Failure of haloperidol to block the effects of phencyclidine and dizocilpine on prepulse inhibition of startle

doi:10.1016/0006-3223(91)90025-H

Biological Psychiatry

Volume 30, Issue 6, 15 September 1991, Pages 557-566

https://doi.org/10.1016/0006-3223(91)90025-H Get rights and content

Abstract

Prepulse inhibition of acoustic or tactile startle (PPI), a form of sensorimotor gating, occurs when a weak prestimulus precedes a startling stimulus and inhibits the startle response. Studies of PPI have revealed that schizophrenic patients exhibit a deficit in this form of sensorimotor gating. In rats, PPI is blocked by dopamine agonists such as apomorphine or quinpirole, effects that are antagonized by haloperidol. Phencyclidine (PCP) has been suggested as a possible model psychotogen and produces a deficit in PPI that is similar to what is observed in schizophrenic patients. Dizocilpine is an anticonvulsant drug that, like PCP, is a noncompetitive antagonist on N-methyl-D-aspartate (NMDA)-induced excitations in brain and also disrupts PPI. In the present study, PPI of acoustic and tactile startle was measured in male Sprague-Dawley rats after injections of 5.0 mg/kg PCP with or without pretreatment with 0.02 or 0.1 mg/kg haloperidol, or with 0.5 mg/kg dizocilpine with or without pretreatment with 0.1 mg/kg haloperidol. The 0.1 mg/kg dose of haloperidol blocks the effects of apomorphine or quinpirole on PPI in rats. Startle was elicited by noise bursts at 105 or 120 dB or by air-puffs (tactile) and was inhibited by 75 or 85 dB prepulse stimuli presented 100 msec before the startle stimuli. The different eliciting stimuli produced different levels of startle in both control and drug-treated animals. Both NMDA antagonists significantly reduced the amount of PPI induced by the 75 bB perstimulus, independently of the level of startle responses elicited by the startle stimuli. Haloperidol did not block the disruption of PPI induced by either PCP or dizocilpine. In addition, PCP was unable to block PPI when the 85 rather than the 75 dB prepulse was used to inhibit either acoustic or tactile startle. These results confirm that putative NMDA antagonists inhibit sensorimotor gating in rats and suggest that these effects are not mediated by the activation of central dopamine systems.

