Effect of psychotropic substances on orienting-exploratory behavior after startling caused by acoustic stimulation

Frightening sound stimulation induced alarm and alertness which resulted in weakening of attention to novel environment and increasing of orienting response to the source of the frightening sound. Defense motivation occurring under these conditions failed to alter with the increase of sound loudness. Tranquilizers (diazepam, chlordiazepoxide, benatyzine), antidepressants (amytriptiline, imipramine) and some neuroleptics (trifluoperazine, haloperidol) in a low doze prevented these disturbances. High doses of pentobarbital, chlorpromazine, as well as trifluoperazine and haloperidol did not prevent the mentioned consequences of emotional excitation.     

Variations of rest-activity rhythm and sleep-wake in schizophrenic patients versus healthy subjects: An actigraphic comparative study

The objective of the present study was to compare the pattern of motor activity in unmedicated schizophrenia patients and healthy subjects, and to examine whether the pattern was affected by treatment with typical and atypical antipsychotics. Twenty unmedicated schizophrenic patients wore a wrist actigraph for five days. The actigraph recorded activity levels in one-minute epochs. Patients' pattern of activity was compared with that of healthy subjects. Patients were randomly assigned to treatment with low-dose haloperidol or risperidone. The impact of treatment on the pattern of activity was examined. Compared to controls, untreated patients showed a diminished mean activity count during morning, early and late night periods. Treatment with haloperidol or risperidone at effective doses showed a significant effect on activity level, being more prominent with haloperidol. The results suggest that unmedicated schizophrenic patients exhibit abnormally low levels of motor activity as measured with an objective activity meter. This persists after antipsychotic treatment even though symptoms improve. Future studies should clarify whether motor disturbances are a primary effect of the illness, or related to the illness-related lifestyle.     

A comparative analysis of the change in the EEG spectral characteristics of rats during the activation and suppression of the catecholaminergic systems]

To find EEG-markers of catecholaminergic activation shifts EEG power spectra of white rats were computed before and after intraperitoneal injections of propranolol, metaproterenol, haloperidol, amantadine, or isotonic sodium chloride solution. Differential spectral characteristics were undergone to factor analysis and discriminant analysis. Factors with similar structure for both catecholaminergic systems were revealed in EEG-reactions to mutually antagonistic injections and relatively specific factors as well. The leading factor of adrenotropic injections described the augmentation of the spectral power in the range of 9-16 Hz induced by propranolol and its reduction by metaproternol. Similar factor was also revealed in reactions to dopaminotropic injections with the smaller value of discriminant function coefficient. One more common feature of EEG-reactions to catecholaminergic disturbances was found to consist of the reciprocal narrow-band shifts in the theta- and delta-diapasons. The leading factor for the recognition of dopaminotropic disturbances described the increase of EEG power in the band of 19-30 Hz at activation and its reduction at suppression of the transmitter system.     

Interactions between estradiol and haloperidol on perseveration and reversal learning in amphetamine-sensitized female rats

There are sex differences associated with schizophrenia, as women exhibit later onset of the disorder, less severe symptomatology, and better response to antipsychotic medications. Estrogens are thought to play a role in these sex differences; estrogens facilitate the effects of antipsychotic medications to reduce the positive symptoms of schizophrenia, but it remains unclear whether estrogens protect against the cognitive symptoms of this disorder. Amphetamine sensitization is used to model some symptoms of schizophrenia in rats, including cognitive deficits like excessive perseveration and slower reversal learning. In this experiment female rats were administered a sensitizing regimen of amphetamine to mimic these cognitive symptoms. They were ovariectomized and administered either low or high estradiol replacement as well as chronic administration of the antipsychotic haloperidol, and were assessed in tests of perseveration and reversal learning. Results of these experiments demonstrated that, in amphetamine-sensitized rats, estradiol alone does not affect perseveration or reversal learning. However, low estradiol facilitates a 0.25 mg/day dose of haloperidol to reduce perseveration and improve reversal learning. Combined high estradiol and 0.25 mg/day haloperidol has no effect on perseveration or reversal learning, but high estradiol facilitates the effects of 0.13 mg/day haloperidol to reduce perseveration and improve reversal learning. Thus, in amphetamine-sensitized female rats, 0.25 mg/day haloperidol only improved perseveration and reversal learning when estradiol was low, while 0.13 mg/day haloperidol only improved these cognitive processes when estradiol was high. These findings suggest that estradiol facilitates the effects of haloperidol to improve perseveration and reversal learning in a dose-dependent manner.     

