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PubMed1982

Effect of apomorphine, piribedil and haloperidol on adrenal ornithine decarboxylase activity of the rat.

The administration of the dopaminergic drugs, apomorphine and piribedil to rats resulted in an increase in the activity of ornithine decarboxylase of the adrenal medulla and cortex. Pretreatment of the rats with the dopamine-receptor antagonist haloperidol caused a partial blockade of the apomorphine-induced effect at 4 hr in both medulla and cortex. At 6 hr, however, haloperidol did not block the effect of apomorphine and produced an increase in ornithine decarboxylase activity of both structures when administered alone. Hypophysectomy abolished the cortical ornithine decarboxylase response to apomorphine and haloperidol and the medullary response to haloperidol. The results suggest that the response of cortical ornithine decarboxylase activity to apomorphine and haloperidol is entirely mediated by the hypophysis and that the effect of apomorphine and the antagonistic action of haloperidol towards apomorphine in regard to the induction of adrenal medullary ornithine decarboxylase must be taking place at some central site independent of the hypothalamic-hypophyseal system.

Adrenal Glands↗

PubMed1990

Decreased striatal release of acetylcholine following withdrawal from long-term treatment with haloperidol: modulation by cholinergic, dopamine-D1 and -D2 mechanisms.

The effect of chronic treatment with haloperidol (2.7-5.3 mumol/kg/day) on K(+)-evoked release of [3H]acetylcholine (ACh) from superfused slices of the striatum was assessed. Acute injections of haloperidol (0.7-13.3 mumol/kg) produced 5-54% increases in the release of [3H]ACh in the striatum. Chronic treatment with haloperidol for 2.5 and 5 months also resulted in enhanced release of [3H]ACh in the striatum (28-35%). However, withdrawal from 2.5 and 5 months of treatment produced 34 and 38% decreases in K(+)-evoked release of [3H]ACh in the striatum, respectively. The drug SKF 38393 (D1-agonist), produced concentration-dependent (0.1-10 microM) increases (24-59%) in the release of [3H]ACh in the striatum which were blocked by the selective D1-antagonist, SCH 23390. The effect of stimulation of D1-receptors was significantly reduced after 2.5 or 5 months of chronic treatment with haloperidol. Both LY171555 (D2-agonist) and carbachol (muscarinic agonist) produced concentration-dependent (0.1-10 microM) inhibitions of the release of [3H]ACh in the striatum (LY171555: 28-62%; carbachol: 23-63%). Long-term treatment with haloperidol (2.5 and 5 months) elicited increases in sensitivity to the effect of LY171555, while the effect of carbachol was diminished only after the 5-month treatment period. These findings demonstrate that withdrawal from chronic exposure to haloperidol in the rat results in a reduction in the release of acetylcholine in the striatum. This effect is accompanied by (1) attenuated dopaminergic D1 mechanisms which ordinarily facilitate evoked release of ACh, (2) enhanced D2 mechanism which elicits inhibition of the release of ACh in the striatum, and (3) diminished muscarinic inhibitory influence which regulates the release of ACh.

Acetylcholine↗

PubMed1990

Involvement of the cholinergic system in haloperidol-induced release of dopamine from slices of striatum in the rat.

The effects of cholinergic and anticholinergic drugs on spontaneous or haloperidol-induced release of dopamine (DA) were studied in vitro. The slices of striatum were placed in a chamber and continuously superfused with Krebs' solution, containing various concentrations of haloperidol, with or without atropine, d-tubocurarine (d-TC), tetrodotoxin (TTX), physostigmine or carbachol. Haloperidol, enhanced the release of endogenous DA from the slices of striatum at an EC50 value of 25.6 microM. The effect of haloperidol was significantly reduced by atropine (2.5 microM), while it was unaffected by d-TC (10 microM) and TTX (1 microM). In contrast, physostigmine (3.7 microM) significantly increased the haloperidol-induced efflux of DA from the slices of striatum. In addition, acetylcholine (ACh), in the presence of physostigmine or carbachol, enhanced the basal efflux of DA at EC50 values of 2.8 microM and 83 microM, respectively. The effect of ACh on the efflux of DA was antagonized by atropine. These data suggest that haloperidol-induced release of DA is, at least partially, mediated by the activation of muscarinic ACh receptors located in the striatum.

Acetylcholine↗

PubMed1991

The effect of theophylline and immobilization stress on haloperidol-induced catalepsy and on metabolism in the striatum and hippocampus, studied with lactography.

