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PubMed1997

The effects of haloperidol on visual search, eye movements and psychomotor performance.

The effects of single doses of haloperidol (2, 4 and 6 mg) were compared with lorazepam 2.5 mg and placebo in 15 healthy subjects. Visual search strategy was measured, along with a range of psychomotor and eye movement tests. Patients with Parkinson's disease have been shown to exhibit a shift from parallel to serial processing in visual search, but we demonstrated that this does not occur following administration of either haloperidol or lorazepam. Haloperidol was detected by visual analogue rating scales and peak saccadic velocity, the latter being the more sensitive measure. Haloperidol had no statistically significant effect on smooth pursuit position error, velocity error or saccadic intrusions. Digit symbol substitution performance was clearly diminished by haloperidol, but there was no effect on the continuous attention test. Lorazepam decreased performance in all tests apart from saccadic latency.

Adolescent↗

PubMed1998

Effects of subchronic administration of clozapine, thioridazine and haloperidol on tests related to extrapyramidal motor function in the rat.

Clozapine, thioridazine (THIO) and haloperidol were administered for 14 consecutive days, and separate groups of rats were used to study the effects of these drugs on tremulous jaw movements and lever pressing. Rats were observed on day 13 for the ability of the antipsychotic drugs to induce jaw movements. Haloperidol produced a dose-related increase in jaw movements, while clozapine and THIO failed to induce jaw movements. On day 14, rats were challenged with 5.0 mg/kg of the anticholinesterase tacrine, which induces a very high level of jaw movement activity. Clozapine significantly reduced tacrine-induced tremulous jaw movements, while haloperidol did not. Although previous work had shown that acute THIO could suppress jaw movements, repeated THIO failed to do so. In order to provide an additional behavioral test for comparisons of the relative potencies of the antipsychotic drugs, rats were tested for the effects of these drugs on fixed ratio 5 lever pressing. All three drugs significantly suppressed lever pressing. Haloperidol showed sensitization with repeated injections, while clozapine showed tolerance. Data were analyzed by taking the ratio of the ED50 for suppression of tacrine-induced jaw movement over the ED50 for suppression of lever pressing on day 14. Clozapine reduced tacrine-induced jaw movements in a dose range slightly lower than that required for reduction of lever pressing. In contrast, THIO and haloperidol failed to affect tacrine-induced jaw movements even at doses that were 5-18 times the ED50 for suppression of lever pressing. Thus, tests of jaw movement activity and lever pressing after repeated administration may be useful for assessing atypical antipsychotic drugs.

Animals↗

PubMed1999

Effects of acute and chronic administration of olanzapine in comparison to clozapine and haloperidol on extracellular recordings of substantia nigra reticulata neurons in the rat brain.

RATIONALE: Previously, we have shown that the atypical antipsychotics clozapine and risperidone, unlike haloperidol, decreased the firing rate of substantia nigra reticulata (SNR) neurons. As the SNR receives substantial input from the striatum, an area where motoric side-effects of antipsychotics are thought to be mediated, the SNR might be an interesting brain structure with regard to motor side-effects. OBJECTIVE: The newly developed atypical antipsychotic olanzapine was studied for its effects on the firing rate of SNR cells. In addition, to gain insight in the implications of our experimental setup for clinical use, responses upon clozapine, olanzapine and haloperidol were studied after chronic treatment. METHODS: In chloralhydrate-anaesthetized male Wistar rats, extracellular recordings were made from SNR neurons upon intravenously (i.v.) administered cumulative doses of the antipsychotics. Naive rats and rats that were subcutaneously (SC) injected for 21 days with an antipsychotic were used. RESULTS: Olanzapine (50-1600 mg/kg; i.v.), significantly inhibited the firing rate of the SNR neurons. Upon 21 days of treatment with a daily SC injection of 20 mg/kg clozapine, the challenge on day 22 with cumulative injections of clozapine (200 6400 mg/kg; i.v.) significantly inhibited the firing rate of the SNR neurons. Olanzapine (50-1600 mg/kg; i.v.) also significantly inhibited the SNR activity when pretreated with olanzapine in an SC administered dose of 1 mg/kg, but not 5 mg/kg. Haloperidol (12.5-800 microg/kg; i.v.) did not significantly affect the SNR activity in rats pretreated with SC administered 0.5 mg/kg haloperidol. CONCLUSIONS: Upon acute and chronic administration of clozapine and olanzapine versus haloperidol, differential effects on SNR neuronal firing could be obtained. The experimental setup seem to be valid for further studies into the mechanism of action of typical versus (relatively low doses of) atypical antipsychotics. The implications of the inhibitory effect of atypical antipsychotics on the SNR firing rate are presently unknown, but could be associated with the lower propensity to induced motoric side-effects. On the other hand, the SNR activity might also reflect non-motoric activity possibly related to negative symptoms.

