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Background: Haloperidol is a commonly used antipsychotic drug and may increase neuronal oxidative stress associated with the side effects, including tardive dyskinesia and neurite withdraw. Autophagy plays a protective role in response to the accumulated reactive oxygen species (ROS) induced mitochondria damage. Resveratrol is an antioxidant compound having neuroprotective effects; however, it is unknown if resveratrol may stimulate autophagy and decrease mitochondria damage induced by haloperidol., Hypothesis: We hypothesis that resveratrol stimulates the autophagic process and protects mitochondria lesion induced by haloperidol., Methods: MitoSOX™ Red Mitochondrial Superoxide Indicator and MitoTracker™ Green FM staining were used to measure the amount of the mitochondria ROS production and mitochondria mass in human SH-SY5Y cells treated with haloperidol and/or resveratrol. Autophagic related dyes and Western blot were applied to study the autophagic process and related protein expression. Besides, tandem monomeric mRFP-GFP-LC3 was used to investigate the fusion of autophagosome and lysosome. Transmission electron microscopy was used to investigate the mitochondrial and autophagic ultrastructures with or without haloperidol and resveratrol treatment., Results: Haloperidol administration significantly increased mitochondria ROS and mitochondrial mass, indicating the increase of mitochondria dysfunction. Although haloperidol increased the autophagosomes and lysosome formation, the autophagosome-lysosome fusion and degradation were impaired. This was because we found an increased p62 after haloperidol treatment, an indication of autophagy incompletion. Importantly, resveratrol promoted the degradation of p62, upregulated the formation of autophagolysosome, and reversed haloperidol-induced mitochondria damage., Conclusion: These results collectively suggest that resveratrol may be introduced as a protective compound against haloperidol-induced mitochondria impairment and aberrant autophagy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Human exposure to organophosphate flame retardants (OPFRs) is widespread, including pregnant women and young children with whom developmental neurotoxic risk is a concern. Given similarities of OPFRs to organophosphate (OP) pesticides, research into the possible neurotoxic impacts of developmental OPFR exposure has been growing. Building upon research implicating exposure to OP pesticides in dopaminergic (DA) dysfunction, we exposed developing zebrafish to the OPFR tris(1,3-dichloroisopropyl) phosphate (TDCIPP), during the first 5 days following fertilization. On day 6, larvae were challenged with acute administration of dopamine D 1 and D 2 receptor antagonists and then tested in a light-dark locomotor assay. We found that both developmental TDCIPP exposure and acute dopamine D 1 and D 2 antagonism decreased locomotor activity separately. The OPFR and DA effects were not additive; rather, TDCIPP blunted further D 1 and D 2 antagonist-induced decreases in activity. Our results suggest that TDCIPP exposure may be disrupting dopamine signaling. These findings support further research on the effects of OPFR exposure on the normal neurodevelopment of DA systems, whether these results might persist into adulthood, and whether they interact with OPFR effects on other neurotransmitter systems in producing the developmental neurobehavioral toxicity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Rationale: The dopaminergic system has been proposed to mediate alcohol-induced locomotor activity, yet the mechanisms underlying this behavioral response remain poorly understood., Objectives: This study was conducted to investigate the role of dopamine D2-like receptors in mediating alcohol-induced behavioral responses., Methods: In experiment 1, we examined the effects of high concentrations (0, 2.5, 5, 10 μM) of haloperidol on motor responses. In experiment 2, we examined the effects of low concentrations (0, 0.625, 1.25, 2.5 μM) of haloperidol on anxiety-like behavioral responses using the novel tank test. In experiment 3, we examined the effect of pre-treating zebrafish with different concentrations of haloperidol (0, 0.625, 2.5 μM) and subsequently exposing them to 0 or 1 % alcohol., Results: In experiment 1, haloperidol induced an inverted U-shaped concentration-dependent increase in locomotor activity. In experiment 2, haloperidol (2.5 μM) reduced the absolute turn angle and freezing behavior in a new environment. In experiment 3, acute alcohol exposure significantly increased locomotor activity and decreased anxiety-like behavioral responses. Pre-treating zebrafish with the lower dose of haloperidol (0.625 μM) abolished the alcohol-induced locomotor activity, without altering anxiety-like behavioral responses. However, pre-treating with the higher dose of haloperidol (2.5 μM) abolished both alcohol-induced increase of locomotor activity and reduction of anxiety-like behavioral responses., Conclusion: The results suggest alcohol-induced locomotor hyperactivity in zebrafish is mediated via activation of dopamine D2-like receptors, whereas anxiety-like behavioral responses may only be altered by a high haloperidol concentration, at which dose the drug may affect receptors other than D2-R.

Tardive Dyskinesia is a severe side effect of chronic neuroleptic treatment consisting of abnormal involuntary movements, characterized by orofacial dyskinesia. The study was designed to investigate the protective effect of lycopene against haloperidol induced orofacial dyskinesia possibly by neurochemical and neuroinflammatory modulation in rats. Rats were administered with haloperidol (1mg/kg, i.p for 21 days) to induce orofacial dyskinesia. Lycopene (5 and 10mg/kg, p.o) was given daily 1hour before haloperidol treatment for 21 days. Behavioral observations (vacuous chewing movements, tongue protrusions, facial jerking, rotarod activity, grip strength, narrow beam walking) were assessed on 0th, 7th(,) 14th(,) 21st day after haloperidol treatment. On 22nd day, animals were killed and striatum was excised for estimation of biochemical parameters (malondialdehyde, nitrite and endogenous enzyme (GSH), pro-inflammatory cytokines [Tumor necrosis factor, Interleukin 1β, Interleukin 6] and neurotransmitters level (dopamine, serotonin, nor epinephrine, 5-Hydroxyindole acetic acid (5-HIAA), Homovanillic acid, 3,4- dihydroxyphenylacetic acid. Haloperidol treatment for 21 days impaired muscle co-ordination, motor activity and grip strength with an increased in orofacial dyskinetic movements. Further free radical generation increases MDA and nitrite levels, decreasing GSH levels in striatum. Neuroinflammatory markers were significantly increased with decrease in neurotransmitters levels. Lycopene (5 and 10mg/kg, p.o) treatment along with haloperidol significantly attenuated impairment in behavioral, biochemical, neurochemical and neuroinflammatory markers. Results of the present study attributed the therapeutic potential of lycopene in the treatment (prevented or delayed) of typical antipsychotic induced orofacial dyskinesia., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Dopamine D(3) receptors are highly expressed in the cerebellum; however, their pathophysiological functions are not fully understood. Here, we conducted microinjection studies to clarify the role of cerebellar D(3) receptors in modulating locomotion and cataleptogenicity in rats. Microinjection of the preferential D(3) agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) into lobe 9 of the cerebellum significantly reduced spontaneous locomotor activity with a U-shaped dose-response curve. The intracerebellar microinjection of 7-OH-DPAT did not elicit catalepsy by itself, but markedly potentiated catalepsy induction with a low dose (0.3mg/kg) of haloperidol. The catalepsy enhancement by 7-OH-DPAT occurred in a dose-dependent manner and was not associated with the locomotor inhibition. U-99194A (a selective D(3) antagonist) or AD-6048 (a preferential D(3) vs. D(2) antagonist) antagonized both the catalepsy enhancement and the locomotor inhibition with 7-OH-DPAT. In addition, U-99194A and AD-6048 per se significantly alleviated catalepsy induced by a high dose (0.5mg/kg) of haloperidol. Furthermore, microinjection of 7-OH-DPAT into the nucleus accumbens or the dorsolateral striatum neither affected spontaneous locomotor activity nor haloperidol (0.3mg/kg)-induced catalepsy. The present results illustrate for the first time the role of cerebellar D(3) receptors in modulating cataleptogenicity of antipsychotic agents, implying that blockade of cerebellar D(3) receptors contributes to the reduction of extrapyramidal side effects., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Akathisia is a subset of the larger antipsychotic side effect profile known as extrapyramidal syndrome (EPS). It is associated with antipsychotic treatment and is characterized as a feeling of inner restlessness that results in a compulsion to move. There are currently no primate models available to assess drug-induced akathisia; the present research was designed to address this shortcoming. We developed a novel rating scale based on both the Barnes Akathisia Rating Scale (BARS) and the Hillside Akathisia Scale (HAS) to measure the objective, observable incidence of antipsychotic-induced akathisia-like behavior in Cebus apella non-human primates (NHPs). To induce akathisia, we administered the atypical antipsychotic aripiprazole (1 mg/kg) or the selective phosphodiesterase 10A (PDE10A) inhibitor MP-10 (1-3 mg/kg). Treatment with both compounds produced significantly greater akathisia scores on the rating scale than vehicle treatment. Characteristic behaviors observed included vocalizations, stereotypies, teeth grinding, restless limb movements, and hyperlocomotion. Adenosine A2A receptor antagonists have previously been shown to be effective in blocking antipsychotic-induced EPS in primates. The selective A2A receptor antagonist, SCH 412348 (10-30 mg/kg), effectively reduced or reversed akathisia-like behavior induced by both aripiprazole and MP-10. This work represents the first NHP measurement scale of akathisia and demonstrates that NHPs are responsive to akathisia-inducing agents. As such, it provides a useful tool for the preclinical assessment of putative antipsychotics. In addition, these results provide further evidence of the utility of A2A receptor antagonists for the treatment of antipsychotic-induced movement disorders., (Copyright © 2013 Elsevier Inc. All rights reserved.)