Anti-idiotypes against a monoclonal anti-haloperidol antibody bind to dopamine receptor

Anti-idiotypic antibodies were raised in rabbits by immunization with a monoclonal anti-haloperidol antibody. Some of these anti-idiotypic antibodies bind in a concentration dependent manner to bovine striatal membranes. Following affinity purification, these antibodies inhibit haloperidol binding to striatal membranes and deplete [3H]-spiperone binding sites from a solubilized preparation of striatal membranes. It is thus concluded that these anti-idiotypic antibodies are an internal image of haloperidol and as such can interact with D2-dopamine receptors.     

Translocation of AIF in the human and rat striatum following protracted haloperidol, but not clozapine treatment

Loss of mitochondrial membrane integrity and consequent release of apoptogenic factors may be involved in mediating striatal neurodegeneration after prolonged treatment with the typical antipsychotic drug haloperidol. Apoptosis-inducing factor (AIF), an intramitochondrial protein, may have a large influence on mediating haloperidol-induced striatal neuron destruction. Translocation of this protein from mitochondria to the nucleus promotes cell death independently of the caspase cascade. To examine how AIF may contribute to haloperidol-induced apoptosis, AIF translocation was observed in three haloperidol treatment paradigms. SH-SY5Y cells were treated with both haloperidol and clozapine and examined for AIF immunofluorescence. Immunohistochemistry was also performed on human striatal sections obtained from the Stanley Foundation Neuropathology Consortium and on rat brain sections following 28 days of antipsychotic drug treatment. In the cellular model haloperidol, but not clozapine treatment increased the nuclear AIF immunofluorescent signal and decreased cell viability. Corollary to these findings, striatal sections from patients who had taken haloperidol and rats who were administered haloperidol both had an elevated nuclear AIF signal. The results provide novel evidence implicating the involvement of AIF in haloperidol-associated apoptosis and its relevance to the development of typical antipsychotic drug-related adverse effects such as tardive dyskinesia.     

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<0.005, Wilcoxon test; % increase in RBC neuroleptic activity, 11–121%; mean + SD, 59 ± 40%, P<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.     

Effects of ethanol and haloperidol on plasma levels of hepatic enzymes, lipid profile, and apolipoprotein in rats.

This work studied the effects of ethanol in the absence and presence of haloperidol under two experimental conditions. In protocol 1, rats were treated daily with ethanol (4 g/kg, p.o.) for 7 days, and received only haloperidol (1 mg/kg, i.p.) from the 8th day to the 14th day. In protocol 2, animals received ethanol, and the treatment continued with ethanol and haloperidol from the 8th day to the 14th day. Results show increases in alanine transaminase (ALT; 48% and 55%) and aspartate transaminase (AST; 32% and 22%) levels after ethanol or haloperidol (14 days) treatments, as compared with controls. Apolipoprotein A-1 (APO A1) levels were increased by haloperidol, after 7- (148%) but not after 14-day treatments, as compared with controls. Levels of lipoprotein (high-density lipoprotein (HDL-C)) tended to be increased only by ethanol treatment for 14 days. ALT (80%) and AST (43%) levels were increased in the haloperidol plus ethanol group (protocol 2), as compared with controls. However, an increase in APO A1 levels was observed in the haloperidol group pretreated with ethanol (protocol 1), as compared with controls and ethanol 7-day treatments. Triglyceride (TG) levels were increased in the combination of ethanol and haloperidol in protocol 1 (234%) and 2 (106%), as compared with controls. Except for a small decrease in haloperidol groups, with or without ethanol, as related to ethanol alone, no other effect was observed in HDL-C levels. In conclusion, we showed that haloperidol might be effective in moderating lipid alterations caused by chronic alcohol intake.     