Animals↗

PubMed2003

Olanzapine, risperidone and haloperidol in the treatment of adolescent patients with schizophrenia.

OBJECTIVES: To evaluate and compare the drug response and side effects of adolescents with schizophrenia treated with olanzapine, risperidone, and haloperidol. METHODS: Forty-three patients were treated with olanzapine (n = 19), risperidone (n = 17) and haloperidol (n = 7) for 8 weeks in an open clinical trial. Clinical improvement was evaluated with the Positive and Negative Syndrome Scale (PANSS), and side effects with the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale. RESULTS: Significant clinical improvement was observed by week 4 for all medications. Olanzapine and haloperidol induced fatigability more frequently than risperidone. Haloperidol was associated with a higher frequency of depression and more severe extrapyramidal symptoms. CONCLUSIONS: To the best of our knowledge this is the first study in adolescents to compare the efficacy and side effects of three most commonly prescribed antipsychotic medications. Olanzapine, risperidone and haloperidol appear to be equally effective for the treatment of schizophrenia in adolescent inpatients but have different side effect profiles.

Adolescent↗

PubMed1998

Adult treatment with haloperidol increases dentate granule cell proliferation in the gerbil hippocampus.

Male gerbils were bred and reared grouped under enriched semi-natural environmental conditions. The objective of the present study was to examine the influence of an acute treatment with the neuroleptic haloperidol on adult granule cell neurogenesis in the hippocampus. For that purpose, at the age of postnatal day 90 adult animals received 4 challenges of either haloperidol (5 mg/kg, i.p.) or saline. Proliferation of granule cells was identified by in-vivo labeling with 5-bromo-2'-desoxyuridine (BrdU) which was applied 1 hour after the final dose of haloperidol. BrdU-labeled granule cell nuclei were identified in consecutive horizontal slices along the mid-septotemporal axis of the hippocampus and light-microscopically quantified 7 days after the BrdU-labeling. It was found that in both saline- and haloperidol-treated animals there was a highly significant spatial septotemporal gradient in granular cell proliferation with numbers of BrdU-labeled cells gradually declining from the septal towards the temporal pole. The acute treatment with haloperidol stimulated granule cell proliferation by about 75% and the septotemporal gradient of mitotic activity became significantly enhanced. The present results are discussed with regard to known factors regulating cell proliferation in the hippocampus and other cell systems.

Animals↗

PubMed1987

Enzymatic hydrolysis of haloperidol decanoate and its inhibition by proteins.