In order to assess whether caffeine and theophylline have the same potency and efficacy to reverse the impairment of motor function caused by acute or chronic interruption of striatal dopamine transmission, a comparison of their dose-response relationship was made in the acute model of haloperidol-induced catalepsy, and the chronic model of unilateral lesion of the dopamine nigrostriatal pathway with 6-hydroxydopamine. At equimolar doses, both drugs reduced catalepsy intensity and increased its onset latency in a dose-dependent fashion, showing comparable potencies and attaining the maximal effect at similar doses. Catalepsy intensity: caffeine ED₅₀ = 24.1 μmol/kg [95% CI, 18.4-31.5]; theophylline ED₅₀ = 22.0 μmol/kg [95% CI, 17.0-28.4]. Catalepsy latency: caffeine ED₅₀ = 27.0 μmol/kg [95% CI, 21.1-34.6]; theophylline ED₅₀ = 28.8 μmol/kg [95% CI, 22.5-36.7]. In one group of hemiparkinsonian rats (n = 5), caffeine caused a dose-dependent recovery of the contralateral forepaw stepping: ED₅₀ = 2.4 μmol/kg/day [95% CI, 1.9-3.1]), reaching its maximum at the dose of 5.15 μmol/kg/day. When the treatment of these same rats was switched to 5.15 μmol/kg/day of theophylline, the stepping recovery was only 51 ± 12% of that induced by caffeine. Assessing the dose-response relationship of theophylline in another group of hemiparkinsonian rats (n = 7) revealed that it caused stepping recovery in an all-or-none fashion. Thus, the three lower doses had no effect, but at the dose of 5.15 μmol/kg/day theophylline suddenly increased the stepping to 56 ± 5% of the maximal effect observed when the treatment of these same rats was switched to an equimolar dose of caffeine. Increasing the dose of theophylline up to 15.45 μmol/kg/day caused no further stepping improvement since it was only 41 ± 6% of the maximal effect produced by caffeine at the dose of 5.15 μmol/kg/day. Given that theophylline showed less potency and efficacy than caffeine to reverse the motor impairment caused by chronic, but not acute, interruption of striatal dopaminergic transmission in rats, it is suggested that caffeine would provide more benefits than theophylline to improve the motor function in patients with Parkinson's disease., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Group III metabotropic glutamate (mGlu) receptors are localized in presynaptic terminals within basal ganglia (BG) circuitry that become hyperactive due to dopamine depletion in Parkinson's disease (PD). For this reason, group III mGlu receptors, in particular mGlu4, have been considered as key strategic targets for non-dopaminergic pharmacological treatments aimed at modulating these synapses, without producing the well known side-effects of l-DOPA, in particular the highly disabling l-DOPA-induced dyskinesia (LID). Herein we add physiological and functional support to this hypothesis using Lu AF21934, a novel selective and brain-penetrant mGlu4 receptor positive allosteric modulator (PAM) tool compound. By in vitro electrophysiological recordings we demonstrate that Lu AF21934 inhibits corticostriatal synaptic transmission and enhances the effect of the orthosteric mGlu4 receptor-preferred agonist LSP1-2111. In naïve rats, Lu AF21934 dose-dependently (10 and 30 mg/kg) alleviated haloperidol-induced catalepsy. In hemiparkinsonian rats (unilateral 6-hydroxydopamine lesion of the substantia nigra pars compacta), Lu AF21934 alone did not affect akinesia at the doses tested (10 and 30 mg/kg). However, when Lu AF21934 was combined with sub-threshold doses of l-DOPA (1 and 5 mg/kg), it acted synergistically in alleviating akinesia in a dose-dependent manner and, notably, also reduced the incidence of LID but not its severity. Interestingly, these effects occurred at Lu AF21934 brain free concentrations that showed functional activity in in vitro screens (calcium flux and electrophysiology assays). These results support the potential for antiparkinsonian clinical use of a combined treatment consisting in l-DOPA and a mGlu4 receptor PAM to reduce efficacious l-DOPA doses (generally known as l-DOPA sparing), while maintaining the same benefit on PD motor troubles, and at the same time minimizing the development of LID. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Dopamine D2 and adenosine A(2A) receptors interact to regulate aspects of motor and motivational function, and it has been suggested that adenosine A(2A) antagonists could be useful for the treatment of parkinsonism and depression. The present experiments were performed to characterize the effects of Lu AA47070, which is a phosphonooxymethylene prodrug of a potent and selective adenosine A(2A) receptor antagonist, for its ability to reverse the motor and motivational effects of D2 antagonism. In the first group of studies, Lu AA47070 (3.75-30 mg/kg IP) was assessed for its ability to reverse the effects of the D2 receptor antagonist pimozide (1.0 mg/kg IP) using several measures of motor impairment, including catalepsy, locomotion, and tremulous jaw movements, which is a rodent model of parkinsonian tremor. Lu AA47070 produced a significant reversal of the effects of pimozide on all three measures of parkinsonian motor impairment. In addition, Lu AA47070 was able to reverse the effects of a low dose of the D2 antagonist haloperidol on a concurrent lever pressing/chow feeding task that is used as a measure of effort-related choice behavior. The ability of Lu AA47070 to reverse the effects of D2 receptor blockade suggests that this compound could have potential utility as a treatment for parkinsonism, and for some of the motivational symptoms of depression., (Copyright © 2011. Published by Elsevier Inc.)

The neurotoxic organomercurial thimerosal (THIM), used for decades as vaccine preservative, is a suspected factor in the pathogenesis of some neurodevelopmental disorders. Previously we showed that neonatal administration of THIM at doses equivalent to those used in infant vaccines or higher, causes lasting alterations in the brain opioid system in rats. Here we investigated neonatal treatment with THIM (at doses 12, 240, 1440 and 3000 μg Hg/kg) on behaviors, which are characteristically altered in autism, such as locomotor activity, anxiety, social interactions, spatial learning, and on the brain dopaminergic system in Wistar rats of both sexes. Adult male and female rats, which were exposed to the entire range of THIM doses during the early postnatal life, manifested impairments of locomotor activity and increased anxiety/neophobia in the open field test. In animals of both sexes treated with the highest THIM dose, the frequency of prosocial interactions was reduced, while the frequency of asocial/antisocial interactions was increased in males, but decreased in females. Neonatal THIM treatment did not significantly affect spatial learning and memory. THIM-exposed rats also manifested reduced haloperidol-induced catalepsy, accompanied by a marked decline in the density of striatal D₂ receptors, measured by immunohistochemical staining, suggesting alterations to the brain dopaminergic system. Males were more sensitive than females to some neurodisruptive/neurotoxic actions of THIM. These data document that early postnatal THIM administration causes lasting neurobehavioral impairments and neurochemical alterations in the brain, dependent on dose and sex. If similar changes occur in THIM/mercurial-exposed children, they could contribute do neurodevelopmental disorders., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Although haloperidol is widely prescribed for the treatment of schizophrenia, its beneficial effects are accompanied by extrapyramidal side effects (EPS). Role of 5-HT-2A/2C receptors in the attenuation of acute Parkinsonian-like effects of typical antipsychotics is investigated by prior administration of mianserin and mesulergine to rats injected with haloperidol. In the first part of study effects of various doses of haloperidol (0.5, 1.0, 2.5 and 5.0 mg/kg) were determined on motor activity and a selected dose (1 mg/kg) was used to monitor attenuation of parkinsonian effects by two different doses of 5-HT-2A/2C receptor antagonists mianserin (2.5 & 5.0 mg/kg) and mesulergine (1.0 & 3.0 mg/kg). Rats treated with haloperidol at doses of 0.5-5.0 mg/kg exhibited impaired motor coordination and a decrease in exploratory activity in an open field. The dose response curve showed that at a dose of 1 mg/kg significant and submaximal effects are produced on motor coordination and exploratory activity. Coadministration of mianserin and mesulergine attenuated and reversed haloperidol-induced motor deficits in a dose dependent manner. The mechanism involved in the attenuation / reversal of haloperidol-induced parkinsonian like symptoms by mianserin and mesulergine is discussed. Prior administration of mianserin or mesulergine may be of use in the alleviation of EPS induced by conventional antipsychotic drugs.The findings have potential implication in the treatment of schizophrenia and motor disorders.

