Repeated Administration Of Haloperidol Research Articles

Antioxidant effects of rice bran oil mitigate repeated haloperidol-induced tardive dyskinesia in male rats.

Tardive dyskinesia (TD) is associated with the use of antipsychotic drugs such as D2 antagonist haloperidol (HP). The chronic use of HP is involved in the causation of free radicals and/or oxidative stress. In view of the nootropic, anti-anxiety, anti-inflammatory-like effects of rice bran oil (RBO) in a variety of investigations, we assessed the protective properties of RBO on HP-induced TD and neurochemical alteration. Rats treated with HP orally at a dose of 0.2mg/kg/day for a period of 5weeks developed VCMs which increased progressively as the treatment continued for 5weeks. Co-administration of RBO by oral tubes at a dose of 0.4ml/day prevented the induction of HP-induced VCMs. Repeated administration of HP increases the turnover of dopamine metabolism in the striatum. Conversely animals treated with HP+RBO decrease the metabolism of DA than water+HP treated animals. Striatal, malondieldehyde (MDA), hydrogen peroxide (H2O2) and antioxidant enzyme superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were also determined. It is suggested that beneficial role of RBO in attenuation of HP-induced TD. The results therefore recommended that supplementation of RBO may be useful in the HP-induced TD. The findings have also potential implication in the treatment of schizophrenia and motor disorders.

Zinc Tempers Haloperidol-induced Behavioural Changes in Healthy Mice

Objective: Behavioural changes secondary to haloperidol/zinc administration were studied, with a view to understanding the patterns of behavioural responses that may be exhibited after such treatment in healthy mice. Methodology: 6 month old Swiss mice (24-30 g each, n=12), were given vehicle (distilled water), haloperidol (2 mg/kg), zinc (as Zinc gluconate, 2.5 and 5 mg/kg) or haloperidol/zinc combination, orally for 21 days. Behaviours were assessed after the first and last dose of haloperidol/zinc. Results: Zinc administration led to a significant reduction of haloperidol-induced suppression of horizontal locomotion, rearing and grooming behaviours. Zn also prevented the deterioration in Y-maze and radial-arm maze working-memory that was associated with repeated haloperidol administration. Finally, an enhanced anxiolytic effect was seen with co-administration of haloperidol with the lower dose of zinc. Conclusion: Co-administration of haloperidol with zinc can reduce some unwanted effects that are known to be associated with haloperidol therapy; hence zinc may be a beneficial adjunct to haloperidol administration.

Tea component, epigallocatechin gallate, potentiates anticataleptic and locomotor-sensitizing effects of caffeine in mice.

Tea is the most popular beverage worldwide. Caffeine, the psychoactive principle of tea, pharmacologically interacts with several drugs and bioactive molecules. Epigallocatechin gallate (EGCG) is a major component of tea and its known interactions with caffeine make it worthwhile to further study them by investigating the influence of EGCG on the anticataleptic and locomotor-sensitizing effects of caffeine. In the present investigation, we observed that (a) administration of caffeine or EGCG alone inhibited haloperidol-induced catalepsy, a widely used animal model to study parkinsonism, and (b) a combination of caffeine and EGCG produced greater inhibition of haloperidol-induced catalepsy. Furthermore, after repeated administration of caffeine and EGCG, either alone or in combination, we observed that (c) caffeine and EGCG contrasted the sensitization of catalepsy observed after repeated haloperidol administration by significantly reducing the duration of catalepsy. Furthermore, as haloperidol-induced catalepsy was also associated with increased lipid peroxidation, we observed that (d) EGCG administration reduced striatal lipid peroxide levels in a dose-dependent manner and that (e) the combination of caffeine with EGCG was most effective in reducing haloperidol-increased striatal lipid peroxide. Finally, we observed that (f) chronic caffeine and EGCG significantly elicited locomotor sensitization and that (g) their combination resulted in significantly greater effects. In conclusion, EGCG potentiated the effects of caffeine on haloperidol-induced catalepsy and of caffeine-elicited locomotor sensitization. Overall, these observations indicate critical interactions between caffeine and EGCG in an animal model of parkinsonism and locomotor activity and suggest that tea consumption might reduce antipsychotic-induced side effects.

