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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.)

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.)

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.)

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.

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.

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.

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.

Dopamine receptor-blocking neuroleptics produce progressive decrements in response output during behavioral test sessions. If these response decrements reflect Parkinson-like motor effects of neuroleptic treatment, then within-session decrements should be ameliorated by concurrent anticholinergic treatment. To investigate this question, new within-session data analyses were performed on previously published data that addressed haloperidol-scopolamine influences across the entire session (Fowler and Das, 1994). The peak force and duration of individual licks were recorded for 36 rats along with the number of licks emitted in each daily 2-min session. The effects on this behavior of vehicle and three doses of haloperidol (0.06, 0.12, and 0.24 mg/kg, IP, 45 min before sessions) were evaluated alone and in combination with vehicle and two doses of scopolamine HCl (0.1 and 0.2 mg/kg, SC, 60 min before sessions). Despite the brief sessions, haloperidol produced pronounced within-session decrements, and pretreatment with scopolamine reversed the haloperidol-induced within-session decrements in lick emission. Scopolamine by itself produced within-session increments in all three measures of lapping behavior. The results support the idea that within-session decrements in licking behavior are Parkinson-like and diminish confidence in hedonic interpretations of neuroleptic-induced within-session decrements.

Acute and chronic administration of vigabatrin, a selective inactivator of GABA-T, suppresses haloperidol-induced dyskinesias at low doses without preventing the enhancement of striatal dopamine D2 receptor density or the development of vacuous chewing movements. The long-term administration of vigabatrin does not attenuate its effect. The observations presented in this work support the GABA hypothesis of haloperidol-induced vacuous chewing behavior in rats, and suggest that vigabatrin is an appropriate means to enhance nigral GABAergic activity.

To investigate the hypothesis that haloperidol's impairment of tongue protrusion in rats is Parkinson-like, the effects of centrally active scopolamine hydrochloride (0.1 or 0.2 mg/kg, SC) were evaluated in 36 rats that were also administered haloperidol (0.06, 0.12, or 0.24 mg/kg, IP). Rats were trained to lick water from a force-sensing disk, and the peak force and duration of each tongue contact were recorded along with the number of licks emitted in a 2-min session. Scopolamine hydrochloride significantly reversed haloperidol-induced deficits observed for peak force, duration, and number of licks. When given alone, scopolamine hydrochloride decreased peak force and duration. Fourier methods showed that the basic rhythm of licking was slowed by scopolamine hydrochloride but not by haloperidol. Taken together, the data suggest that central nervous system dopaminergic-cholinergic interactions importantly modulate tongue dynamics in the rat in a manner consistent with such interactions in neuroleptic-treated human patients.

The nootropic drug oxiracetam (50 mg/kg) prevented passive avoidance impairment induced by posttraining administration of haloperidol (0.25 and 0.5 mg/kg). Conversely, oxiracetam did not antagonize either locomotor depression or suppression of active avoidance responses induced by the dopamine receptor blocking agent. The results indicate that prevention of haloperidol-induced retention impairment, by oxiracetam, may be due to a not yet defined protective action, common to other nootropic agents, on different types of experimental amnesias, rather than to a specific interaction with dopaminergic mechanisms.

Behavioral supersensitivity of dopamine receptors was induced in mice by chronic administration of haloperidol (1 mg/kg/day for 21 days) and its subsequent withdrawal for 48 hr. This was evidenced by enhanced spontaneous locomotor activity and hypothermic responses to a dopamine agonist, apomorphine. Concurrent administration of cyclo (Leu-Gly), the enzymatically resistant diketopiperazine, an analog of melantropin release inhibiting factor, blocked haloperidol-induced dopamine receptor supersensitivity as evidenced by the blockade of apomorphine induced responses. Since many studies have linked the development of neuroleptic induced tardive dyskinesias with enhanced sensitivity of brain dopamine receptors, and the latter was blocker by cyclo (Leu-Gly), this agent may be of value in preventing the development of symptoms of neuroleptic-induced tardive dyskinesias.

Sprague Dawley rats, pretreated with nine daily injections of 20 mg/Kg cocaine or saline, were evaluated for aspects of their behavioral response to apomorphine, haloperidol, or cocaine, twenty-four hours after their last pretreatment injection. Data obtained from saline and cocaine pretreated animals indicated that: cocaine pretreated rats were more sensitive to haloperidol-induced catalepsy, less responsive to some of the stereotypic effects of apomorphine and similar in their responses to the anticataleptic properties of cocaine.

The operant lever-pressing response has previously (Ljungberg, Pharmacol Biochem Behav 27: 341-350, 1987) been found to be inhibited by lower doses of haloperidol than the corresponding consummatory act, i.e., water intake. In the present study it was found that the attenuation of the lever-pressing response caused by the neuroleptic, but not the attenuation of the water intake, could be counteracted by scopolamine. The results support the notion that blockade of operant responding by low doses of neuroleptics are probably related to the extra-pyramidal side-effects of neuroleptics seen in the clinic, as both phenomena can be counteracted by anticholinergics. These results therefore conflict with the anhedonia hypothesis put forward as an explanation of the attenuating effects of neuroleptics in operant settings. The findings also have a clear bearing on the role of dopamine in feeding and drinking behavior, as the results implies that different aspects of the control of water intake (i.e., the operant vs. the consummatory phase) are governed by different mechanisms in the CNS.