Rationale: Mesolimbic dopamine (DA), particularly in the nucleus accumbens, importantly regulates activational aspects of maternal responsiveness. DA antagonism and accumbens DA depletions interfere with early postpartum maternal motivation by selectively affecting most forms of active maternal behaviors, while leaving nursing behavior relatively intact. Considerable evidence indicates that there is a functional interaction between DA D2 and adenosine A(2A) receptors in striatal areas, including the nucleus accumbens., Objective: This study was conducted to determine if adenosine A(2A) receptor antagonism could reverse the effects of DA receptor antagonism on early postpartum maternal behavior., Methods: The adenosine A(2A) receptor antagonist MSX-3 (0.25-2.0 mg/kg, IP) was investigated for its ability to reverse the effects of the DA D2 receptor antagonist haloperidol (0.1 mg/kg, IP) on the maternal behavior of early postpartum female rats., Results: Haloperidol severely impaired the expression of active maternal components, including retrieval and grouping the pups at the nest site, pup licking, and nest building. Co-administration of MSX-3 (0.25-2.0 mg/kg, IP) with haloperidol produced a dose-related attenuation of the haloperidol-induced behavioral deficits in early postpartum females. Doses of MSX-3 that effectively reversed the effects of haloperidol (0.5, 1.0 mg/kg), when administered in the absence of haloperidol, did not affect maternal responding or locomotor activity., Conclusions: Adenosine and DA systems interact to regulate early postpartum maternal responsiveness. This research may potentially contribute to the development of strategies for treatments of psychiatric disorders during the postpartum period, with particular emphasis in maintaining or restoring the mother-infant relationship.

Objective: The globus pallidus plays a critical role in movement regulation. Previous studies have indicated that the globus pallidus receives neurotensinergic innervation from the striatum, and systemic administration of a neurotensin analog could produce antiparkinsonian effects. The present study aimed to investigate the effects of pallidal neurotensin on haloperidol-induced parkinsonian symptoms., Methods: Behavioral experiments and electrophysiological recordings were performed in the present study., Results: Bilateral infusions of neurotensin into the globus pallidus reversed haloperidol-induced parkinsonian catalepsy in rats. Electrophysiological recordings showed that microinjection of neurotensin induced excitation of pallidal neurons in the presence of systemic haloperidol administration. The neurotensin type-1 receptor antagonist SR48692 blocked both the behavioral and the electrophysiological effects induced by neurotensin., Conclusion: Activation of pallidal neurotensin receptors may be involved in neurotensin-induced antiparkinsonian effects.

Blonanserin is a novel antipsychotic agent that preferentially interacts with dopamine D(2) and 5-HT(2A) receptors. To assess the atypical properties of blonanserin, we evaluated its propensity to induce extrapyramidal side effects (EPS) and to enhance forebrain Fos expression in mice. The actions of AD-6048, a primary metabolite of blonanserin, in modulating haloperidol-induced EPS were also examined. Blonanserin (0.3-10mg/kg, p.o.) did not significantly alter the pole-descending behavior of mice in the pole test or increase the catalepsy time, while haloperidol (0.3-3mg/kg, p.o.) caused pronounced bradykinesia and catalepsy. Blonanserin and haloperidol at the above doses significantly enhanced Fos expression in the shell (AcS) region of the nucleus accumbens and dorsolateral striatum (dlST). The extent of blonanserin-induced Fos expression in the AcS was comparable to that induced by haloperidol. However, the striatal Fos expression by blonanserin was less prominent as compared to haloperidol. Furthermore, combined treatment of AD-6048 (0.1-3mg/kg, s.c.) with haloperidol (0.5mg/kg, i.p.) significantly attenuated haloperidol-induced bradykinesia and catalepsy. The present results show that blonanserin behaves as an atypical antipsychotic both in inducing EPS and enhancing forebrain Fos expression. In addition, AD-6048 seems to contribute at least partly to the atypical properties of blonanserin., (Copyright 2010 Elsevier Inc. All rights reserved.)

Novel thiazolotriazolopyrimidine derivatives (23-33) designed as potential adenosine A(2A) receptor (A(2A)R) antagonists were synthesized. Molecular docking studies revealed that all compounds (23-33) exhibited strong interaction with A(2A)R. The strong interaction of the compounds (23-33) with A(2A)R in silico was confirmed by their high binding affinity with human A(2A)R stably expressed in HEK293 cells using radioligand-binding assay. The compounds 24-26 demonstrated substantial binding affinity and selectivity for A(2A)R as compared to SCH58261, a standard A(2A)R antagonist. Decrease in A(2A)R-coupled release of endogenous cAMP in treated HEK293 cells demonstrated in vitro A(2A)R antagonist potential of the compounds 24-26. Attenuation in haloperidol-induced motor impairments (catalepsy and akinesia) in Swiss albino male mice pre-treated with compounds 24-26 further supports their role in the alleviation of PD symptoms., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Previously, the gastric pentadecapeptide BPC 157, (PL 14736, Pliva) has been shown to have several beneficial effects, it exert gastroprotective, anti-inflammatory actions, stimulates would healing and has therapeutic value in inflammatory bowel disease. The present study aimed to study the effect of naloxone and BPC 157 on morphine-induced antinociceptive action in hot plate test in the mouse. It was found that naloxone and BPC 157 counteracted the morphine (16 mg/kg s.c.) - analgesia. Naloxone (10 mg/kg s.c.) immediately antagonised the analgesic action and the reaction time returned to the basic values, the development of BPC 157-induced action (10 pg/kg, 10 ng/kg, 10 microg/kg i.p.) required 30 minutes. When haloperidol, a central dopamine-antagonist (1 mg/kg i.p.), enhanced morphine-analgesia, BPC 157 counteracted this enhancement and naloxone reestablished the basic values of pain reaction. BPC 157, naloxone, and haloperidol per se failed to exert analgesic action. In summary, interaction between dopamine-opioid systems was demonstrated in analgesia, BPC 157 counteracted the haloperidol-induced enhancement of the antinociceptive action of morphine, indicating that BPC acts mainly through the central dopaminergic system.

Haloperidol (HAL) is a widely used neuroleptic drug for the treatment of acute and chronic psychosis. Tardive dyskinesia (TD) is a complex hyperkinetic syndrome consisting of choreiform and athetoid movements, which persists for months or years after withdrawal. Increased levels of thiobarbituric acid reactive products are found in the cerebrospinal fluid and plasma of patients treated with neuroleptics, especially those with movement disorders. Alpha lipoic acid (ALA), a natural metabolic antioxidant, is effective in both prevention and treatment of numerous types of neurological disorders. It is proposed to study the effect of ALA on TD induced by HAL and to correlate it with oxidative stress by studying total antioxidant status and lipid peroxidation (LP). HAL (1 mg/kg/i.p.) was used to induce vacuous chewing movements in rats. ALA was suspended in 0.2% carboxy methyl cellulose at a dose of 25, 50 and 100 mg/kg and was administered orally by oral gavage 1 h before HAL on 21st day of treatment. ALA supplementation significantly decreased HAL-induced TD at a dose of 100 mg/kg and catalepsy dose dependently. ALA improved TD and catalepsy by decreasing HAL-induced LP. ALA and its metabolite dihydro lipoic acid protect against HAL-induced TD and catalepsy by scavenging reactive oxygen species and reactive nitrogen species.

