Histamine H1 receptor involvement in prepulse inhibition and memory function: relevance for the antipsychotic actions of clozapine

Histamine H(1) blockade is one of the more prominent actions of the multi-receptor acting antipsychotic clozapine. It is currently not known how much this H(1) antagonism of clozapine contributes to the therapeutic or adverse side effects of clozapine. The current studies with Sprague-Dawley rats were conducted to determine the participation of histaminergic H(1) receptor subtype in sensorimotor plasticity and memory function affected by clozapine using tests of prepulse inhibition (PPI) and radial-arm maze choice accuracy. The PPI impairment caused by the glutamate antagonist dizocilpine (MK-801) was significantly attenuated by clozapine. In the current project, we found that the selective H(1) antagonist pyrilamine also reversed the dizocilpine-induced impairment in PPI of tactile startle with an auditory prepulse. In the radial-arm maze (RAM), pyrilamine, like clozapine, impaired working memory and caused a significant dose-related slowing of response. Pyrilamine, however, decreased the number of reference memory errors. We have previously shown that nicotine effectively attenuates the clozapine-induced working memory impairment, but in the current study, nicotine did not significantly alter the effects of pyrilamine on the RAM. In summary, the therapeutic effect of clozapine in reversing PPI impairment was mimicked by the H(1) antagonist pyrilamine, while pyrilamine had a mixed effect on cognition. Pyrilamine impaired working memory but improved reference memory in rats. Thus, H(1) antagonism seems to play a role in part of the beneficial actions of antipsychotics, such as clozapine.     

Knockout mice reveal opposite roles for serotonin 1A and 1B receptors in prepulse inhibition.

The serotonergic system is involved in the modulation of prepulse inhibition (PPI) and habituation of startle, which are deficient in schizophrenia patients. PPI is the reduction in startle amplitude that occurs when a weak "prepulse" precedes a startling stimulus by 30-500 msec. The roles of 5-HT(1A) and 5-HT(1B) receptors in modulating PPI and habituation were examined using wild-type (WT), 5-HT(1A) knockout (1AKO), and 5-HT(1B) knockout (1BKO) mice. The 5-HT(1A/1B) agonist RU24969 reduced PPI and habituation in WT and 1AKO, but not 1BKO mice, whereas the 5-HT(1A) agonist 8-OH-DPAT increased PPI in WT and 1BKO, but not in 1AKO mice. Similarly, the selective 5-HT(1B) agonist anpirtoline reduced PPI in WT, but not in 1BKO mice. In experiments using intact 129Sv mice, the 5-HT(1A) agonist flesinoxan increased PPI while anpirtoline decreased PPI and habituation. Findings suggest that 5-HT(1B) receptor activation decreases PPI and habituation, and 5-HT(1A) receptor activation increases PPI in mice.     

Disruption of the prepulse inhibition of the startle reflex in vasopressin V1b receptor knockout mice: reversal by antipsychotic drugs.

In the present study, we investigated whether mice lacking the arginine vasopressin (AVP) V1b receptor (V1bR) exhibit deficits of prepulse inhibition (PPI) of the startle reflex, reminiscent of the sensorimotor gating deficits observed in a large majority of schizophrenic patients. V1bR knockout (KO) mice displayed significantly reduced levels of PPI of the startle reflex. In addition to PPI deficits, V1bR KO mice showed increased acoustic startle response. However, acoustic startle response was not significantly correlated to the PPI of the startle reflex in V1bR KO mice. V1bR KO mice also showed a decrease in basal levels of extracellular dopamine (DA) in the medial prefrontal cortex, which is thought to be an important brain region for PPI. Moreover, PPI deficits observed in the V1bR KO mice are significantly reversed by atypical antipsychotics such as risperidone and clozapine but not by a typical neuroleptic haloperidol, like in schizophrenic patients. By contrast, we did not observe any significant differences between V1bR KO mice and wild-type mice in the open-field, light/dark, elevated plus maze, and forced swimming tests. The results of the present study indicate that V1bR may be involved in the regulation of PPI of the startle reflex. The V1bR has been considered an important molecular target for the development of antipsychotic drugs.     