Whether inducing catalepsy in the rat by an intraperitoneal injection of haloperidol (0.5 mg/kg) had an effect on metabolism in the striatum and in the hippocampus, as determined by lactography, and whether reducing the cataleptic state with stress or theophylline (8 mg/kg i.v.) had any impact on metabolism in these two regions of the brain was investigated. Furthermore, whether theophylline reduced catalepsy in rats through the adrenals was investigated. Haloperidol caused a significant increase in the metabolism of lactate, both in the striatum and in the hippocampus. Reducing haloperidol-induced catalepsy with short-term immobilisation stress did not affect the metabolism of lactate, neither in the striatum nor in the hippocampus. Reducing haloperidol-induced catalepsy with theophylline caused a significant rise in the metabolism of lactate in the striatum, while no effect was seen in the hippocampus. Adrenalectomy did not compromise the anti-cataleptic property of theophylline. It is concluded theophylline is a potent antagonist of haloperidol-induced catalepsy, and that this effect is not mediated by the adrenals. Furthermore, it is reported that haloperidol influenced metabolism in regions of the brain not considered to be its primary target. Lactography is considered to be a very useful tool in the study of metabolism during activity.

Adrenalectomy↗

PubMed1982

Circadian rhythm of brain susceptibility to haloperidol during chronic administration.

Circadian fluctuation has been reported to exist to the effects of haloperidol after acute administration. In an attempt to clarify the viability of chronotherapy with haloperidol, the antiapomorphine effect of haloperidol after chronic administration was investigated in the present paper. Haloperidol was administered once daily at the same time for 21 consecutive days to rats which were kept under 12 hr lighting conditions with light onset at 19:30. Then the chronology of the antiapomorphine effect was investigated. The antiapomorphine effect was significantly stronger in the group treated at 19:30 than that treated at 13:30. These data agreed with the results found after the acute administration of the drug. After chronic administration, no difference was found in the plasma and brain level of haloperidol due to the time of administration. These experimental results seem to suggest that a circadian rhythm in the brain susceptibility to haloperidol exists even during chronic administration.

Animals↗

PubMed1982

A comparison of atropine, benztropine and diphenhydramine on the reversal of haloperidol induced suppression of self-stimulation.

Acute haloperidol administration (0.25, 0.5 mg/kg) produced a severe reduction in locomotor activity and operant responding for intracranial self-stimulation in rats. If the rats were also given 10 mg/kg of either diphenhydramine or benztropine, this behavioral inhibition was substantially reversed. Atropine (10 mg/kg), however, did not significantly alter the haloperidol inhibition. In a second study, the rats were tested 30 and 120 minutes after the haloperidol treatment (0.25 mg/kg). Again, diphenhydramine and benztropine but not atropine substantially reversed the haloperidol suppression after 30 minutes. When retested after 120 minutes, however, atropine and benztropine but not diphenhydramine partially reversed the haloperidol suppression. Thus, the present study provides support that diphenhydramine can be effective in reversing haloperidol induced suppression of self-stimulation but for a shorter duration than benztropine.

Animals↗

PubMed1984

Force requirements in lever-pressing and responding after haloperidol.

One hypothesis regarding the actions of neuroleptic drugs on operant responding is that they interfere in some manner with the motoric capability of the animal. To further explore this possibility, we investigated the effects of haloperidol on a bar press response after animals were trained on levers with different force requirements. In the first experiment, two groups of rats were trained to press levers having either low (30 g) or high (100 g) force requirements. The effects of haloperidol on bar pressing when both groups were responding on the light lever were then examined. Under these conditions, the groups showed similar declines in response rates, indicating little transfer between previous experience on the heavy lever and responding in the presence of haloperidol. In the second experiment, the same groups of rats received further training exclusively on either the heavy or the light lever; the rate of responding was similar for the two groups. The effects of haloperidol on pressing either the heavy or the light lever were then examined. It was found that the rate-decreasing effects of haloperidol were similar in both groups. However, when the lever-pressing response was subsequently extinguished, rats working on the heavy lever were significantly more resistant to extinction than the light lever groups. The results of these experiments fail to indicate that the putative motoric effects of haloperidol interact significantly with response force demands. Furthermore, the data provide yet further evidence that blockade of dopamine receptors and removal of reinforcement are not equivalent.

Animals↗

PubMed1993

Gender differences in escape-avoidance behavior of mice after haloperidol administration.