We studied the effects of tandospirone, a 5-HT(1A) agonistic anxiolytic agent, on haloperidol-induced catalepsy and forebrain Fos expression in mice. Haloperidol (0.5 mg/kg, i.p.) markedly increased the catalepsy time and enhanced Fos expression in the shell (AcS) and core (AcC) regions of the nucleus accumbens, the dorsolateral striatum (dlST), and the lateral septal nucleus (LSN). Tandospirone (0.1 - 1 mg/kg, s.c.) significantly alleviated haloperidol-induced catalepsy in a dose-dependent manner, which was antagonized by WAY-100135 (a selective 5-HT(1A) antagonist). The anticataleptic dose of tandospirone (1 mg/kg, s.c.) significantly reduced haloperidol-induced Fos expression in the dlST. This inhibition by tandospirone was regionally specific, and it failed to affect haloperidol-induced Fos expression either in the AcS, AcC, or LSN. In addition, the reversal of haloperidol-induced striatal Fos expression by tandospirone was antagonized by WAY-100135. These results support the notion that stimulation of 5-HT(1A) receptors region-specifically counteracts the D(2)-blocking actions of haloperidol in the striatum, which may account for the ameliorative effects of 5-HT(1A) agonists on antipsychotic-associated extrapyramidal disorders.

Functional alterations in the neurotrophin, brain-derived neurotrophic factor (BDNF) have recently been implicated in the pathophysiology of schizophrenia. Furthermore, animal studies have indicated that several antipsychotic drugs have time-dependent (and differential) effects on BDNF levels in the brain. For example, our previous studies in rats indicated that chronic treatment with the conventional antipsychotic, haloperidol, was associated with decreases in BDNF (and other neurotrophins) in the brain as well as deficits in cognitive function (an especially important consideration for the therapeutics of schizophrenia). Additional studies indicate that haloperidol has other deleterious effects on the brain (eg increased apoptosis). Despite such limitations, haloperidol remains one of the more commonly prescribed antipsychotic agents worldwide due to its efficacy for the positive symptoms of schizophrenia and its low cost. Interestingly, the hematopoietic hormone, erythropoietin, in its recombinant human form rhEPO has been reported to increase the expression of BDNF in neuronal tissues and to have neuroprotective effects. Such observations provided the impetus for us to investigate in the present study whether co-treatment of rhEPO with haloperidol could sustain the normal levels of BDNF in vivo in rats and in vitro in cortical neuronal cultures and further, whether BDNF could prevent haloperidol-induced apoptosis through the regulation of key apoptotic/antiapoptotic markers. The results indicated that rhEPO prevented the haloperidol-induced reduction in BDNF in both in vivo and in vitro experimental conditions. The sustained levels of BDNF in rats with rhEPO prevented the haloperidol-induced increase in caspase-3 (p<0.05) and decrease in Bcl-xl (p<0.01) protein levels. Similarly, in vitro experiments showed that rhEPO prevented (p<0.001) the haloperidol-induced neuronal cell death as well as the decrease in Bcl-xl levels (p<0.01). These findings may have significant implications for the development of neuroprotective strategies to improve clinical outcomes when antipsychotic drugs are used chronically.

Tardive dyskinesia (TD) is a motor disorder of the orofacial region resulting from chronic neuroleptic treatment. A high incidence and irreversibility of this hyperkinetic disorder has been considered a major clinical issue in the treatment of schizophrenia. The molecular mechanism related to the pathophysiology of tardive dyskinesia is not completely known. Various animal studies have demonstrated an enhanced oxidative stress and increased glutamatergic transmission as well as inhibition in the glutamate uptake after the chronic administration of haloperidol. The present study investigated the effect of curcumin, an antioxidant, in haloperidol-induced tardive dyskinesia by using different behavioural (orofacial dyskinetic movements, stereotypy, locomotor activity, % retention), biochemical (lipid peroxidation, reduced glutathione levels, antioxidant enzyme levels (SOD and catalase) and neurochemical (neurotransmitter levels) parameters. Chronic administration of haloperidol (1 mg/kg i.p. for 21 days) significantly increased vacuous chewing movements (VCM's), tongue protrusions, facial jerking in rats which was dose-dependently inhibited by curcumin. Chronic administration of haloperidol also resulted in increased dopamine receptor sensitivity as evident by increased locomotor activity and stereotypy and also decreased % retention time on elevated plus maze paradigm. Pretreatment with curcumin reversed these behavioral changes. Besides, haloperidol also induced oxidative damage in all major regions of brain which was attenuated by curcumin, especially in the subcortical region containing striatum. On chronic administration of haloperidol, there was a decrease in turnover of dopamine, serotonin and norepinephrine in both cortical and subcortical regions which was again dose-dependently reversed by treatment with curcumin. The findings of the present study suggested for the involvement of free radicals in the development of neuroleptic-induced tardive dyskinesia and point to curcumin as a possible therapeutic option to treat this hyperkinetic movement disorder.

We have previously shown that the orexin-1 antagonist SB-334867 blocks the electrophysiological effects of haloperidol and olanzapine on the activity of A9 and A10 dopamine neurons. To evaluate if orexin-1 antagonists might block other effects of antipsychotic drugs in animals, we examined the effects of SB-334867 on behavioral, neurochemical, and neuroendocrine effects of antipsychotic drugs. Pretreatment with SB-334867 (0.01-10 mg/kg, intraperitoneal [IP]) significantly decreased the catalepsy produced by the administration of haloperidol (1 mg/kg, subcutaneous [SC]), risperidone (2 mg/kg, SC), and olanzapine (10 mg/kg, SC). Administration of SB-334467 also reversed catalepsy after it had been established in animals pretreated 2 hours earlier with haloperidol. However, pretreatment with SB-334867 (1-10 mg/kg, IP) did not block the decreases in exploratory locomotor activity produced by administration of haloperidol (0.1 mg/kg, SC) or risperidone (0.3 mg/kg, SC). In addition, pretreatment with SB-334867 (1-10 mg/kg, IP) neither blocked the increased levels of dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens or striatum nor the elevation in serum prolactin produced by administration of haloperidol (0.1 mg/kg, SC) and risperidone (1 mg/kg, SC). Administration of SB-334867 alone neither changed locomotor activity and DOPAC or prolactin levels nor produced catalepsy. These results show that orexin-1 antagonists block the catoleptogenic effects of antipsychotics but do not block other locomotor, neurochemical, or neuroendocrine effects of antipsychotics. Because catalepsy is thought to be a good predictor of extrapyramidal symptoms in humans, treatment with orexin-1 antagonists might decrease the occurrence or severity of antipsychotic treatment-emergent extrapyramidal symptoms in humans.

Tardive dyskinesia (TD), a syndrome of involuntary hyperkinesias in the orofacial region that develops in patients chronically treated with neuroleptic agents is a major limitation of the therapy. Rats chronically treated with haloperidol exhibit vacuous chewing movements (VCMs) with the twitching of facial musculature and tongue protrusion. The syndrome is widely used as an animal model of TD. Evidence suggests a role of 5-hydroxytryptamine (5-HT; serotonin)-1A receptors in the pathogenesis and treatment of TD because repeated administration of haloperidol resulted in an increase in the effectiveness of 5-HT-1A receptors while drugs with agonist activity at 5-HT-1A receptors could attenuate haloperidol-induced VCMs. The present study was designed to test the hypothesis that a decrease in the responsiveness of somatodendritic 5-HT-1A receptors by the coadministration of buspirone could reverse the induction of VCMs and supersensitivity at 5-HT-1A receptors by haloperidol. Rats treated with haloperidol at a dose of 1 mg/kg twice a day for 2 weeks displayed VCMs with twitching of facial musculature that increased in a time dependent manner as the treatment continued to 5 weeks. Coadministration of buspirone attenuated haloperidol-induced VCMs after 2 weeks and completely prevented it after 5 weeks. The intensity of 8-hydroxy-2-di (n-propylamino) tetralin (8-OH-DPAT)-induced locomotion was greater in saline+haloperidol injected animals but not in buspirone+haloperidol injected animals. 8-OH-DPAT-induced decreases of 5-HT metabolism were greater in saline+haloperidol injected animals but not in buspirone+haloperidol injected animals. It is suggested that an impaired somatodendritic 5-HT-1A receptor dependent response is a major contributing factor in the pathophysiology of TD and a normalization of the somatodendritic response by drugs may help extending therapeutics in schizophrenia.