When [14C]haloperidol decanoate, a long-acting neuroleptic and an ester of haloperidol and decanoic acid, was incubated in human whole blood and plasma and in rat plasma and homogenates of rat brain, lung, liver, kidney, pancreas and muscle, no hydrolysis of the ester was seen. Although the decanoate was hydrolyzed by partially purified carboxylesterase, addition of rat plasma or liver homogenate to the enzymic reaction mixture resulted in marked inhibition of hydrolysis, whereas addition of the defatted residues of plasma or liver produced only partial inhibition. The enzymic hydrolysis was inhibited also by beta-lipoprotein and albumin, depending on their concentrations. The assumption that interaction between haloperidol decanoate and protein resulted in inhibition of the hydrolytic reaction mediated by the enzyme was validated by kinetic models and experimental data. The kinetics were apparently competitive. Based on the kinetic analysis, the interaction between the decanoate and albumin or beta-lipoprotein was investigated by measuring their equilibrium constants and extent of protein binding. Haloperidol decanoate appeared to interact with several proteins; this was exemplified by other measures of protein binding, an increasing effect of proteins on the solubility, and the partition ratio of the ester. The interaction between haloperidol decanoate and proteins caused marked stabilization of this ester against enzymatic hydrolysis and, thereby, influenced its metabolism.

Animals↗

PubMed1990

Quantitative analyses of plasma cholinesterase isozymes in haloperidol-treated rats.

We describe a quantitative slab gel electrophoresis procedure that allows quantitative determination of plasma levels of discrete cholinesterase isozymes. Using this method, the effects of haloperidol treatment on plasma cholinesterase isozyme levels were examined in normal rats. Eight isozymes were detected by enzymatic reaction with either of two substrates (alpha-naphthyl acetate, NA; acetylthiocholine iodide, AcTCh), and then quantified using densitometric scanning. With AcTCh substrate, the activities of two major isozymes (1 and 2) were found to be linear with increasing quantities of applied plasma. With NA as substrate, Iso-OMPA (a pseudocholinesterase inhibitor) inhibited activities of all isozymes, except isozymes 2 and 8. With either substrate, BW284C51 (acetylcholinesterase inhibitor) inhibited 100% and 13% of activity of isozymes 2 and 8, respectively, and with AcTCh substrate, 37% of isozyme 1. Based on the differential patterns of substrate specificity and action of inhibitors, and the reproducibility of patterns, we propose that these isozymes represent distinct molecular species. Short-term (14 days) and long-term (45 days) haloperidol treatment both resulted in altered levels of specific cholinesterase (ChE) isozymes. On the average, with AcTCh substrate, haloperidol treatment increased levels of isozymes 1 and 2 by 30% and 8%, respectively, after 14 days, and by 50% and 30%, respectively, after 45 days. Isozymes 3 through 8 showed minor changes. Plasma levels of isozymes 1 and 2 returned to baseline pretreatment values after a 40-day drug-free period. No significant change was observed after either short- or long-term treatment with clozapine, imipramine, or saline, or after an acute (less than 5 days) haloperidol treatment. No change was noted in RBC-ChE levels as function of treatment. These findings indicate that, in the rat, chronic haloperidol treatment results in differential changes in the plasma levels of discrete ChE isozymes. We have suggested that these changes reflect an alteration of central dopaminergic-cholinergic balance.

Acetylcholinesterase↗

PubMed1991

Failure of haloperidol to block the effects of phencyclidine and dizocilpine on prepulse inhibition of startle.