Gender differences in the disruptive effects of haloperidol on some reinforced behaviors have been observed in different species. However, the inhibitory action of haloperidol on the acquisition and performance of escape-avoidance behavior has only been investigated in male subjects. The present experiment was designed to investigate possible gender differences in the effects of haloperidol on the initial phase of an escape-avoidance learning task. Male and female mice of the OF1 strain were given a single training session in a shuttle-box. Thirty minutes prior to the behavioral test, mice were injected IP with haloperidol (0.25 mg/kg) or physiological saline (10 ml/kg). Latencies of escape and avoidance responses and the number of nonresponses, escapes, avoidances, pseudoavoidances, crossings during the adaptation period, and crossings during intertrial intervals (ITIs) were evaluated. The disruptive action of haloperidol on the escape-avoidance behavior of the mice was greater in males than in females. The number of nonresponses were higher and the number of escapes lower in treated males than in their female counterparts. These gender differences were not found in control subjects. Activity measures of spontaneous motor behavior (crossings in the adaptation period and during ITIs) did not present gender differences either. Several possible mechanisms responsible for this greater susceptibility of males to the inhibitory effects of haloperidol on escape-avoidance learning are discussed, especially the modulating role of female hormones on dopaminergic activity.

Animals↗

PubMed1996

Cocaine-induced behavioral sensitization: effects of haloperidol and SCH 23390 treatments.

The objective of this study was to determine whether the development of behavioral sensitization to cocaine could be prevented by high doses of the dopamine receptor antagonists haloperidol and SCH 23390. In two experiments, male Wistar rats were injected daily for 4 days with either cocaine (15 mg/kg, IP) or vehicle in combination with haloperidol (1.0 mg/kg, IP), SCH 23390 (0.5 mg/kg, SC), or vehicle. After the daily injections, the rats were tested for locomotor activity in photocell arenas. At 24 h after the last preexposure test session, all rats were given a challenge injection of cocaine (15 mg/kg, IP) and tested for activity. Cocaine treatments produced a greater relative increase in locomotor activity with repeated exposure compared to vehicle treatments (i.e., sensitization). Moreover, the acute activating effects of cocaine over days were blocked by both haloperidol and SCH 23390. The coadministration of haloperidol, but not SCH 23390, blocked the development of behavioral sensitization to cocaine. That is, after the cocaine challenge injection, rats pretreated with SCH 23390 and cocaine did not differ from rats preexposed only to cocaine, whereas rats pretreated with haloperidol and cocaine did not differ from rats pretreated only with vehicle. Pretreatment with haloperidol or SCH 23390 without cocaine enhanced the locomotor-activating effects of the subsequent cocaine challenge injection. These findings suggest that cocaine-induced behavioral sensitization may develop as a result of repeated dopamine D1- or D2-type receptor stimulation, and that brief dopamine antagonist treatments enhance subsequent behavioral sensitivity to cocaine.

Animals↗

PubMed1984

Prolactin response to single and multiple doses of haloperidol in schizophrenic patients.

Serum prolactin and blood levels of haloperidol were assessed in schizophrenic patients after single acute oral doses of haloperidol and during fixed dose treatment with this medication. Although significant intrapatient correlations between prolactin responses to different doses of haloperidol were found, no statistically significant interpatient relationship between haloperidol dose and prolactin response emerged. There were statistically significant relationships between steady-state plasma and red cell haloperidol levels (measured by radioreceptor or gas liquid chromatographic techniques) and serum prolactin response, but not between blood levels after the acute haloperidol dose and prolactin response.

Adolescent↗

PubMed1984

A developmental study of adenohypophyseal dopaminergic receptors and of haloperidol-induced prolactin release in rats.

The ontogenesis of adenohypophyseal dopamine receptors, assessed by haloperidol-displaceable [3H]didydroergocryptine (DHE) binding of 1-, 12-, 20-, 28-day-old female rats was studied in correlation with the prolactin releasing effect of haloperidol (1 mg/kg), a dopaminergic antagonist. A specific dopaminergic receptor could be quantified at the time of birth (Bmax = 2.5 +/- 0.5 fmol/mg; Kd = 1.5 +/- 0.2 microM), anterior pituitary receptor density (fmol bound/mg) increased non-significantly henceforth and a slight ontogenic increase of Kd values was also observed. Haloperidol failed to increase prolactin in newborn female rats; at 4 days, a significant increase was evidenced, and from then onwards the response rose markedly with age. As sex differences in the dopaminergic modulation of prolactin release have been documented, the hyperprolactinemic effect of haloperidol in correlation with [3H]DHE binding in anterior pituitary of 28-day-old female and male rats was studied. Though the prolactinemic increment achieved by haloperidol was significantly higher in female than in male rats, [3H]DHE binding was not statistically different between sexes. These data indicate: (a) a specific binding site for [3H]DHE in anterior pituitary of female rats is present from the first postnatal days. From then onwards, a gradual but slight increment in both, Bmax and Kd for the dopaminergic agonist is observed until puberty; (b) at 28 days, no clear difference in Bmax and Kd is present in [3H]DHE binding between male and female rats; (c) by contrast, haloperidol shows a prolactin releasing effect that increases markedly with age in the female.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Effect of increasing doses of intracaudate haloperidol upon motor expressions that require an intact substantia nigra pars reticulata and/or superior colliculus in cats.