Group III metabotropic glutamate receptors (mGluRs) are widely distributed in the basal ganglia, especially on the terminals of pathways which seem to be overactive in Parkinson's disease. The aim of the present study was to determine whether (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid (ACPT-1), an agonist of group III mGluRs, injected bilaterally into the globus pallidus (GP), striatum or substantia nigra pars reticulata (SNr), can attenuate the haloperidol-induced catalepsy in rats, and whether that effect was related to modulation of proenkephalin (PENK) or prodynorphin (PDYN) mRNA expression in the striatum. Administration of ACPT-1 (0.05-1.6 microg/0.5 microl/side) caused a dose-and-structure-dependent decrease in the haloperidol (0.5 mg/kg i.p. or 1.5 mg/kg s.c.)-induced catalepsy whose order was as follows: GP>striatum>SNr. ACPT-1, given alone to any of those structures, induced no catalepsy in rats. Haloperidol (3 x 1.5 mg/kg s.c.) significantly increased PENK mRNA expression in the striatum, while PDYN mRNA levels were not affected by that treatment. ACPT-1 (3 x 1.6 microg/0.5 microl/side) injected into the striatum significantly attenuated the haloperidol-increased PENK mRNA expression, whereas administration of that compound into the GP or SNr did not influence the haloperidol-increased striatal PENK mRNA levels. Our results demonstrate that stimulation of group III mGluRs in the striatum, GP or SNr exerts antiparkinsonian-like effects in rats. The anticataleptic effect of intrastriatally injected ACPT-1 seems to correlate with diminished striatal PENK mRNA expression. However, since the anticataleptic effect produced by intrapallidal and intranigral injection of ACPT-1 is not related to a simultaneous decrease in striatal PENK mRNA levels, it is likely that a decrease in enkephalin biosynthesis is not a necessary condition to obtain an antiparkinsonian effect.

Effects of coadministration of buspirone were investigated on the time course of haloperidol-induced extrapyramidal symptoms in rats. Rats treated with haloperidol at a dose of 1 mg/kg exhibited impaired motor coordination and a decrease in exploratory activity. Coadministration of buspirone at a dose of 1 mg/kg attenuated haloperidol-induced deficits of motor coordination but no effect was produced on the deficits of exploratory activity, possibly because of a 'floor effect'. Long-term administration of haloperidol (1 mg/kg) twice a day for 5 weeks did not produce tolerance to haloperidol-induced deficits of exploratory activity. The deficits of motor coordination were attenuated after 4-5 weeks of drug administration. Coadministration of buspirone for 3-5 weeks attenuated and reversed haloperidol-induced deficits of exploratory activity. Deficits of motor coordination were smaller in rats cotreated with buspirone after 1 week but not after 2-5 weeks. Administration of haloperidol for 2 weeks elicited vacuous chewing movements with twitching of facial musculature that increased in a time-dependent manner as the treatment continued to 5 weeks. Animals cotreated with buspirone exhibited a gradual reversal of the response during 2-5 weeks of treatment. The mechanism involved in the attenuation/reversal of haloperidol-induced extrapyramidal symptoms by buspirone is discussed. Prior administration of buspirone for 2 weeks may be of help in the improvement of extrapyramidal symptoms induced by antipsychotic drugs.

In order to better define the role of 5-HT(1A) receptors in the modulation of extrapyramidal motor functions, we investigated the effect of 5-HT(1A) agonists on tacrine-induced tremulous jaw movements (TJM) in rats, a putative model of parkinsonian tremor. Acute injection of 5-HT(1A) agonists 8-OH-DPAT and buspirone dose-dependently counteracted the tacrine-induced oral movements (ED(50)=0.04 and 1.0mg/kg, respectively), an effect reversed by the selective 5-HT(1A) antagonist WAY 100,635. In contrast to classical antipsychotics, the atypical antipsychotics risperidone (ED(50)=0.3mg/kg) and clozapine (ED(50)=1.5mg/kg) blocked the oral movements induced by the cholinomimetic agent at or below the doses required for suppression of conditioned avoidance response. The compound F-97013-GD (6-methyl-2-[4-(naphtylpiperazin-1-yl)butyl]-3-(2H)-pyridazinone), a putative antipsychotic drug that in functional in vitro and in vivo assays behaved as a mixed dopamine D(2)-antagonist and 5-HT(1A)-partial agonist, also displayed a potent antitremorgenic effect in this paradigm (ED(50)=0.5mg/kg). Interestingly, pretreatment with WAY 100,635 blocked the inhibitory effect of F-97013-GD but not that of clozapine. The 5-HT depleting agent para-chlorophenylalanine (PCPA) partially attenuated tacrine-induced TJM but did not block the suppressive effect of 5-HT(1A) agonists. In addition, only high doses of F-97013-GD induced catalepsy in rodents and, like 8-OH-DPAT and clozapine, the compound reversed the haloperidol-induced catalepsy in rats. These results show that 5-HT(1A) receptors play a role in the regulation of tacrine-induced TJM and suggest that their activation by novel antipsychotics may not only reduce the extrapyramidal side effects EPS liability, but also be effective in the treatment of parkinsonian tremor.

Aripiprazole,7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-carbostycil (OPC-14597), a novel atypical antipsychotic drug, is a dopamine D2 receptor partial agonist with functional 5-HT2A receptor antagonist, and 5-HT1A receptor partial agonist properties as well. Other atypical antipsychotic drugs, e.g. clozapine, but not typical antipsychotic drugs, e.g. haloperidol, produce significant increases in dopamine and acetylcholine release in the medial prefrontal cortex in rats, effects believed to be related to the ability to improve cognitive function. The increase in the medial prefrontal cortex dopamine release by the atypical antipsychotic drugs has been shown to be partially inhibited by N-[2[4-)2-methoxyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY100635), a selective 5-HT1A receptor antagonist. Aripiprazole, 0.1 and 0.3 mg/kg, significantly increased dopamine release in the hippocampus. Moreover, aripiprazole, 0.3 mg/kg, slightly but significantly increased dopamine release in the medial prefrontal cortex but not in the nucleus accumbens. These increases were significantly inhibited by WAY100635. By contrast, aripiprazole, 3.0 mg/kg and 10 mg/kg, significantly decreased dopamine release in the nucleus accumbens but not the medical prefrontal cortex. However, aripiprazole 10 mg/kg significantly decreased dopamine release in the both regions. Aripiprazole had no effect on acetylcholine release in the medial prefrontal cortex, hippocampus, or nucleus accumbens at any dose, except for 3.0 mg/kg, which decreased acetylcholine release in the nucleus accumbens only. Aripiprazole, 0.3 mg/kg, transiently potentiated haloperidol (0.1 mg/kg)-induced dopamine release in the medial prefrontal cortex but inhibited that in the nucleus accumbens. The present study demonstrated that aripiprazole, at low doses of 0.1 and 0.3 mg/kg, increases dopamine release in the medial prefrontal cortex and hippocampus. It also suggests that the function of both the medial prefrontal cortex and hippocampus may contribute to the ability of aripiprazole to improve negative symptom and cognition., (Copyright 2004 Elsevier B.V.)

The effect of subchronic co-administration of ritanserin (1.5 mg/kg, i.p., twice a day) and haloperidol (1 mg/kg, i.p., twice a day) on rat vacuous chewing movements and on tyrosine hydroxylase-immunostaining was investigated. Ritanserin significantly reduced rat vacuous chewing movements observed following 2, 3 and 4 weeks of haloperidol administration and after 5 days of haloperidol withdrawal. Furthermore, ritanserin prevented the reduction of striatal tyrosine hydroxylase-immunostaining and the shrinkage of nigral dopaminergic cell bodies induced by haloperidol. The present results indicate that ritanserin may possess protective properties on both dopaminergic nigro-striatal neuron alterations and vacuous chewing movements induced by haloperidol, and provide further evidence indicating a possible association between these two haloperidol-induced effects.

Tardive dyskinesia (TD) is a serious motor side effect of long-term neuroleptic treatment that may persist after drug withdrawal. Alterations in striatal enkephalinergic neurons due to excessive glutamatergic activity is a possible pathogenetic mechanism. We studied the effect of the NMDA antagonist memantine in a rat model of TD, in which vacuous chewing movements (VCM) were induced by 20 weeks of haloperidol administration. The striatal density of preproenkephalin mRNA was measured and the number of neurons estimated. Haloperidol induced persistent VCM that was associated with increased striatal expression of preproenkephalin mRNA. Memantine inhibited the development of haloperidol-induced persistent VCM and attenuated the increase in preproenkephalin mRNA expression. This suggests that glutamate-mediated up-regulation of striatal enkephalin plays a role in the development of haloperidol-induced persistent oral dyskinesias.