Prepulse inhibition of acoustic or tactile startle (PPI), a form of sensorimotor gating, occurs when a weak prestimulus precedes a startling stimulus and inhibits the startle response. Studies of PPI have revealed that schizophrenic patients exhibit a deficit in this form of sensorimotor gating. In rats, PPI is blocked by dopamine agonists such as apomorphine or quinpirole, effects that are antagonized by haloperidol. Phencyclidine (PCP) has been suggested as a possible model psychotogen and produces a deficit in PPI that is similar to what is observed in schizophrenic patients. Dizocilpine is an anticonvulsant drug that, like PCP, is a noncompetitive antagonist of N-methyl-D-aspartate (NMDA)-induced excitations in brain and also disrupts PPI. In the present study, PPI of acoustic and tactile startle was measured in male Sprague-Dawley rats after injections of 5.0 mg/kg PCP with or without pretreatment with 0.02 or 0.1 mg/kg haloperidol, or with 0.5 mg/kg dizocilpine with or without pretreatment with 0.1 mg/kg haloperidol. The 0.1 mg/kg dose of haloperidol blocks the effects of apomorphine or quinpirole on PPI in rats. Startle was elicited by noise bursts at 105 or 120 dB or by air-puffs (tactile) and was inhibited by 75 or 85 dB prepulse stimuli presented 100 msec before the startle stimuli. The different eliciting stimuli produced different levels of startle in both control and drug-treated animals. Both NMDA antagonists significantly reduced the amount of PPI induced by the 75 dB prestimulus, independently of the level of startle responses elicited by the startle stimuli. Haloperidol did not block the disruption of PPI induced by either PCP or dizocilpine. In addition, PCP was unable to block PPI when the 85 rather than the 75 dB prepulse was used to inhibit either acoustic or tactile startle. These results confirm that putative NMDA antagonists inhibit sensorimotor gating in rats and suggest that these effects are not mediated by the activation of central dopamine systems.

Animals↗

PubMed1994

Comparative study of dopamine metabolism with local cerebral glucose utilization in rat brain following the administration of haloperidol decanoate.

The effects of haloperidol decanoate on dopamine (DA) metabolism in discrete regions of rat brain were investigated and compared with changes in local cerebral glucose utilization (LCGU). The concentration of DA and its metabolite, homovanillic acid, and the alpha-methyl-p-tyrosine (alpha-MT)-induced decline of DA were measured in 6 brain regions by a high-performance liquid chromatographic assay. LCGU in 26 brain regions were examined by [14C]2-deoxy-D-glucose autoradiography. At 24-hr after intramuscular injection of haloperidol decanoate (60 mg eq/kg to haloperidol), the concentration of homovanillic acid in the prefrontal cortex, caudate-putamen, accumbens nucleus, lateral amygdala, and medial thalamus showed significant increase compared with control values. On day 21, the increase in these regions was significantly attenuated with no significant difference from the controls. Furthermore, chronic haloperidol rats showed alpha-MT-induced decline of DA to a similar extent in the control rats. LCGU on day 21 showed significant decrease in the parietal cortex, and a tendency toward decrease in the prefrontal cortex, lateral amygdala and medial thalamus compared with the controls. There was no significant change in LCGU in the caudate-putamen or accumbens nucleus. Chronic haloperidol would thus appear to affect energy metabolism mainly in the cortico-thalamo-limbic circuits, and this may not correspond well to presynaptic DA metabolism.

Animals↗

PubMed1996

Prolactin monitoring of haloperidol and pimozide treatment in children with Tourette's syndrome.

Neuroleptic therapy of children and adolescents with Tourette's syndrome (GTS) is associated with unpredictable outcome and adverse drug responses (i.e., extrapyramidal symptoms). Assessing the potential outcomes in GTS from a physiologic marker such as plasma prolactin concentration is important in limiting exposure and optimizing therapy. In a double-blind, placebo-controlled, double crossover comparison of pimozide and haloperidol therapy, prolactin, tic severity, and extrapyramidal symptoms were assessed at a 6-week end point. Twenty-six GTS patients (10.5 +/- 2.6 years), experienced clinical response rates of 69% on 3.4 +/- 1.6 mg pimozide and 65% on 3.5 +/- 2.2 mg/day haloperidol. Pimozide responders demonstrate elevated prolactin (26.1 +/- 11.8 ng/mL) versus pimozide nonresponders (10.5 +/- 3.8 ng/mL) (p = .05) and haloperidol treated patients (p = .05). Prolactin may be a marker for tic response to pimozide, and conversely, a potential marker for haloperidol-related incidence of extrapyramidal symptoms during haloperidol therapy.

Adolescent↗

PubMed1980

Morphine versus haloperidol catalepsy in the rat: a behavioral analysis of postural support mechanisms.