Effect of an antagonistic analog of LH-RH on haloperidol-induced hyperprolactinemia in female rats

The effects of prolonged treatment with the antagonistic analog of LH-RH (N-Ac-D-p-Cl-Phe1,2, D-Trp3,D-Arg6,D-Ala10) LH-RH (ORG 30276) on the hyperprolactinemia induced by haloperidol were investigated in intact or ovariectomized female rats. Treatment with ORG 30276 for 20 days significantly reduced prolactin levels elevated by daily injections of haloperidol in intact as well as in ovariectomized rats. Administration of ORG 30276 also significantly decreased serum LH levels in both types of rats. It is concluded that the LH-RH antagonist ORG 30276 is able to counteract the hyperprolactinemic effect of haloperidol. This effect might be due to a blockade of the action of endogenous LH-RH on the gonadotrophs, which results in a suppressing of the paracrine action of these cells on the lactotroph.     

Tourette's disorder and associated complex behaviors: a case report

A case of a man with Tourette's disorder associated with obsessive-compulsive disorder, multiple sexual paraphilias, and aggressive behavior is described. Treatment with haloperidol led to improvement in the characteristic tics of Tourette's disorder as well as to improvement in these three complex-associated behaviors. After haloperidol was discontinued, an exacerbation of tics and the associated behaviors occurred.     

Haloperidol effect on intracellular signals system coupled to alpha1-adrenergic receptor in rat cerebral frontal cortex.

The induction of intracellular signals coupled to alpha1-adrenoceptor by haloperidol, were studied in rat cerebral frontal cortex. The neuroleptic exerts a biphasic effect on nitric oxide synthase (NOS), inhibiting the enzymatic activity at low concentrations (10(-9) M), while higher concentrations (10(-5) M) increased it. Protein kinase C (PKC) and phosphoinositol turnover (PIs) were involved in these actions, as haloperidol induced PKC translocation at low concentrations, and increased PIs turnover at high concentrations. All the effects of haloperidol were blocked by the alpha-adrenoceptor antagonist prazosin and the phospholipase C (PLC) inhibitor NCDC. The possibility that a cross-talk between both enzymatic pathways depending on the neuroleptic concentration used in rat cerebral frontal cortex, is also discussed.     

Taftsin correction of pharmacologically induced behavioral disorders in white rats

Tetrapeptide tuftsin in doses adapted to its physiological blood concentrations partially normalized locomotor activity and orientation behaviour of rats altered by drugs affecting aminergic brain systems. At the same time tuftsin had no effect when applied after the treatment by dopaminergic drugs (DTC, haloperidol, apomorphine). It can be concluded that the central effect observed in the first minutes after tuftsin administration is mediated through dopaminergic system. Elimination of some drug-induced behavioural disturbances by tuftsin opens new prospects for its therapeutic application.     

Effect of chronic neuroleptic or L-DOPA administration on GABA levels in the rat substantia nigra

Male albino rats were administered daily with haloperidol, clozapine or L-DOPA and sacrificed 18 hours after the last dose of the drug. Acutely haloperidol (5mg/kg, i.p.) greatly lowered nigral GABA levels whereas after 167 daily doses the nigral GABA levels were not significantly different from controls, but were significantly increased as compared with the acutely treated animals. In contrast, acute L-DOPA (2 × 100mg, p.o.) greatly raised nigral GABA levels whereas after chronic L-DOPA (167 days) nigral GABA levels were not significantly different from controls and were significantly lower as compared with the animals receiving the acute treatment. Clozapine (20 mg/kg, i.p. either acutely or chronically) did not have as marked an effect on nigral GABA levels as did haloperidol. Of these various drug regimens only chronic L-DOPA significantly affected nigral GAD activity, producing a moderate decrease.     

Behavioural alterations in rats induced by single prenatal exposure of haloperidol

Haloperidol (50 mg/kg, i.p.) treatment was given once to two different groups of pregnant Charles Foster rats on gestational day 9 and 14, these being respectively the critical periods of neural morphogenesis and rapid neural cell proliferation in this species. Pregnant control rats were similarly treated with equal volume of vehicle. The pups born were subjected to open-field exploratory behaviour and elevated plus-maze behaviour tests of anxiety and learned helplessness test of depression at 9 weeks of age. The results indicate that prenatal haloperidol treatment on gestational day 14 induces a significant increase in open-field ambulation and faecal droppings whereas haloperidol treatment on gestational day 9 caused significantly decreased rearing and unaltered ambulation in rat offsprings. Rat offsprings treated with haloperidol on gestational day 9 and 14 also displayed significant anxiogenic behaviour pattern on elevated plus-maze. Significantly increased number of escape failures were observed in learned helplessness tests indicating presence of depression in haloperidol treated rat offsprings. These behavioural alterations were found to be more marked in rat offsprings treated with haloperidol on gestational day 14. The results suggest that prenatal single exposure of high dose of haloperidol during critical period of neural cell proliferation leaves a lasting imprint on offsprings resulting in abnormal emotional state.     