Repeated Haloperidol Administration has No Effect on Vitamin D Signaling but Increase Retinoid X Receptors and Nur77 Expression in Rat Prefrontal Cortex

Both vitamin D (VD) signaling and Nur77 are implicated in dopaminergic neurotransmission and dopamine-related neuropsychiatric disorders, such as schizophrenia and Parkinson's disease. Developmental vitamin D (DVD) deficiency rats exhibit schizophrenia-like behaviors and disturbance of dopamine system, which could be partly normalized by haloperidol treatment. By blocking dopamine D2 receptor, haloperidol induces Nur77 expression, suggesting a modulatory role of Nur77 in brain dopamine system. Rxr is the heterodimeric partner of both Nur77 and vitamin D receptor and also participates in homeostatic regulation of central dopamine neurotransmission. Although D2 antagonist-induced Nur77 expression has been reported by several studies, the change of its active partner Rxr remains elusive. Here, we studied the impact of 2 weeks administration of haloperidol on VD signaling and Nur77/Rxr expression in rat prefrontal cortex. It was found that haloperidol has no effect on local VD signaling, but could significantly increase Nur77, Rxrβ, and Rxrγ expression, which indicated that Nur77/Rxr, but not vdr/Rxr, was implicated in dopamine-related neuroadaptation. Given that VD deficiency is commonly observed in schizophrenia patients, the renal metabolism of VD was also examined.

Evaluation of age and sex differences in locomotion and catalepsy during repeated administration of haloperidol and clozapine in adolescent and adult rats

Adolescence is associated with characteristic behavioral patterns as well as with substantial neuronal pruning and re-organization of the brain. Recent research has determined that the effects of various centrally active drugs differ in adolescents and adults. This study examined the motor effects of two prototypic antipsychotics in adult [>postnatal day 70 (PN70)] and adolescent (PN30–PN39) rats. Rats were injected daily with saline, 0.3 mg/kg haloperidol, or 10 mg/kg clozapine for 10 days and activity and catalepsy were measured. Adolescents of both sexes were less sensitive to the cataleptic effects of haloperidol than were adults. Male adolescents were also less sensitive to the cataleptic effects of clozapine, although this difference was transitory. In contrast, female adults showed decreased sensitivity to clozapine's effects, differing from all other groups. These results suggest that adolescents of both sexes may be less sensitive to the extrapyramidal motor effects of haloperidol. Translational implications of the clozapine results are less clear; however, results suggest that developmental differences in neurochemical systems affected by clozapine that are also related to motor behavior may play a role. These results also emphasize the importance of age and sex as determinants of the pharmacological effects of these antipsychotics.

Enhanced 5-HT2C receptor signaling is associated with haloperidol-induced “early onset” vacuous chewing in rats: implications for antipsychotic drug therapy

Haloperidol is a representative of typical antipsychotics that are still in clinical use and which can lead to abnormal motor activity following repeated administration. The mechanisms underlying antipsychotic-induced dyskinesias are not well understood but are widely held to be related to excessive loss of dopamine function. In several models of dopamine hypofunction, serotonin 5-HT2C receptors have been shown to mediate vacuous chewing movements (VCM), a form of abnormal motor activity. It is well established that repeated haloperidol administration also elicits VCM, but there is no information on how repeated haloperidol administration affects 5-HT2C receptor signaling. In the present study, we tested the hypothesis that repeated daily administration of haloperidol leads to enhanced serotonin 5-HT2C receptor signaling that is associated with increased 5-HT2C-mediated VCM. Rats were treated by subcutaneous injection once daily for 21 days with either vehicle, a low dose of haloperidol (0.1 mg kg(-1) day(-1)), or a high dose of haloperidol (1.0 mg kg(-1) day(-1)). Following 1-day withdrawal, rats were either used for behavioral scoring of VCM or sacrificed for biochemical assessment of 5-HT2 receptor-mediated phospholipase C activity and radioligand binding. VCM were scored following two successive "drug" challenges. The first challenge was an injection of vehicle (0.9% saline), and the second challenge was an injection of the 5-HT2C agonist meta-chlorophenylpiperazine (1.0 mg/kg). In this manner, a measure of "spontaneous" and "5-HT2C-elicited" orofacial activity could be made while minimizing animal use. Following 21-day haloperidol treatment at either dose, there was an increase in expression of meta-chlorophenylpiperazine-induced VCM. In a separate experiment, meta-chlorophenylpiperazine-induced VCM were shown to be mediated through 5-HT2C receptors. Striatal 5-HT2C receptor-mediated phospholipase C (PLC) activity and high-affinity agonist-labeled 5-HT2C receptors were also increased following either dose of haloperidol as compared to vehicle treatment. GTP-stimulated PLC activity and striatal Gq proteins were unchanged by haloperidol suggesting that enhanced signaling could be accounted for by alterations at the level of the receptor and not at downstream mechanisms. Repeated daily administration of haloperidol leads to an adaptive increase in 5-HT2C signaling which may contribute to abnormal motor function associated with antipsychotic use.