Our experiments demonstrate that morphine and haloperidol produce two distinct and contrasting behavioral states, which can be thought of as exaggerated, isolated, and simplified forms of organized adaptive behavioral states functioning as components of normal motivated behavior. Haloperidol catalepsy constitutes an organized state in which tonic reactions subserving the maintenance of stable static equilibrium prevail, at the expense of phasic locomotor reactions. In contrast, morphine produces an immobility state characterized by inhibition of the postural support subsystem, and compatible with or preparatory to locomotor rather than static postural reactions. haloperidol-treated rats (1, 2.5, 5, 10 mg/kg i.p.) display exaggeraged bracing reactions to passive displacement as well as to stimuli which do not actively challenge stable equilibrium. In contrast, rats treated with morphine sulfate (10, 20, 40, 80 mg/kg i.p.) show a dose-dependent suppression of bracing and an exaggerated tendency to run in response to stimuli which produce bracing in haloperidol-treated rats. Further evidence that haloperidol-treated rats are organized to stand still in stable equilibrium includes their typical posture during akinesia (i.e. broad-based support), bradykinesia, tonic grasping and enhanced postural components of contact- and air-righting. Under morphine, however, the postural support subsystem is dispensed with, as evidenced by the posture of akinesia (i.e. a frozen phase of the locomotor step cycle associated with loss of limb support), absence of tonic grasping, and nature of the deficits in contact- and air-righting. Furthermore, the opiate-induced immobility state is accompanied by an increased readiness to locomote. Morphine produces an alternation between two extreme behavioral states: complete immobility (inhibition of the postural support subsystem) versus locomotor paroxysms (varying degrees of 'explosive motor behavior'). We suggest that the postures or actions adopted by morphine-treated rats involve movement subsystems concerned with the adaptive behavioral state known as the 'immobility reflex' ('tonic immobility', 'animal hypnosis').

Animals↗

PubMed1982

Distribution of effects of haloperidol on energy metabolism in the rat brain.

The effects of the putative dopaminergic antagonist, haloperidol (0.01-10 mg/kg, i.v.), on cerebral glucose utilization in 43 anatomically discrete regions of the rat brain have been examined by the quantitative autoradiographic 2-deoxyglucose technique. Dose-dependent reductions in glucose utilization were observed in 10 regions of the CNS (e.g. hippocampus, ventral thalamus and almost the entire neocortex, with the notable exception of anterior cingulate cortex). Two regions of the CNS (nucleus accumbens and pars compacta of the substantia nigra) displayed dose-related increases in glucose utilization following haloperidol administration. In addition to these specific alterations, the largest doses of haloperidol produced widespread, moderate (about 25%) reductions in glucose utilization throughout the CNS. The prior administration of haloperidol (0.1 mg/kg) prevented the effects on glucose utilization of the administration of apomorphine (1.5 mg/kg) in all regions of the CNS examined. The distribution of alterations in glucose utilization following haloperidol administration are considered in relation to the overall functional consequences of dopaminergic receptor blockade.

Animals↗

PubMed1983

Influence of sex steroids and prolactin on haloperidol-induced catalepsy.

The effects of sex steroids and prolactin on haloperidol-induced catalepsy were investigated in male rats. Repeated administration with estradiol benzoate (5 micrograms/rat, twice daily for 10 days) significantly potentiated catalepsy induced by 0.25 or 0.5 mg/kg haloperidol, but no effect was observed 10 min or 1 h after a single injection of estradiol benzoate (5 or 50 micrograms/rat). Conversely, a single administration with the catecholestrogen 2-hydroxyestradiol (50 micrograms/rat) significantly increased haloperidol-induced catalepsy, suggesting that catecholestrogens may directly interfere with nigrostriatal dopaminergic transmission. Haloperidol-induced catalepsy has been found to be attenuated in conditions of hyperprolactinaemia resulting from anterior pituitary isograft underneath the kidney capsule. This is consistent with the hypothesis that prolactin may stimulate nigro-striatal dopaminergic function. Results obtained also indicate that medroxy-acetate progesterone, a progesterone derivative, may influence haloperidol-induced catalepsy. Specifically, a single administration with medroxy-acetate progesterone (5 mg/kg, i.p.) enhanced catalepsy but opposite effects were observed after repeated administration of medroxy-acetate progesterone (5 mg/kg, i.p., once a day for 7 days).