Tardive dyskinesia is a serious motor side effect of chronic neuroleptic therapy. The pathophysiology of this disabling and commonly irreversible movement disorder is still obscure. It may be caused by a loss of dopaminergic cells, due to free radicals as a product of high synaptic dopamine levels. Chronic treatment with neuroleptics leads to the development of abnormal oral movements in rats called vacuous chewing movements. Vacuous chewing movements in rats are widely accepted as an animal model of tardive dyskinesia. Chronic haloperidol (1 mg/kg for 21 days) treatment significantly induced vacuous chewing movements and tongue protrusions in rats, and FK506 (Tacrolimus) [[3S-[3R*[E(1S*,3S*,4S*)],4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*]]-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5, 19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14, 16-dimethoxy-4,10,12, 18-tetramethyl-8-(2-propenyl)-15, 19-epoxy-3H-pyrido[2,1-c][1,4] oxaazacyclotricosine-1,7,20, 21(4H,23H)-tetrone, monohydrate] dose dependently (0.5 and 1 mg/kg) reduced these haloperidol-induced movements. Biochemical analysis revealed that chronic haloperidol treatment significantly induced lipid peroxidation and decreased the levels of glutathione and of the antioxidant defense enzymes, superoxide dismutase and catalase, in the brains of rats. Co-administration of FK506 dose dependently (0.5 and 1 mg/kg) and significantly reduced the lipid peroxidation and restored the decreased glutathione levels induced by chronic haloperidol treatment. It also significantly reversed the haloperidol-induced decrease in brain superoxide dismutase and catalase levels. The major findings of the present study suggest that oxidative stress-induced neuronal death might play a significant role in neuroleptic-induced orofacial dyskinesia. In conclusion, FK506 could be a useful drug for the treatment of neuroleptic-induced orofacial dyskinesia.

Apolipoprotein-D (apoD), a member of the lipocalin family of proteins, binds to arachidonic acid and cholesterol among other hydrophobic molecules. Recently, elevated apoD levels have been reported in the post-mortem brains, as well as plasma, of schizophrenic patients and in rodent brains after chronic treatment with clozapine (CLOZ). These findings and the evidence for altered membrane lipid metabolism in schizophrenia suggest that apoD may have a role in the pathophysiology of illness, and also in the differential clinical outcome following treatment with typical and atypical antipsychotic drugs. Here, we compared the effects of these antipsychotics on the expression of apoD in rat brain. Chronic treatment with typical antipsychotic, haloperidol (HAL) reduced apoD expression in hippocampus, piriform cortex and caudate-putamen (p = 0.027-0.002), whereas atypical antipsychotics, risperidone (RISP) and olanzapine (OLZ) increased (p = 0.051 to < 0.001 and p = 0.048 to < 0.001, respectively) apoD expression. In hippocampus, HAL-induced changes were present in CA1, CA3 and dentate gyrus, however, apoD levels in motor cortex were unchanged. There were also very dramatic effects of HAL on the neuronal morphology, particularly, cellular shrinkage and disorganization with the loss of neuropil. Post-treatment, either with RISP or OLZ, was very effective in restoring the HAL-induced reduction of apoD, as well as cellular morphology. Similarly, pre-treatments were also effective, but slightly less than post-treatment, in preventing HAL-induced reduction of apoD. The increased expression of apoD by atypical antipsychotics may reflect a novel molecular mechanism underlying their favorable effects compared with HAL on cognition, negative symptoms and extra-pyramidal symptoms in schizophrenia.

The possible synergism between caffeine and muscarinic antagonists to inhibit haloperidol-induced catalepsy was investigated with the bar test in rats. Pretreatment with low doses of caffeine (1-3 mg/kg), a non-selective adenosine antagonist, dose dependently reduced the intensity and increased the onset latency of catalepsy induced by haloperidol (0.5-2 mg/kg). Similar effects were produced by the muscarinic antagonists atropine (4.1 mg/kg), and trihexyphenidyl (THP, 0.01-3 mg/kg). THP inhibited catalepsy intensity with an ED(50) of 0.38 mg/kg, and increased its onset latency with an ED(50) of 0.52 mg/kg. The anticataleptic effect of anticholinergics was potentiated when a low dose of caffeine (1 mg/kg) was applied simultaneously. In the presence of caffeine, THP inhibited catalepsy intensity with an ED(50) of 0.19 mg/kg, and prolonged the latency with an ED(50) of 0.30 mg/kg. The synergism was more evident when THP was administered at subthreshold doses that were unable to modify haloperidol-induced catalepsy when applied alone, but produced a clear inhibition of catalepsy when injected with caffeine. To assess whether repeated administration of caffeine could induce tolerance to the synergism with THP, a group of rats was pretreated with three daily doses of caffeine (1 mg/kg) for seven days, and the catalepsy test was performed on the eighth day. In these animals, caffeine was still able to enhance the anticataleptic actions of THP, suggesting that repeated administration of 1 mg/kg caffeine does not induce tolerance to the synergism with anticholinergics. These results indicate that low doses of caffeine enhance the anticataleptic actions of muscarinic antagonists, and leave open the possibility of using caffeine as adjunctive therapy to reduce the doses and the adverse effects of anticholinergics in Parkinson's disease.

The effect of halothane anesthesia on changes in the extracellular concentrations of dopamine (DA) and its metabolites (3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA)) induced by neuroleptics was studied using in vivo microdialysis techniques. Halothane attenuated haloperidol-induced dopamine release and enhanced clozapine-induced dopamine release in the rat striatum.A microdialysis probe was implanted into the right striatum of male SD rats. Rats were given saline or the same volume of 200 microg kg(-1) haloperidol (D(2) receptor antagonist), 10 mg kg(-1) sulpiride (D(2) and D(3) antagonist), or 10 mg kg(-1) clozapine (D(4) and 5-HT(2) antagonist) intraperitoneally with or without 1-h halothane anesthesia (0.5 or 1.5%). Halothane anesthesia did not change the extracellular concentration of DA, but increased the metabolite concentrations in a dose-dependent manner. The increased DA concentration induced by haloperidol was significantly attenuated by halothane anesthesia, whereas the metabolite concentrations were unaffected. Halothane had no effect on the changes in the concentrations of DA or its metabolites induced by sulpiride. The clozapine-induced increases in DA and its metabolites were enhanced by halothane anesthesia. Our results suggest that halothane anesthesia modifies the DA release modulated by antipsychotic drugs in different ways, depending on the effects of dopaminergic or serotonergic pathways.

Antipsychotic drugs such as haloperidol act as dopamine D2 receptor antagonists to produce a number of cellular effects including the induction of immediate-early genes such as c-fos. It has been hypothesized that blockade of D2 receptors by antipsychotics is responsible for the induction of c-fos, but the mechanism has not been determined. Using cultured ventral tegmental area (VTA) dopaminergic neurons as a model, we report that nanomolar concentrations of haloperidol cause a time-dependent increase in Fos expression in dopaminergic neurons.Surprisingly, this induction was not mimicked by sulpiride, a selective D2 receptor antagonist, and was not blocked by Rp-cAMPS, an antagonist of protein kinase A (PKA), thus suggesting that D2 receptors and the cAMP cascade are not required. The induction of Fos expression was blocked by tetrodotoxin, BAPTA and KN-93, thus showing that it is activity- and calcium-dependent and requires the activation of a calmodulin-dependent kinase (CaMK). Together, these results suggest that haloperidol induces Fos expression in dopaminergic neurons through a D2 receptor-independent increase in intracellular calcium, leading to CaMK activation.

In the present experimental paradigm, we examine the effect of L-prolyl-L-leucyl-glycinamide (PLG) co-administration with haloperidol on vacuous chewing movements (VCM) in rats-a model of tardive dyskinesia (TD) in humans. We examined the dose dependent induction of VCM through both injected and orally administered PLG (MIF-1). Our results show significant levels of VCM attenuation (P<0.05) in rats treated with 10mg/kg of PLG. Doses of 1 and 100mg/kg were ineffective. Reductions were present in both orally treated and injected rats. We also examined the therapeutic effect of a peptidomimetic of PLG-PAOPA. PAOPA was able to produce similar behavioral effects to PLG at a dose, which was 100-fold lower than the effective dose of PLG. These results suggest that PLG may play a role in D2 receptor expression and function, as well as providing a therapy for neuroleptic induced TD.

It is established that the haloperidol catalepsy is much less pronounced in Wistar females than in males. Estradiol (10 mg/kg, i.p.) decreased intensity of the haloperidol catalepsy, reduced the haloperidol-induced increase in the dopamine turnover, and decreased the level of dopamine metabolites in nucleus accumbens of both female and male test animals. However, these effects are also more pronounced in females.