Subchronic treatment with either clozapine, olanzapine or haloperidol produces a hyposensitive response of the rat cortical cells to N-methyl- d-aspartate

Using the technique of intracellular recording in in vitro brain slice preparations, we examined the effects produced by repeated administration of the antipsychotic drugs clozapine, olanzapine and haloperidol, on N-methyl- d-aspartic acid-induced responses in pyramidal cells of the rat medial prefrontal cortex. Rats were anesthetized and decapitated 24 h after the conclusion of daily intraperitoneal injection with either clozapine (25 mg/kg), olanzapine (1, 5 or 10 mg/kg) or haloperidol (0.5 mg/kg) for 21 days, and the slices from medial prefrontal cortex were used for electrophysiological recordings. The concentration–response curves for N-methyl- d-aspartic acid to activate cortical cells shifted markedly to the right in rats which received the subchronic antipsychotic drug treatment, compared with those obtained from rats which received repeated injections of vehicle (1 ml/kg/day, i.p. for 21 days). In addition, repeated exposure to antipsychotic drugs caused a significant reduction in the ability of these antipsychotic drugs to augment the N-methyl- d-aspartic acid-induced inward current in pyramidal cells of the rat medial prefrontal cortex. Repeated administration of haloperidol, but not clozapine or olanzapine, significantly hyperpolarized the resting membrane potential and increased membrane resistance in pyramidal cells of the medial prefrontal cortex. Moreover, subchronic treatment with haloperidol, but not clozapine or olanzapine, depressed (±)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid-induced responses. The desensitized response of medial prefrontal cortex cells to N-methyl- d-aspartic acid could be the result of a compensatory response to the facilitating action of antipsychotic drugs on N-methyl- d-aspartic acid receptor-mediated transmission. The inhibitory action of haloperidol on (±)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid responses may also contribute to the rightward shift of the N-methyl- d-aspartic acid concentration–response curve. Thus, the present study suggests that the atypical antipsychotic drugs, clozapine and olanzapine, as well as the typical antipsychotic drug haloperidol strongly modulate glutamatergic transmission after prolonged treatment. This might be an important factor in the mechanisms by which these drugs alleviate symptoms in schizophrenic patients.

Dose Dependency of Sex Differences in the Effects of Repeated Haloperidol Administration in Avoidance Conditioning in Mice

Sex differences in the effects of haloperidol in active avoidance conditioning in mice have previously been found in various studies carried out in our laboratory. Males were more affected than females by the disruptive effects of this neuroleptic. The work described here broadens the study of these sex differences to higher doses of haloperidol (0.1 and 0.2 mg/kg) using a repeated administration schedule (5 days). The results did not show sex differences in the deteriorating effects of this dopamine antagonist in the escape-avoidance response, but a tendency in the number of nonresponses was observed in the same direction as former results: male animals were more sensitive than females to the inhibitory effect of the low dose of haloperidol. It is concluded that the appearance of sex differences in the effects of haloperidol on active avoidance conditioning is a dose-dependent phenomenon.