Animals↗

PubMed1984

Increase of calmodulin-stimulated striatal particulate phosphorylation response in chronic haloperidol-treated rats.

Calcium- and calmodulin-dependent protein kinase and phosphatase activities were studied in rat striatal particulate preparations. The effect of Ca2+ (0.1-0.5 mM) on phosphorylation was completely abolished in the preparation which had been washed 3 times with a buffer containing ethylene glycol bis-(beta-aminoethyl ether)-N,N'-tetraacetic acid (EGTA, 1.2 mM). Ca2+-stimulated phosphorylation was restored in a dose-dependent manner after calmodulin (1 microgram) was added to the assays. Ca2+ and calmodulin promoted the phosphate incorporation into two major striatal protein bands with estimated Mr at 52 and 40 kdaltons. The presence of phosphatase in the EGTA-pretreated preparations was negligible. Chronic treatment in rats with haloperidol (1 mg/kg, 20 days) produced a significant decrease in the Ca2+-independent phosphorylation but an increase in the extent of Ca2+ and calmodulin-dependent phosphorylation in the striatum. The chronic haloperidol treatment did not alter the striatal [125I]calmodulin binding curve. In vitro, haloperidol (even at 10(-4) M) had no effect on calmodulin-dependent phosphorylation. Haloperidol (10(-4) M) did not reduce the number but decreased the rate of [125I]calmodulin bindign to the striatal particulates. These data suggest that the link between dopamine receptors and calmodulin-dependent enzyme is dissociated in vitro. On the other hand, the potentiated sensitivity of calmodulin-dependent protein kinase in the chronic haloperidol-treated rats correlated with the supersensitive dopamine receptor responses occurred in these rats. Therefore, calmodulin-dependent protein kinase may biochemically regulate dopamine receptor functions in the striatum in vivo.

Animals↗

PubMed1989

Effects of acute and chronic treatments with clozapine and haloperidol on serotonin (5-HT2) and dopamine (D2) receptors in the rat brain.

The effects of acute and chronic treatments with haloperidol or clozapine on the binding of [3H]spiperone to D2 and 5-HT2 receptors were examined in 6 discrete regions of the striatum, n. accumbens and frontal cortex using quantitative autoradiography. Acute treatment with haloperidol, 0.1-2.0 mg/kg, i.p., produced a dose-dependent reduction to 60% of control in the binding of [3H]spiperone to D2 receptors in the striatum and n. accumbens and no effect on the binding of [3H]spiperone to 5-HT2 receptors in the striatum, n. accumbens or frontal cortex. Acute treatment with clozapine, 10-40 mg/kg, i.p., produced a dose-dependent reduction in D2-specific binding in both the n. accumbens and the striatum and also significant reductions to 24% of control in the binding of [3H]spiperone to cortical 5-HT2 receptors. Chronic treatment with haloperidol, 1 mg/kg/day, i.p., significantly increased (40-65%) the maximal number of D2-specific [3H]spiperone binding sites in the n. accumbens and the dorsolateral and ventrolateral regions of the striatum, whereas small increases (20-29%) were seen in the ventromedial, dorsomedial, rostral and caudal regions of the striatum. Chronic treatment with clozapine, 20 mg/kg/day, i.p., did not change the maximal number of D2 receptors in the n. accumbens or any region of the striatum. Chronic treatments with clozapine produced a decrease in the maximal number of cortical 5-HT2 receptors to 55% of control whereas haloperidol had no effect. This study demonstrates regional differences in the up-regulation of striatal D2 receptors following chronic treatment with haloperidol and different effects of a typical and atypical neuroleptic on 5-HT2 receptors following acute and chronic treatments.

