA receptors in rats. N-Methyl-D-aspartate (NMDA, 500 ng/0.5 mu l), alpha-amino-3-hydroxy-5-methyl-4-isoxasole-propionic acid (AMPA, 1000 ng/0.5 mu l) or kainic acid (50 ng/0.5 mu l), injected into the intermediate and caudal parts of the caudate-putamen, induced contralateral head turns and rotations. Haloperidol was given to animals in a dose of ca. 1 mg/kg per day in drinking water for 6 weeks. On day 5 of withdrawal, haloperidol decreased the number of contralateral head turns, but did not significantly influence the contralateral rotations induced by NMDA, AMPA and kainic acid. At the same time, haloperidol enhanced the stereotypy induced by apomorphine (0.25 mg/kg s.c.). The present results seem to suggest that, apart from supersensitivity to dopamine, chronic treatment with haloperidol also induces subsensitivity of striatal NMDA and non-NMDA receptors.

Animals↗

PubMed1996

Subchronic haloperidol administration decreases aminopeptidase N activity and [Met5]enkephalin metabolism in rat striatum and cortex.

Previously we have shown that subchronic intraperitoneal (i.p.) administration of haloperidol decreases the degradation of [Met5]enkephalin by regional brain slices (Waters et al., 1995, J. Pharmacol. Exp. Ther. 274, 783). In the present study, subchronic (7-day i.p.) administration of haloperidol (1 mg/kg) decreased the accumulation of aminopeptidase-derived fragments Tyr and Gly-Gly-Phe-Met on cortical and striatal slices. The accumulation of Tyr-Gly-Gly, however, was not altered by haloperidol treatment on slices from either region. Further, aminopeptidase N activity was decreased in P2 membranes isolated from either the cortex or striatum of haloperidol-treated animals. These data suggest that the haloperidol-induced decrease in [Met5]enkephalin metabolism results, at least in part, from a reduction in the activity of aminopeptidase N.

Amino Acid Sequence↗

PubMed1996

Arginine-aspartate and haloperidol-induced neurobehavioral effects in the rat.

This study determined the effects, in the rat, of 8-day treatment with arginine-aspartate on haloperidol-induced catalepsy, decrease of locomotor activity and change of striatal dopamine, homovanillic acid (HVA) and dihydroxy-phenylacetic acid (DOPAC) content. Arginine-aspartate was able to attenuate the haloperidol-induced decrease of locomotor activity and to significantly reduce the catalepsy. Moreover, arginine-aspartate treatment itself increased striatal dopamine content and produced a significant decrease of the HVA/dopamine ratio. Pretreatment with arginine-aspartate was able to partially counteract the haloperidol-induced changes of dopamine metabolism: the haloperidol-induced increases of the DOPAC/dopamine and HVA/dopamine ratios were significantly reduced in arginine-aspartate- pretreated rats. These results suggest that the action of arginine-aspartate on haloperidol-induced neurobehavioral effects is probably mediated by interference with striatal dopaminergic innervation.

Animals↗

PubMed1983

Electric convulsive therapy (ECT) increases plasma and red blood cell haloperidol neuroleptic activities.

In nine schizophrenic patients (five males and four females) on haloperidol treatment, plasma and red blood cell (RBC) haloperidol neuroleptic activities were measured before and after ECT by radioreceptor assay. Five patients randomly selected from these patients also served as controls on another occasion and neuroleptic activities in plasma and RBC were examined before and after the premedication only. All patients given ECT showed a considerable increase in plasma and RBC haloperidol neuroleptic activities after ECT (% increase in plasma neuroleptic activity, 28-409%; mean + SD, 136 +/- 155%, P less than 0.005, Wilcoxon test; % increase in RBC neuroleptic activity, 11-121%; mean + SD, 59 +/- 40%, P less than 0.005). However, no significant increase was observed for either plasma or RBC haloperidol neuroleptic activity, when patients were examined after premedication only. It was suggested that ECT induced a transient redistribution of haloperidol. It remains to be studied whether this phenomenon is causally related to the previous observation that the combination therapy of ECT and neuroleptics is more effective in the treatment of schizophrenia than ECT alone.

Adult↗