Nicotine has been shown in a variety of studies to improve memory performance. The cognitive effects of nicotine are particularly important with regard to schizophrenia. In the current studies nicotine interactions with three different antipsychotic drugs, haloperidol, clozapine and risperidone, were assessed with regard to memory function. Female Sprague-Dawley rats were trained on the radial-arm maze to asymptotic levels of choice accuracy. They were then administered nicotine alone or in combination with haloperidol, clozapine or risperidone. Acute haloperidol (0.04 mg/kg) did not by itself affect memory performance. Co-administration of haloperidol with nicotine, however, decreased memory performance compared with nicotine administration in isolation. Acute clozapine (1.25 and 2.5 mg/kg) caused a significant memory impairment, an effect reversed by acute nicotine co-treatment. Risperidone (0.05 mg/kg), like haloperidol, did not by itself affect memory performance. Risperidone co-administration with nicotine, however, did significantly attenuate the improvement caused by nicotine administration in isolation. The similar interaction of haloperidol and risperidone with nicotine may be due to their common action of blocking D(2) receptors, a mechanism of action not shared by clozapine. In contrast to the interaction of nicotine with haloperidol or risperidone, nicotine effectively reversed clozapine-induced memory impairment. These studies demonstrate interactions between nicotine and antipsychotic drugs in terms of memory, which may have important impacts on the treatment of schizophrenia.

Neurotensin (NT) is a tridecapeptide neurotransmitter in the central nervous system. It has been implicated in the therapeutic effects of neuroleptics. Central activity of NT can only be demonstrated by direct injection into the brain, since it is readily degraded by peptidases in the periphery. We have developed many NT(8-13) analogs that are resistant to peptidase degradation and can cross the blood-brain barrier (BBB). In this study, we report on one of these analogs, NT77L. NT77L induced hypothermia (ED(50)=6.5 mg/kg, i.p.) but induced analgesia only at the highest dose examined (20 mg/kg, i.p.). Like the atypical neuroleptic clozapine, NT77L blocked the climbing behavior in rats induced by the dopamine agonist apomorphine (600 microg/kg) with an ED(50) of 5.6 mg/kg (i.p.), without affecting the licking and the sniffing behaviors. By itself NT77L did not cause catalepsy, but it moderately reversed haloperidol-induced catalepsy with an ED(50) of 6.0 mg/kg (i.p.). Haloperidol alone did not lower body temperature, but it potentiated the body temperature lowering effect of NT77L. In studies using in vivo microdialysis NT77L showed similar effects on dopamine turnover to those of clozapine, and significantly different from those of haloperidol in the striatum. In the prefrontal cortex, NT77L significantly increased serotonergic transmission as evidenced by increased 5-hydroxyindole acetic acid:5-hydroxytryptamine (5-HIAA:5-HT) ratio. Thus, NT77L selectively caused hypothermia, over antinociception, while exhibiting atypical neuroleptic-like effects.

Brain microdialysis was used to study in vivo releases and changes in dopamine (DA) concentration induced by neuroleptics in the rat striatum during halothane anesthesia. Rats were implanted with a microdialysis probe into the right striatum and allowed to move freely. After acquiring steady state of DA and metabolites concentrations, apomorphine 50 micrograms.kg-1 or haloperidol 200 micrograms.kg-1 was administered intraperitoneally with or without 1.5% halothane anesthesia for 1 h. Halothane anesthesia showed no effect on the decrease of DA induced by apomorphine, but halothane antagonized the increase of DA induced by haloperidol. Administration of haloperidol produced an increase in metabolites of DA and it was unchanged by halothane. Malignant syndrome is a well known complication caused by interaction of neuroleptics and anesthesia. The results of the present investigation suggest that the mechanism of malignant syndrome might be associated with the dopaminergic activity.

Tardive dyskinesia is a serious motor side effect of chronic neuroleptic therapy. Chronic treatment or rats with neuroleptics leads to the development of abnormal oral movements called vacuous chewing movements. Vacuous chewing movements in rats are widely accepted as an animal model of tardive dyskinesia. Atypical antipsychotics such as clozapine and rispiridone are associated with a lower incidence of extrapyramidal side effects and tardive dyskinesia. The present study was aimed to explore the role of 5-HT1A, 5-HT2A/2C receptors in the expression of neuroleptic-induced orofacial dyskinesia. In the present study rats were chronically (for 21 days) treated with haloperidol (1.5 mg/kg, i.p.) to elicit vacuous chewing movements. The neuroleptic-induced vacuous chewing movements, viz., vertical jaw movements, tongue protrusions and bursts of jaw tremors, were counted during a 5-min observation period. Acute treatment with 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, dose-dependently (0.05, 0.1 and 0.2 mg/kg, i.p.) reduced the haloperidol-induced vacuous chewing movements and headshakes. Both acute and chronic administration of seganserin, ketanserin and ritanserin, 5-HT2A/2C receptor antagonists, also reduced haloperidol-induced vacuous chewing movements in a dose-dependent (0.05, 0.1 and 0.2 mg/kg, i.p.) manner. In acute studies a higher dose of ritanserin (1 mg/kg) but not ketanserin (1 mg/kg) increased vacuous chewing movements, whereas a higher dose of seganserin (1 mg/kg) did not have any effect on vacuous chewing movements. All the drugs reduced haloperidol-induced headshakes in a dose-dependent fashion. These findings indicate that the serotonergic system, and particularly 5-HT1A and 5-HT2A/2C receptors, may be involved in haloperidol-induced orofacial dyskinesia, and that 5-HT receptors may provide novel targets for the development of drugs that can be used to reverse or prevent the extrapyramidal side effects associated with long-term antipsychotic treatment.

The effects of long-term administration of the dopamine D(2) receptor antagonist haloperidol on Parkinsonian symptoms have been shown to persist after cessation of the drug treatment. In order to determine whether the level of tyrosine hydroxylase could be affected by subchronic administration of haloperidol, we examined tyrosine hydroxylase-positive immunoreactive cells in the substantia nigra after blockade of dopaminergic receptors with this antipsychotic. Three weeks of injections with haloperidol (1.5 mg/kg, i.p.) caused a significant decrease in tyrosine hydroxylase-positive cell counts at 24 h (27%), 5 days (21%) and 2 weeks (10%) after the last administration, an effect that was blocked by concurrent administration of the antioxidant, vitamin C. The level of tyrosine hydroxylase returned to baseline after 4 weeks withdrawal, no change being observed at later time-points. Nissl staining demonstrated that no damage to the cell bodies was observed, suggesting that the decrease in tyrosine hydroxylase-positive cells was not due to dopaminergic cell loss. These results demonstrate a depleting action of a short course of haloperidol on nigral tyrosine hydroxylase that outlasts the period of application by 2-4 weeks. Moreover, the current study has shown the effect of the antioxidant vitamin C in protecting haloperidol effects on tyrosine hydroxylase-immunostaining.

In the first experiment, separate groups of rats (n = 7) were treated with either saline, cocaine (10 mg/kg), haloperidol (0.1 mg/kg), or cocaine (10 mg/kg) plus haloperidol (0.1 mg/kg). Locomotor behavior was measured in an open-field environment, and cocaine induced a reliable locomotor stimulant effect compared to saline-treated animals. Haloperidol produced a progressive decline in locomotion over the 5 test days. Haloperidol also blocked cocaine stimulant effects compared to cocaine-treated animals. In the second experiment, five groups (n = 7) of animals were treated either with saline, cocaine (10 mg/kg), 8-OH DPAT (0.2 mg/kg), 8-OH DPAT (0.2 mg/kg) plus haloperidol (0.1 mg/kg), or 8-OH DPAT (0.2 mg/kg) plus haloperidol 0.1 mg/kg plus cocaine (10 mg/kg). Over the course of 5 days of treatment, cocaine induced a locomotor stimulant effect. Saline and 8-OH DPAT animals did not differ in terms of locomotion. The 0.1 mg/kg haloperidol plus 0.2 mg/kg 8-OH DPAT treatment decreased locomotion compared to the saline group, but the group given 0.2 mg/kg 8-OH DPAT plus 0.1 mg/kg haloperidol plus cocaine (10 mg/kg) exhibited a locomotor stimulant effect equivalent to the cocaine group. In a third experiment, it was found that the 0.2 mg/kg 8-OH DPAT treatment did not enhance the locomotor stimulant effect of cocaine. Thus, the 8-OH DPAT treatment was able to restore a cocaine locomotor stimulant effect in animals treated with haloperidol without directly enhancing the locomotor stimulant effects of cocaine. In Experiments 2 and 3, entries into the central zone of the open field were measured. Cocaine reliably increased central zone entries. The 8-OH DPAT treatment, however, selectively blocked this behavioral effect of cocaine suggesting a qualitative influence of 5-HT(1A) receptors upon cocaine, independent of locomotion activation by cocaine. Ex vivo measurements of dopamine and 5-hydroxytryptamine metabolism in limbic tissue were consistent with the established effects of cocaine, haloperidol, and 8-OH DPAT upon dopamine and 5-hydroxytryptamine neurotransmission. In addition, measurement of cocaine brain concentration indicated that neither haloperidol or 8-OH DPAT affected cocaine concentration in brain.