Animals↗

PubMed1992

Comparative effects of electroconvulsive shock and haloperidol on in vivo tyrosine hydroxylation and tetrahydrobiopterin in the brain of rats with 6-hydroxydopamine lesions.

We have evaluated the effects of electroconvulsive shock (ECS) and haloperidol treatment on the in vivo tyrosine hydroxylation rate and the tetrahydrobiopterin levels in the nigrostriatal system of 6-OHDA-lesioned rats. The rate of DOPA accumulation was significantly decreased by 96% in the ipsilateral striatum and by 50% in substantia nigra of the 6-OHDA-lesioned rats compared to the control activity of contralateral non-lesioned striatum and substantia nigra. The loss of total biopterin was found to be 75% and 50% in the ipsilateral striatum and substantia nigra, respectively. Following administration of haloperidol, the rate of DOPA accumulation increased significantly in the striatum and substantia nigra on the lesioned side compared to that in the vehicle treatment group. Application of ECS also significantly increased the rate of DOPA accumulation in the ipsilateral striatum and substantia nigra compared to that obtained in the non-shocked rats. The biopterin levels in the nigrostriatal system of 6-OHDA-lesioned were elevated significantly in the striatum after haloperidol treatment; in contrast the biopterin levels were unchanged in response to ECS. Our results show that both haloperidol and ECS significantly enhanced the rate of in vivo tyrosine hydroxylation in the striatum and substantia nigra of rats with greater than 90% lesions. These results suggest that the nigrostriatal system, although up-regulated following 6-OHDA lesions, still maintains the potential for further up-regulation of dopaminergic function in response to haloperidol and ECS treatment.

Animals↗

PubMed1995

Effect of muscimol on haloperidol-induced alteration of neurotensin gene expression in the striatum and nucleus accumbens in the rat.

Acute neuroleptic administration increases the expression of neurotensin/neuromedin (NT/N) gene in rat dorsolateral striatum and shell sector of the nucleus accumbens. The purpose of this study was to examine modulation of neuroleptic induction of NT/N and the proto-oncogene c-fos expression by the GABAA agonist muscimol. Adult male Sprague-Dawley rats were treated with saline, haloperidol (1 mg/kg); muscimol (3.2 mg/kg); or haloperidol (1 mg/kg) plus muscimol (3.2 mg/kg). Animals were sacrificed 1 h after drug administration. Expression of NT/N and c-fos mRNA was examined by in situ hybridization using 35S-antisense probes. Muscimol alone had no measurable effect on basal levels of NT/N or c-fos mRNA in either the dorsolateral striatum or the nucleus accumbens. However, co-administration of muscimol with haloperidol reduced haloperidol-induced increases in NT/N as well as c-fos mRNA in the dorsolateral striatum. In contrast, NT/N mRNA expression in accumbal shell induced by haloperidol was not modulated by co-administration of muscimol. These data suggest that GABAA receptors may be involved in regulation of NT/N gene expression in the DLSt, but not in the nucleus accumbens.

Animals↗

PubMed1977

Tolerance of haloperidol catalepsy.

Haloperidol (0.75 and 1.5 mg/kg p.o.) was administered daily for 16 days to male Wistar rats. The animals received an acute injection of haloperidol (0.5-2.0 mg/kg i.p. or 1.0-4.0 mg/kg p.o.) and catalepsy was measured. After 16 days on haloperidol, all animals became tolerant to the drug, exhibiting decreased cataleptic response to haloperidol; the intensity of catalepsy returned to normal after an additional 16 days abstinence from the drug. In addition, a group of animals treated and tested daily for catalepsy demonstrated that the time course of tolerance development to haloperidol was biphasic, with a rapid phase (T1/2 = 2.5 days) and a slower phase (T1/2 = 5.5 days).

Administration, Oral↗