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.

Fos is not involved in the regulation of the proenkephalin gene by haloperidol in the mouse striatum.

The aim of the study was to determine whether the haloperidol-produced induction of the c-fos gene in the mouse striatum is the cause of the increased expression of the striatal proenkephalin (PENK) gene after repeated haloperidol administration. Mice were treated with haloperidol (1 mg/kg, i.p., once daily), MK-801 (1 mg/kg, i.p., twice daily), or with both those drugs for 9 days. Pretreatment with MK-801 prevented the haloperidol-produced induction of the striatal c-fos mRNA. In animals injected with haloperidol for 9 days, levels of the striatal PENK mRNA were increased by 100%. Coadministration of MK-801 did not reduce that increase. These results suggest that Fos is not necessary for activation of the PENK gene expression, produced by chronic haloperidol application, in the striatum.

Effect of repeated haloperidol administration on phencyclidine discrimination in rats

Wiley, Jenny L.: Effects of repeated haloperidol administration on phencyclidine discrimination in rats. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1995, 19(4): 699–711. 1. 1. Previous research has shown that acute doses of haloperidol block many of themotor stimulatory effects of phencyclidine (PCP) and other PCP-like drugs. In addition, when given acutely, haloperidol produces partial attenuation of PCP's discriminative stimulus effects in rats. 2. 2. Haloperidol is often administered chronically in clinical situations; hence, it is important to investigate the effects of repeated, as well as acute, dosing with this drug. 3. 3. The purpose of the present study was to examine the effects of repeated administration of haloperidol on PCP discrimination in rats. Rats were trained to discriminate PCP (2.0 mg/kg) from saline in a two-lever drug discrimination procedure and were tested with cumulative doses of PCP before and after repeated administration of saline and of haloperidol (0.5 mg/kg/day). 4. 4. Discrimination training was suspended during the two 14–15-day repeated dosing regimens. Suspended training with repeated saline administration had little effect on the dose-effect curve for % PCP-lever responding. 5. 5. Repeated administration of haloperidol produced some diminution of PCP discrimination. After haloperidol, the ED 50 for % PCP-lever responding was 1.4 mg/kg, compared to the pre-haloperidol ED 50 of 0.7 mg/kg. 6. 6. These results are consistent with those of acute dosing studies with haloperidol in PCP-trained rats and suggest that repeated administration of haloperidol may disrupt PCP's discriminative stimulus effects, although most rats were still able to discriminate the higher doses of PCP.

Haloperidol treatment differentially regulates [ 3H]DTG and [ 3H](+)-3-PPP labeled σ binding sites

The effect of repeated haloperidol administration on σ binding sites in brain membranes was assessed using [ 3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP) and [ 3H]1,3-di-o-tolylguanidine (DTG). Administration of haloperidol (1 mg/kg, i.p.) to guinea pigs for 14 consecutive days followed by a 4 day drug-free period prior to sacrifice resulted in 75% and 6% decreases in the specific binding of [ 3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine and [ 3H]1,3-di-o-tolylguanidine, respectively, when measured using a single concentration (2 nM) of radioligand. Scatchard analysis revealed a reduction in both the maximum number of [ 3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine binding sites and the affinity of these sites for the radioligand; the potency of 1,3-di-o-tolylguanidine to inhibit [ 3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine binding was also reduced. In parallel studies, the potency of 1,3-di-o-tolylguanidine to inhibit [ 3H]1,3-di-o-tolylguanidine binding was unaffected by haloperidol treatment, but the potency of (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine against [ 3H]1,3-di-o-tolylguanidine was reduced 3-fold. Phenytoin, which increased (10-fold) the potency of dextromethorphan to inhibit [ 3H]1,3-di-o-tolylguanidine binding in control membranes, had no effect in membranes obtained from haloperidol-treated animals. The reduction in [ 3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine binding was dependent upon the duration of the drug-free period and amounted to 73% and 25% in brain membranes prepared from animals sacrificed 14 days and 28 days, respectively, following cessation of drug treatment. Repeated administration of other antipsychotic and σ agents including DTG, dextromethorphan, spiperone, chlorpromazine and clozapine had no effect on [ 3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine or [ 3H]1,3-di-o-tolylguanidine binding. These findings suggest that repeated haloperidol administration selectively regulates [ 3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine binding in guinea pig brain membranes. However, the observations that repeated drug treatment resulted in (1) reduced affinity of (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine for [ 3H]1,3-di-o-tolylguanidine binding sites, and (2) a loss of the ability of phenytoin to increase dextromethorphan's potency against [ 3H]1,3-di-o-tolylguanidine, suggest that [ 3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine and [ 3H]1,3-di-o-tolylguanidine binding sites are distinct but functionally coupled.