On the relation between haloperidol-induced alterations in DA release and DA metabolism in rat striatum

Haloperidol (1 mg/kg) was administered to rats pretreated with α-methyl-para-tyrosine-methylester. HCl (αMpT) and the levels of dopamine (DA) as well as HVA and DOPAC were measured in the striatum. While the release of DA was stimulated by haloperidol for at least 60 min, HVA and DOPAC levels were markedly increased only at 30 min, but not at 60, 90, or 120 min, after haloperidol administration. In rats not pretreated with αMpT, on the other hand, a strong increase in metabolite levels was observed between 60 and 120 min after haloperidol administration. It is concluded that a direct relation between DA release and metabolite levels does not exist in the present experiments. DA biosynthesis and processes involved with the clearance of metabolites appear to be important factors in the haloperidol-induced increase in metabolite levels. The relative importance of these three processes remains to be clarified.     

Bauhinia forficata Prevents Vacuous Chewing Movements Induced by Haloperidol in Rats and Has Antioxidant Potential In Vitro

Classical antipsychotics can produce motor disturbances like tardive dyskinesia in humans and orofacial dyskinesia in rodents. These motor side effects have been associated with oxidative stress production in specific brain areas. Thus, some studies have proposed the use of natural compounds with antioxidant properties against involuntary movements induced by antipsychotics. Here, we examined the possible antioxidant activity of Bauhinia forficata (B. forficata), a plant used in folk medicine as a hypoglycemic, on brain lipid peroxidation induced by different pro-oxidants. B. forficata prevented the formation of lipid peroxidation induced by both pro-oxidants tested. However, it was effective against lipid peroxidation induced by sodium nitroprusside (IC₅₀ = 12.08 μg/mL) and Fe²⁺/EDTA (IC₅₀ = 41.19 μg/mL). Moreover, the effects of B. forficata were analyzed on an animal model of orofacial dyskinesia induced by long-term treatment with haloperidol, where rats received haloperidol each 28 days (38 mg/kg) and/or B. forficata decoction daily (2.5 g/L) for 16 weeks. Vacuous chewing movements (VCMs), locomotor and exploratory activities were evaluated. Haloperidol treatment induced VCMs, and co-treatment with B. forficata partially prevented this effect. Haloperidol reduced the locomotor and exploratory activities of animals in the open field test, which was not modified by B. forficata treatment. Our present data showed that B. forficata has antioxidant potential and partially protects against VCMs induced by haloperidol in rats. Taken together, our data suggest the protection by natural compounds against VCMs induced by haloperidol in rats.     

Chronic haloperidol increases voltage-gated Na currents in mouse cortical neurons

Typical antipsychotics are characterized by extrapyramidal syndrome (EPS). Previous studies demonstrated that typical antipsychotics could inhibit neuronal voltage-gated sodium channel (VGSC). However, EPS typically emerge only upon prolonged exposure. As a result, we examined effects of haloperidol, a prototype typical antipsychotic, on neuronal VGSC upon incubation for varying duration. Briefly, VGSC currents were activated and recorded using a whole-cell patch-clamp technique in primary culture of mouse cortical neurons. VGSC activity was inhibited by acute haloperidol exposure (for minutes), but enhanced in a time- and concentration-dependent manner by chronic haloperidol exposure (for hours). The effects of chronic haloperidol were associated with increased expression of VGSC subunits as well as corresponding electrophysiological channel properties. In summary, we found enhanced VGSC currents upon chronic haloperidol exposure in cortical neurons in contrast to inhibition by acute haloperidol exposure. Such a results may contribute to EPS of typical antipsychotics.     