In the present study it was investigated whether intracaudate (CN) injections of increasing doses of haloperidol progressively affect movements that require the integrity of the substantia nigra pars reticulata (SNR) and/or the deeper layers of the superior colliculus (dl-SC) in cats. Therefore, cats were trained to walk from one side of a narrow bar to the other side both under full light and under stroboscopic illumination (2 flashes/s). Previously it has been shown that this set-up is useful for assessing changes in the execution of dl-SC and SNR-related non-externally guided targeting movements. Moreover, cats were trained to step out of a startbox on a rotating cylinder which, according to previous studies, also implies the execution of a dl-SC- and SNR-related non-externally guided targeting movement. CN application of 25 micrograms/5 microliters haloperidol, but not CN injection of 12.5 micrograms/5 microliters haloperidol or apomorphine (0.6 micrograms/5 microliters), reduced the occurrence of these dl-SC- and SNR-related targeting movements. Dl-SC injection of picrotoxin (100 ng/0.5 microliter) did not restore the haloperidol (25 micrograms/5 microliter) induced decrement in the occurrence of these targeting movements. In addition, CN application of 25 micrograms/5 microliter haloperidol, but not 12.5 micrograms/5 microliter haloperidol, reduced the feline ability to execute SNR-specific limb movements while crossing a revolving cylinder. The present results show that only a severe but not a moderate inhibition of dopamine receptors within the CN affects motor expressions characteristic of the SNR and/or dl-SC.

Animals↗

PubMed1990

The effect of acute haloperidol treatment on brain proneurotensin mRNA: in situ hybridization analyses using a novel fluorescence detection procedure.

These studies describe the normal anatomical distribution of neurons containing the mRNA coding for neurotensin (proneurotensin/neuromedin N) in the rat forebrain and midbrain and examine how that distribution is altered by acute administration of the dopamine antagonist haloperidol. A novel fluorescence detection method was developed and employed with biotinylated oligonucleotides to permit the rapid, sensitive visualization of in situ hybridization. The hybridization was temperature-sensitive, eliminated by ribonuclease, and co-localized in neurotensin-immunoreactive perikarya in the midbrain. In the forebrain of control rats, proneurotensin mRNA-containing neurons were found in the dorsomedial and ventrolateral caudate/putamen, in the nucleus accumbens, in the ventral striatum including the olfactory tubercles, and in the septal nuclei. Haloperidol induced significant increases in the frequencies and distributions of hybridization-positive neurons in the striatum and septal nuclei. In the midbrain, the highest frequency of hybridization-positive neurons occurred in the substantia nigra and the superior colliculus. Prominent populations were also present in the dorsal and ventral periaqueductal gray, the oculomotor region, and the medial longitudinal fasciculus. Less prominent were populations of neurons in the dorsomedial deep mesencephalic nuclei and the ventral tegmental area. Haloperidol induced only modest increases in the frequency of pro-neurotensin mRNA-containing neurons in the ventral tegmental area, and had no effects elsewhere in the midbrain. These results show that the fluorescent detection techniques used in this analysis provide a very rapid, reliable method for localizing hybridized mRNA in the rat brain. This study also suggests that a subpopulation of striatal neurons begin to express proneurotensin mRNA in response to haloperidol treatment. This effect of haloperidol on striatal neurons contrasts with results from additional studies of enkephalin mRNA in the striatum, suggesting that the mechanisms of haloperidol stimulation may differ between neurotensin and enkephalin-containing neurons.

Animals↗

PubMed1994

Coexpression of neurotensin and c-fos mRNAs in rat neostriatal neurons following acute haloperidol.