Synaptophysin: A test of the etiological hypotheses

Developing and adult Sprague-Dawley rats were tested after acute or repeated haloperidol administration. Although 8-day-old rat pups showed a form of immobility in response to a single injection of haloperidol (1 mg/kg), 14-day-old rats did not show any behavioral response to the neuroleptic. By 21 days of age, an acute dose of haloperidol induced a cataleptic response similar to that described for adult animals. Following 7 days of repeated haloperidol administration, the cataleptogenic effects of haloperidol were attenuated in animals aged 21 days and older, but not in 8- and 14-day-old rats. Subjects were sacrificed 70 min after the injection of the test dose of haloperidol or saline and the corpus striatum and olfactory tubercles were dissected for HPLC determination of dopamine (DA) and its metabolites, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC). In the corpus striatum, an area believed to be important for DA-related catalepsy, acute and repeated haloperidol induced a slight increase in concentrations of HVA in 8-day-old rats, and an increase in both DOPAC and HVA concentrations in animals aged 14 days and older. Tolerance after repeated haloperidol administration, in the form of an attenuation of the haloperidol-induced increase in DA metabolites, was not apparent until 35 days of age. These data contrast with the behavioral data, which indicate that the ability to develop a tolerance to the cataleptogenic effects of haloperidol matures by 21 days of age. The pattern of responses in the olfactory tubercles differed from those observed in the striatum. Following acute haloperidol, subjects did not show any increase in HVA until 14 days of age, and in both HVA and DOPAC until 21 days of age. At no age, including adults, was one week of repeated administration of haloperidol sufficient to induce tolerance to the effects of haloperidol on DA metabolites in the olfactory tubercles. In addition to providing information about the development of certain aspects of DA systems in rats these studies suggest that an attenuation of the haloperidol-induced increase in DA metabolites is not necessary for the development of tolerance to haloperidol-induced catalepsy.

Regulation of σ receptors and responsiveness to guanine nucleotides following repeated exposure of rats to haloperidol: further evidence for multiple σ binding sites

The σ binding sites are postulated to be involved in various central nervous system (CNS) disorders. The neuroleptic drug, haloperidol, displays high affinity for these receptor sites in the CNS. In the present study the effect of repeated exposure of rats to haloperidol (4 mg/kg/day for 14 days) on σ binding sites labeled with (+)-3-(3-hydroxyphenyl- N-1-(propyl)piperidine ((+)-3-PPP) and 1,3-di- o-tolyl-gun (DTG) was investigated. In addition, the regulatory effect of guanine nucleotides on the binding of these two ligands to brain membranes derived from saline and haloperidol-treated rats was examined. Repeated administration of haloperidol induced down-regulation of (+)[ 3H]-3-PPP binding sites (75% decrease in the number of binding sites compared to control) which persisted for at least 7 days after termination of the haloperidol-treatment. The down-regulation of (+)-3-PPP binding sites was accompanied by reduced responsiveness to guanine nucleotides (i.e. 5-guanylylimidodiphosphate (Gpp(NH)p) compared to the sensitivity of (+)-3-PPP binding sites to the nucleotides tested in control membranes. However, at the 28th day after termination of the haloperidol-treatment, a complete recovery in the total number of (+)[ 3H]-3-PPP binding sites was observed, and the sensitivity to guanine nucleotide was regained. These findings suggest a marked plasticity in (+)-3-PPP/σ receptor binding activity. In contrast, [ 3H]DTG binding sites expressed neither sensitivity to the repeated exposure to haloperidol nor to guanine nucleotides, suggesting a distinction between DTG and (+)-3-PPP binding sites in rat brain.