The present study deals with the functional interaction of antipsychotic drugs and NMDA receptors. We show that both the conventional antipsychotic drug haloperidol and the atypical antipsychotic drug clozapine mediate gene expression via intracellular regulation of NMDA receptors, albeit to different extents. Data obtained in primary striatal culture demonstrate that the intraneuronal signal transduction pathway activated by haloperidol, the cAMP pathway, leads to phosphorylation of the NR1 subtype of the NMDA receptor at (897)Ser. Haloperidol treatment is likewise shown to increase (897)Ser-NR1 phosphorylation in rats in vivo. Mutation of (896)Ser and (897)Ser to alanine, which prevents phosphorylation at both sites, inhibits cAMP-mediated gene expression. We conclude that antipsychotic drugs have the ability to modulate NMDA receptor function by an intraneuronal signal transduction mechanism. This facilitation of NMDA activity is necessary for antipsychotic drug-mediated gene expression and may contribute to the therapeutic benefits as well as side effects of antipsychotic drug treatment.

Neurotensin (NT) is a neuropeptide neurotransmitter in the central nervous system. It has been implicated in the therapeutic and in the adverse effects of neuroleptics. Activity of NT in brain can only be shown by direct injection of the peptide into that organ. However, we have developed a novel analog of NT(8-13), NT69L, which is active upon intraperitoneal (i.p.) injection. Like atypical neuroleptics, NT69L blocked the climbing behavior in rats, but not the licking and sniffing behaviors of a high dose (600 microgram/kg) of the non-selective dopamine agonist apomorphine. Its blockade of climbing was very potent with an ED(50) (effective dose at 50% of maximum) of 16 microgram/kg. Both apomorphine and NT69L caused a long-lasting hypothermia, which was greater with the peptide but not synergistic in combination with apomorphine. The ED(50) of NT69L for hypothermia was 390 microgram/kg. NT69L (up to 5 mg/kg i.p.) did not produce catalepsy. However, when given before haloperidol, NT69L, but not clozapine, completely prevented catalepsy. When given after haloperidol, NT69L, but not clozapine, reversed haloperidol's cataleptic effects with an ED(50) of 260 microg/kg. There was no significant difference between the ED(50)s for hypothermia and anticataleptic effects of NT69L. However, the ED(50) for blocking the effects of apomorphine was significantly lower than the other two. These data suggest that NT69L may have neuroleptic properties in humans and may be useful in the treatment of extrapyramidal side effects caused by typical neuroleptics such as haloperidol.

Acute treatment of rats with haloperidol results in a rapid and transient increase in striatal c-fos mRNA and Fos immunoreactivity. The induction of immediate early genes by haloperidol may be involved in the development of extrapyramidal side effects. L-Prolyl-L-leucyl-glycinamide (PLG, or MIF-1) has been observed to antagonize the development of haloperidol-induced D(2) receptor supersensitivity in rats. We investigated the modulatory effects of PLG on haloperidol-induced c-fos and Fos protein expression in the rat striatum. We report that coadministration of either PLG or the potent analog of PLG, 3(R)-[(2(S)-pyrrolidylcarbonyl)amino]-2-oxo-1-pyrrolidineacetam ide (PAOPA), attenuated haloperidol-induced c-fos and Fos expression. Haloperidol induced [2 mg/kg, intraperitoneally (i.p.)] c-fos and Fos expression by 500% and 100%, respectively. These responses were attenuated by 170% and 75%, respectively, when coadministered with PLG (20 mg/kg, i.p.) or by 79% by PAOPA (10 microg/kg, i.p.).

NMDA receptor antagonists have been shown to block several forms of neural and behavioural plasticity. The prototypical and most widely-used noncompetitive NMDA receptor antagonist is dizocilpine (MK-801). Here we have examined the effect of MK-801 on the context-dependent augmentation ('sensitization') of catalepsy in rats which develops with repeated administration of haloperidol. It was found that over a 7-day treatment period animals receiving haloperidol (0.25 or 0.5 mg/kg) plus MK-801 (0.16 mg/kg) showed a context-dependent day-to-day increase in catalepsy similar to animals that received haloperidol alone. However, when all animals were treated with haloperidol alone on day 8 of the experiment, animals that had received haloperidol plus MK-801 before displayed a much smaller cataleptic response, similar to that observed in the haloperidol group on the first treatment day, i.e. the previously-established enhancement of catalepsy was no longer expressed. These results may be explained in terms of state-dependency effects induced by MK-801. Implications of these findings for the clinical use of NMDA receptor antagonists in the treatment of Parkinson's disease are discussed.

In research towards the development of new atypical antipsychotic agents, one strategy is that the dopaminergic system can be modulated through manipulation of the serotonergic system. The synthesis and preliminary pharmacological evaluation of a series of potential atypical antipsychotic agents based on the structure of 1-(1,2-dihydro-2-acenaphthylenyl)piperazine (7) is described. Compound 7e, 5-{2-[4-(1,2-dihydro-2-acenaphthylenyl)piperazinyl]ethyl}-2,3-dihy dro-1H- indol-2-one, from this series showed significant affinities at the 5-HT1A and 5-HT2A receptors and moderate affinity at the D2 receptor. 7e exhibits a high reversal of catalepsy induced by haloperidol indicating its atypical antipsychotic nature.

Previous studies have shown that the atypical neuroleptic clozapine is less potent at inducing Fos expression in the dorsolateral striatum than are typical neuroleptics. We report here that pretreatment with clozapine (5-20 mg/kg) actually attenuates the striatal Fos expression induced by the typical neuroleptics haloperidol and raclopride. These results suggest clozapine has pharmacological properties which actively antagonize the effects of dopamine D2 receptor blockade on striatal immediate-early gene expression.

Objective: The present study was conducted to identify in vitro the cytochrome P450(CYP) isoform involved in the metabolic conversion of reduced haloperidol to haloperidol using microsomes derived from human AHH-1 TK +/- cells expressing human cytochrome P450s. The inhibitory and/or stimulatory effects of reduced haloperidol or haloperidol on CYP2D6-catalyzed carteolol 8-hydroxylase activity were also investigated., Results: The CYP isoform involved in the oxidation of reduced haloperidol to haloperidol was CYP3A4. CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 2E1 were not involved in the oxidation. The kM value for the CYP3A4 expressed in the cells was 69.7 micromol x l(-1), and the Vmax was 4.87 pmol x min(-1) x pmol(-1) P450. Troleandomycin, a relatively selective probe for CYP3A enzymes, inhibited the CYP3A4-mediated oxidation of reduced haloperidol in a dose-dependent manner. Quinidine and sparteine competitively inhibited the oxidative reaction with a k(i) value of 24.9 and 1390 micromol x l(-1), respectively. Carteolol 8-hydroxylase activity, which is a selective reaction probe for CYP2D6 activity, was inhibited by reduced haloperidol with a k(i) value of 4.3 micromol x l(-1). Haloperidol stimulated the CYP2D6-mediated carteolol 8-hydroxylase activity with an optimum concentration of 1 micromol x l(-1), whereas higher concentrations of the compound (> 10 micromol x l(-1)) inhibited the hydroxylase activity., Conclusion: It was concluded that CYP3A4, not CYP2D6, is the principal isoform of cytochrome P450 involved in the metabolic conversion of reduced haloperidol to haloperidol. It was further found that reduced haloperidol is a substrate of CYP3A4 and an inhibitor of CYP2D6, and that haloperidol has both stimulatory and inhibitory effects on CYP2D6 activity.

Although recently developed drugs have brought significant improvement, the treatment of psychotic disorders still presents serious drawbacks. Because inherent complexity and lack of satisfactory understanding of the underlying pathophysiology impose limits for rational drug design, resourceful approaches in the search for antipsychotics are pertinent. This article reports pharmacological properties of alstonine, a heteroyohimbine-type alkaloid, which exhibited an antipsychotic-like profile, inhibiting amphetamine-induced lethality, apomorphine-induced stereotypy, and potentiating barbiturate-induced sleeping time. Atypical features of alstonine were the prevention of haloperidol-induced catalepsy and lack of direct interaction with D1, D2 and 5-HT2A receptors, classically linked to antipsychotic mechanism of action.