Concurrent treatment with benztropine and haloperidol attenuates development of behavioral hypersensitivity but not dopamine receptor proliferation

Groups of male rats (n = 16 each) were treated with normal saline, haloperidol (0.75 mg/kg), benztropine (1.8 mg/kg) or haloperidol and benztropine once a day for 24 days. Following a 96 hour drug free interval, subsets of these animals were assessed for apomorphine-induced (0.75 mg/kg) stereotypic behavior, sacrificed and analyzed for striatal dopamine biochemistry or sacrificed and analyzed for spiroperidol binding sites. Benztropine cotreatment attenuated the development of behavioral hypersensitivity to haloperidol but did not alter either the dopamine receptor proliferation or the striatal dopamine biochemical changes induced by haloperidol. These results suggest that behavioral hypersensitivity is not an automatic manifestation of dopamine receptor proliferation but must depend, in part, on other factors.     

Dopamine receptor sites in the anterior pituitary.

An immunocytochemical method was developed to visualize dopamine receptor sites on dispersed anterior pituitary cells of the rat. Dopamine receptors were labeled with the antagonist haloperidol. Some cells were incubated with haloperidol and a 100-fold excess of the potent antagonist D-butaclamol to determine nonspecific binding. The labeled sites were stained with an antibody against haloperidol and the peroxidase anti-peroxidase (PAP) technique. PAP complexes which served as markers for dopamine binding sites appeared on the outer plasmalemmal surface of the vast majority of mammotrophs. PAP complexes attached to the inner surface of endocytotic vesicle membrane suggested internalization of receptor-rich portions of the plasmalemma. Some gonadotrophs and somatotrophs were specifically stained to a lesser extent. However, high receptor site density and internalization of PAP complexes were never observed on cell types other than mammotrophs. The presence of dopamine receptors on the plasmalemma of mammotrophs provides strong additional evidence that dopamine acts upon these cells as a prolactin inhibitory hormone.     

Gastric mucosal lesions induced by complete dopamine system failure in rats. The effects of dopamine agents, ranitidine, atropine, omeprazole and pentadecapeptide BPC 157.

Up to now, for gastric lesions potentiation or induction, as well as determination of endogenous dopamine significance, dopamine antagonist or dopamine vesicle depletor were given separately. Therefore, without combination studies, the evidence for dopamine significance remains split on either blockade of dopamine post-synaptic receptor or inhibition of dopamine storage, essentially contrasting with endogenous circumstances, where both functions could be simultaneously disturbed. For this purpose, a co-administration of reserpine and haloperidol, a dopamine granule depletor combined with a dopamine antagonist with pronounced ulcerogenic effect, was tested, and the rats were sacrificed 24 h after injurious agent(s) administration. Haloperidol (5 mg x kg(-1) b.w. i.p.), given alone, produced the lesions in all rats. Reserpine (5 mg x kg(-1) b.w. i.p.), given separately, also produced lesions. When these agents were given together, the lesions were apparently larger than in the groups injured with separate administration of either haloperidol or reserpine alone. Along with our previous results, when beneficial agents were co-administered, all dopaminomimetics (bromocriptine 10 mg, apomophine 1 mg, amphetamine 20 mg x kg(-1) i.p.) apparently attenuated the otherwise consistent haloperidol-gastric lesions. Likewise, an apparent inhibition of the reserpine-lesions was noted as well. However, if they were given in rats injured with combination of haloperidol and reserpine, their otherwise prominent beneficial effects were absent. Ranitidine (10 mg), omeprazole (10 mg), atropine (10 mg), pentadecapeptide BPC 157 (Gly-Glu-Pro-Pro-Pro-Gly-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val) (10 microg or 10 ng x kg(-1) i.p.) evidently prevented both haloperidol-gastric lesions and reserpine-gastric lesions. Confronted with potentiated lesions following a combination of haloperidol and reserpine, these agents maintained their beneficial effects, noted in the rats treated with either haloperidol or reserpine alone. The failure of dopaminomimetics could be most likely due to more extensive inhibition of endogenous dopamine system activity, and need for remained endogenous dopamine for their salutary effect, whereas the beneficial activities of ranitidine, omeprazole, atropine, pentadecapeptide BPC 157 following dopamine system inhibition by haloperidol+reserpine suggest their corresponding systems parallel those of dopamine system, and they may function despite extensive inhibition of endogenous dopamine system activity.