Regulation of striatonigral prodynorphin peptides by dopaminergic agents

The primary purpose of this study was to examine the regulation of prodynorphin peptides by dopaminergic agents in the central nervous system. The indirectly acting catecholamine agonistd-amphetamine sulfate (AMPH) and the dopamine receptor antagonist haloperidol (HAL) were administered to rats across a variety of treatment schedules and drug doses. The striatum, substantia nigra and hippocampus were dissected and examined by radioimmunoassay for 5 different prodynorphin peptides, covering all 3 opioid domains in the prodynorphin precursor: dynorphin A(1–8) and dynorphin A(1–17) of the dynorphin A domain, dynorphin B(1–13) of the dynorphin B domain, and α-neo-endorphin and ß-neo-endorphin of the neo-endorphin domain. In addition, the proenkephalin peptide Met-enkephalin-arg6-gly7-leu8 (MERGL) was examined in the striatum. AMPH administered one hour prior to sacrifice caused a dose-dependentdepletion of prodynorphin peptides in both the striatum and substantia nigra. In animals treated with AMPH once each day for 7 days and sacrificed 24 h later, a dramatic dose-dependentincrease in prodynorphin peptides was observed in these brain regions. Animals treated with AMPH once each day for 7 days and sacrificed one hour after the final injections showed no changes in prodynorphin peptides. In addition to changes in individual prodynorphin peptides, AMPH treatment caused alterations in the relationships between intermediate peptides (dynorphin A(1–17) and α-neo-endorphin) and their immediate products (dynorphin A(1–8) and ß-neo-endorphin). AMPH caused no consistent changes in prodynorphin peptides in the hippocampus, or in MERGL in the striatum. Taken together these data suggest that acute dopaminergic activation causes depletion of dynorphins from striatonigral prodynorphin neurons, presumably due to dopamine-dependent release of these peptides; repeated activation causes repeated release, with a rebound increase in biosynthesis. HAL, in contrast to AMPH caused relatively subtle changes in striatonigral prodynorphin peptides. Although no significant changes in individual prodynorphin peptides were observed, HAL treatment caused a change in the relationship between dynorphin A(1–17) and dynorphin A(1–8), a change in direction to that observed with AMPH treatment. As has been previously reported, repeated HAL administration caused a dose-dependent increase in the proenkephalin peptide MERGL. The relatively subtle effects of HAL on prodynorphin peptides suggests that tonic dopamine activity is not important in the regulation of striatonigral prodynorphin neurons. The potential functional and behavioral significance of the present results are discussed.

Changes in pancreatic exocrine secretion after repeated haloperidol administration

The effect of repeated administration of haloperidol on the pancreatic secretion was studied in urethane-anesthetized Swiss mice. Haloperidol (2 mg/kg) injected daily i.p. for 7 days, increase the volume and protein content of the basal pancreatic juice significantly. This secretory activity was partially blocked by i.p. injection of atropine (5 mg/kg), both in control and treated animals. The volume of the secretory response to bethanechol, a cholinergic agonist, was decreased by haloperidol without any change in amylase release. From these findings it is concluded that repeated haloperidol treatment produces an increase of basal pancreatic secretion, which is probably the result of changes in the sensitivity of dopamine receptors of the gland.

Repeated haloperidol administration changes basal release of striatal dopamine and subsequent response to haloperidol challenge

The effects of acute or repeated administration of haloperidol on release of dopamine (DA) and homovanillic acid (HVA) from striata of awake rats were studied using a microdialysis probe. A single injection of haloperidol (1 mg/kg, i.p.) produced a time-dependent increase in DA and HVA in the perfusate. Comparative studies in rats anesthetized with 300 mg/kg of chloral hydrate given i.p. found that anesthesia decreased the basal release of DA, but not HVA, and significantly blocked haloperidol-induced increases in DA, while haloperidol-induced increases in HVA were not affected. Studies done in awake rats found that 21 repeated daily injections of haloperidol increased the basal release of DA, but not HVA. Subsequent challenge with haloperidol indicated a significant decrease in responsiveness to haloperidol-induced release of DA, but not HVA, in chronically dosed rats. These data suggest that repeated exposure to haloperidol causes a compensatory increase in extracellular DA release. That these compensatory changes may be associated with the increased therapeutic efficacy or extrapyramidal side effects of neuroleptics following repeated dosing warrants further study.