Our previous studies have shown several fold induction of neurotensin/neuromedin N (NT/N) primary transcripts and mature cytosolic mRNA in the dorsolateral region of the rat neostriatum (DLSt) following a single dose of the neuroleptic, haloperidol. The apparent enhancement of NT/N gene transcription by haloperidol is preceded by increases in the expression of c-fos mRNA in the same region. The present study used double-labeling in situ hybridization technique to study cellular localization of NT/N and c-fos mRNA following acute haloperidol treatment. Simultaneous detection of NT mRNA and c-fos mRNA was achieved using cRNA probes synthesized in vitro with digoxigenin- and 35S-labeled UTP, respectively. Interestingly, approximately 75% of DLSt neurons expressing NT/N mRNA also displayed c-fos mRNA in rats treated with haloperidol (1 mg/kg, i.p.) for 1 h. Colocalization of c-fos mRNA in haloperidol-responsive NT neurons in the DLSt suggests that haloperidol's induction of NT/N gene transcription may involve participation of the transcription factor Fos and the AP-1 consensus sequence in regulatory region of the NT/N gene.

Animals↗

PubMed1995

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.

Analysis of Variance↗

PubMed1995

The effect of haloperidol on met-enkephalin, beta-endorphin, cholecystokinin and substance P in the pituitary, the hypothalamus and the striatum of rats during aging.

1. Haloperidol increased the Met-enk level in the striatum at all age groups. However, the Met-enk level was decreased in AL of young and middle-aged rats by the drug. 2. Haloperidol elevated the beta-end level in AL and CCK level in NIL in young rats only. 3. The SP content in NIL was decreased by haloperidol in all age groups. 4. With regard to the effect of aging, Met-enk level in AL of middle-aged rats was higher than that in young rats. The beta-end level in AL also increased in old rats. 5. Aging modified the haloperidol effect on beta-end level in AL and CCK level in NIL as the effect was only observed in young rats. 6. In addition, aging caused a blunted response of Met-enk level to haloperidol in the striatum but an increased response of SP content to haloperidol in the NIL.

Aging↗

PubMed1988

Effects of haloperidol on neurotransmitter activity in the rat vas deferens.

1. The effects of haloperidol on the responses of the isolated rat vasa deferentia to catecholamines and ACh were studied. 2. Haloperidol produced a competitive antagonism to responses elicited by NA and DA in the vas deferens. 3. The M1 and M2 muscarinic responses to ACh of the vas deferens were potentiated by this neuroleptic. 4. The AChE activity of the vas deferens was significantly depressed by pretreatment with haloperidol. 5. The ability of haloperidol to lower AChE activity was compared with that of neostigmine and it may be due to a similar molecular mechanism. 6. The present results suggest that haloperidol has anti-AChE properties that may be responsible for the potentiation of the responses to ACh. 7. The study indicates that haloperidol has a wider range of pharmacological actions than previously reported.

Acetylcholinesterase↗

PubMed1995

Haloperidol-induced Fos expression in striatum is dependent upon transcription factor cyclic AMP response element binding protein.

Haloperidol has been shown to induce rapid and transient expression of c-fos messenger RNA and Fos protein in striatal neurons via dopamine D2 receptors. Regulation of the c-fos gene by cyclic AMP and Ca2+ has been shown to be dependent on a DNA regulatory element within its promoter that binds the constitutively expressed transcription factor cyclic AMP response element binding protein. Cyclic AMP response element binding protein binds to an oligonucleotide containing the calcium/cyclic AMP response element of the c-fos promoter sequence in striatal cell extracts; the amount of binding is not regulated by haloperidol treatment. We have previously shown that haloperidol induces cyclic AMP response element binding protein phosphorylation in the striatum. Here we show by intrastriatal injection of antisense oligonucleotides that haloperidol-induced Fos expression is dependent on cyclic AMP response element binding protein. Intrastriatal injections of phosphorothioate oligonucleotides, in antisense orientation to cyclic AMP response element binding protein messenger RNA, reduce levels of cyclic AMP response element binding protein and completely prevent haloperidol-mediated induction of Fos. Oligonucleotides in sense orientation have no such effect. We observed a markedly different time course of the Fos protein inhibition by cyclic AMP response element binding protein antisense oligonucleotides compared to c-fos antisense oligonucleotides. This most likely reflects the different half-lives of c-fos and cyclic AMP response element binding protein messenger RNA and proteins. Neither cyclic AMP response element binding protein nor c-fos antisense oligonucleotide injection reduced c-Jun immunostaining in the striatum. We conclude that haloperidol induces Fos via transcription factor cyclic AMP response element binding protein.

Activating Transcription Factor 2↗