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Animal models of schizophrenia for molecular and pharmacological intervention and potential candidate molecules
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Citation Excerpt :
In most of the animal models, first generation antipsychotic drugs such as haloperidol are effective in reducing spontaneous and drug-induced hyperactivity but have little effect on behavioral changes related to negative symptoms and cognitive dysfunctions. In contrast, second generation antipsychotic drugs such as clozapine are reported to be effective in ameliorating most of the behavioral abnormalities (Amitai et al., 2009; Bakshi et al., 1994; Becker and Grecksch, 2003; Keith et al., 1991; Le Pen and Moreau, 2002; Lipska et al., 1993; Okuyama et al., 1999; Qiao et al., 2001; Sarter et al., 2009; Zuckerman et al., 2003) (Table 7). However, the efficacy of first and second antipsychotic treatment on cognitive dysfunction in patients with schizophrenia continues to be debated (Jones et al., 2006; Young et al., 2012), because the effect of antipsychotics on cognition may be influenced by several factors such as coadministration of multiple drugs (Keefe et al., 1999) and the dosage amount (Young et al., 2012).
Schizophrenia is a severe and common psychiatric disease with a lifetime prevalence of 0.5% to 1% globally. Because of limitations of the experimental approach in humans, valid animal models are essential in the effort to identify novel therapeutics for schizophrenia. In most animal models of schizophrenia, second generation antipsychotic drugs are reported to be effective in ameliorating behavioral abnormalities, while clinical evidence indicates that some of the patients are resistant to the antipsychotic drug therapy. Accordingly, animal models of antipsychotic drug-resistant schizophrenia are needed for screening of novel agents that may be more effective than the existing antipsychotic drugs. Furthermore, utilization of appropriate behavioral tasks with reference to human testing is essential to facilitate the development of novel pharmacotherapeutic approaches for the treatment in schizophrenia. Experimental data suggest that there are different types of potential candidate molecules as novel antipsychotic drugs with some therapeutic effects on negative symptoms and cognitive deficits in schizophrenia. It is proposed that to develop novel antipsychotic drugs the efficacy of potential candidate molecules should be evaluated using animal models for treatment-resistant schizophrenia with appropriate behavioral tasks in reference to human testing.
Pharmacological characterizations of memantine-induced disruption of prepulse inhibition of the acoustic startle response in mice: Involvement of dopamine D<inf>2</inf> and 5-HT<inf>2A</inf> receptors
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Citation Excerpt :
The findings at 100 ms prepulse intervals are consistent across reports. For example, other NMDA receptor antagonists such as PCP and dizocilpine also reliably disrupt PPI in rodents using by 100 ms prepulse intervals [22,30]. However, memantine is known to have both PPI-increasing and PPI-decreasing effects in rats and humans, using different (short- or long-) prepulse-pulse intervals [63] and, additionally, there is evidence of cross-species differences in the NMDA regulation of PPI [63].
It has recently been reported that psychotic symptoms in patients such as those with Parkinson's disease dementia (PDD) and Lewy body dementia (LBD) may worsen following treatment with memantine, a non-competitive NMDA receptor antagonist. Prepulse inhibition (PPI) of the acoustic startle response (ASR) is used as a measure for sensorimotor gating and it has been reported that PPI is disrupted by memantine. However, the mechanism of memantine-induced PPI disruption remains unclear. In the present study, we investigated the effects of memantine on PPI of the ASR in mice. Memantine (1.25–20 mg/kg, intraperitoneally) increased the ASR and dose-dependently decreased PPI for all prepulse intensities tested. This effect of memantine on PPI was attenuated by pretreatment with the antipsychotics clozapine (3 and 6 mg/kg), risperidone (0.3 mg/kg) and haloperidol (0.5 mg/kg), the selective D₂ antagonist sulpiride (40 mg/kg) and 5-HT_2A/2C antagonist ketanserin (2 and 4 mg/kg) but not with the selective D₁ antagonist SCH23390 (0.05 and 0.1 mg/kg). Clozapine (6 mg/kg) and risperidone (0.3 mg/kg) significantly attenuated the increased startle amplitude in the memantine-treated groups. These results suggest that involvement of dopaminergic and/or serotonergic neurotransmission may play a crucial role in memantine-induced PPI disruption, and additionally, indicate that blockade of either the D₂ or 5-HT_2A receptor may prevent disruption of PPI induced by memantine in mice. Conceivably, memantine may exacerbate psychotic symptoms in patients with PDD and LBD.
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Citation Excerpt :
Finally, ASR was not altered by any of the PCP doses used for local administration into the medial PFC. The PPI-disruptive effects of PCP have been attributed to its ability to act as a non-competitive open channel blocker at the NMDA receptor (Keith et al., 1991). Indeed, decreased PPI can be observed following administration of a number of high- and medium-affinity NMDA receptor antagonists (Wiley et al., 2003).
A well established theory proposes that glutamate signalling via the NMDA receptor is compromised in patients with schizophrenia. Deficits related to NMDA receptor signalling can be observed in several brain regions including the prefrontal cortex (PFC), an area extensively linked to the cognitive dysfunction in this disease and notably affected by NMDA receptor antagonists such as phencyclidine (PCP). In addition, a number of studies suggest that normalizing of PFC function could constitute a treatment rationale for schizophrenia. To further study the role of PFC function we investigated the effect of local PFC NMDA receptor blockade on impaired prepulse inhibition (PPI) induced by systemic administration of PCP. Mice received prefrontal injections of PCP (0.01, 0.1 or 1 mM) before PCP treatment (5 mg/kg) and were thereafter tested for PPI. PCP induced deficits in PPI were ameliorated by prefrontal PCP (0.1 mM) treatment whereas PPI was not affected by prefrontal cortex PCP administration per se at any of the doses tested. Taken together, inhibition of NMDA receptors in the PFC does not seem to be enough to impair PPI per se but NMDA receptor mediated signalling in the PFC may be a key factor for the PPI-disruptive effects of global NMDA receptor inhibition. This indicates that targeting PFC NMDA receptor signalling may have potential as a treatment target for schizophrenia although further studies are needed to understand pharmacology and pathophysiological role of PFC NMDA receptors.

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^☆: This work was supported by grants from the National Institute of Mental Health (MH42228) and the National Institute on Drug Abuse (DA02925). M.A. Geyer was supported by as Research Scientis Development Award from the National Institute of Mental Health (MH00188).

^∗∗: We thank Virginia Lehmann-Masten, Richard Sharp, Diana Martinez, and Daven Addington for their assistance in conducting these studies.

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Failure of haloperidol to block the effects of phencyclidine and dizocilpine on prepulse inhibition of startle☆

Abstract

Brain Res Bull

Neuropharmacology

Eur J Pharmacol

Eur J Pharmacol

Biol Psychiatry

Eur J Pharmacol

Evaluation of antagonists of the discriminative stimulus and response-rate effects of phencyclidine

J Pharmacol Exp Ther

Effects of phencyclidine, amphetamine and related compounds on dopamine release from and uptake into striatal synaptosomes

J Pharmacol Exp Ther

Sensorimotor gating and schizophrenia: Human and animal model studies

Arch Gen Psychiatry

Prestimulus effects on human startle reflex in normals and schizophrenics

Psychophysiology

Apomorphine disrupts the inhibition of acoustic startle induced by weak prepulses in rats

Psychopharmacology