Kindling: a model for the development of tardive dyskinesia?

Tardive dyskinesia (TD) from long-term neuroleptic treatment may be irreversible; therefore prevention has become a major concern. A controversial issue with regard to the clinical use of neuroleptic drugs is the possible influence on the development of TD of drug holidays. The major characteristics of kindling, theories of TD and the role of multiplicity in the development of TD are described. Some clinical studies point to interruption of neuroleptic therapy being a risk factor for development of irreversible TD. Induction of dyskinesia in non-human primates has been demonstrated after repeated administration of haloperidol. Rodent studies have not been conclusive. Several experimental results link TD with kindling: both conditions involve repeated stimulations, both seem to involve increased receptor responsiveness and in both conditions does depression in GABA transmission in SNR (substantia nigra; pars reticulata) play an important role. It is concluded that the kindling hypothesis is relevant to the investigation of TD.

Kindling: A Model for the Development of Tardive Dyskinesia?

Tardive dyskinesia (TD) from long-term neuroleptic treatment may be irreversible; therefore prevention has become a major concern. A controversial issue with regard to the clinical use of neuroleptic drugs is the possible influence on the development of TD of drug holidays. The major characteristics of kindling, theories of TD and the role of multiplicity in the development of TD are described. Some clinical studies point to interruption of neuroleptic therapy being a risk factor for development of irreversible TD. Induction of dyskinesia in non-human primates has been demonstrated after repeated administration of haloperidol. Rodent studies have not been conclusive. Several experimental results link TD with kindling: both conditions involve repeated stimulations, both seem to involve increased receptor responsiveness and in both conditions does depression in GABA transmission in SNR (substantia nigra; pars reticulata) play an important role. It is concluded that the kindling hypothesis is relevant to the investigation of TD.

Modification of the function of D 1 and D 2 dopamine receptors in striatum and nucleus accumbens of rats chronically treated with haloperidol

With the aim of evaluating the possible functional modifications of both D 1 and D 2 dopamine receptor subpopulations after repeated administration of neuroleptics, the ability of selective D 1 and D 2 dopamine agonists to stimulate or inhibit, respectively, the activity of adenylate cyclase in the striatum and nucleus accumbens of rats treated with either saline or haloperidol for 21 days, was studied. It was found that stimulation of the activity of adenylate cyclase elicited by the selective D 1 receptor agonist SKF 38393 was significantly greater in homogenates of striatum in rats treated with haloperidol, than in those of saline-treated rats. Similarly, the inhibitory effect on the activity of the enzyme elicited by the selective D 2 agonist bromocriptine was much more evident in homogenates of the striatum from rats treated with neuroleptic than in those from saline-treated rats. When dopamine, sodium fluoride (NaF), or 5-guanylyl imidodiphosphate (Gpp(NH)p), were used as agonists to stimulate the activity of adenylate cyclase, the amount of cyclic AMP formed appeared the same in rats treated with haloperidol or saline. Dopamine receptors in nucleus accumbens behaved like those in the striatum in the pattern of modifications after repeated administration of haloperidol. Indeed, the inhibitory effect elicited by bromocriptine, as well as the stimulatory effect elicited by SKF 38393, was much more evident in nucleus accumbens from rats treated with haloperidol than in that from controls, whereas activation of adenylate cyclase induced by dopamine and sodium fluoride was similar in both experimental groups. Thus, the present results indicate that long-term treatment with haloperidol caused an up-regulation of both D 1 and D 2 subpopulations of dopamine receptors in striatum and nucleus accumbens of the rat.