Sleep deprivation disrupts prepulse inhibition of the startle reflex: reversal by antipsychotic drugs

Sleep deprivation (SD) is known to induce perceptual impairments, ranging from perceptual distortion to hallucinatory states. Although this phenomenon has been extensively described in the literature, its neurobiological underpinnings remain elusive. In rodents, SD induces a series of behavioural patterns that might be reflective of psychosis and mania, such as hyperlocomotion and sensitization to psychotogenic drugs. Notably, such changes are accompanied by transitory alterations of dopaminergic signalling. Based on the hypothesis that both psychotic and manic disorders reflect gating impairments, the present study was aimed at the assessment of the impact of SD on the behavioural model of prepulse inhibition (PPI) of the startle reflex, a reliable paradigm for the study of informational filtering. Rats subjected to SD (24 h, 48 h, 72 h) exhibited a time-dependent increase in startle reflex and a dramatic deficit in PPI. Both alterations were reversed 24 h after termination of the SD period. Interestingly, PPI disruption was efficiently prevented by haloperidol (0.1 mg/kg i.p.) clozapine (5 mg/kg i.p.) and risperidone (1 mg/kg i.p.). Conversely, neither the anxiolytic diazepam (5 mg/kg i.p.) nor the antidepressant citalopram (5 mg/kg i.p) affected the PPI disruption mediated by SD, although diazepam reversed the enhancement in startle reflex magnitude induced by this manipulation. Our data suggest that SD induces gating deficits that might be relevant to the hallucinatory phenomena observed in humans, and provide a novel reliable animal model where such relationship can be studied.     

Modulation of prepulse inhibition through both M1 and M4 muscarinic receptors in mice

Rationale  

Muscarinic cholinergic M₁ and M₄ receptors may participate in schizophrenia’s etiology and have been proposed as targets for antipsychotic medications.     

Effect of antipsychotic treatment on the prepulse inhibition deficit of mGluR5 knockout mice

Rationale Prepulse inhibition of the startle response (PPI), a model of sensorimotor gating, is deficient in persons with schizophrenia. In rodents, the reversal of induced deficits in PPI demonstrates predictive validity for identifying antipsychotic treatments. Metabotropic glutamate receptor 5 (mGluR5) has been implicated in schizophrenia, in part because mGluR5 knockout (KO) mice exhibit PPI deficits.Objective We examined whether mGluR5 KO mice might serve as a novel model for detecting antipsychotic treatments.Methods Using C57BL/6J or 129SvPasIco mice, we first determined doses of the typical antipsychotic raclopride or the atypical antipsychotic clozapine that were effective in blocking the PPI-disruptive effects of amphetamine or ketamine, respectively. We then examined the effects of these doses on the deficit in PPI in mGluR5 KO mice.Results Administration of raclopride or clozapine reversed either an amphetamine or a ketamine-induced PPI deficit, as had the novel mood stabilizer lamotrigine in previous studies. In contrast, the PPI deficit of the mGluR5 KO mice was not altered by administration of raclopride, clozapine, or lamotrigine. The serotonin_2A antagonist M100,907 was also ineffective in reversing the mGluR5 KO deficit in PPI.Conclusions Most of the compounds examined ameliorated at least a subset of pharmacologically induced PPI deficits. That none of the antipsychotic treatments attenuated the PPI deficit in the mGluR5 KO mice indicates that this model is not predictive of known treatments for schizophrenia, but does not preclude a role for the mGluR5 receptor in schizophrenia or other psychiatric disorders.     

Evaluation of antipsychotic and relative drugs using disruption of prepulse inhibition as an animal model for schizophrenia

The prepulse inhibition (PPI) is a phenomenon in which a weak prepulse attenuates the response to a subsequent startling stimulus. The PPI, a model of sensorimotor gating, is deficient in patients with schizophrenia and some other psychiatric disorders. In rodents, PPI can be disrupted by methamphetamine or phencyclidine, which causes psychotomimetic symptoms, and the dopaminergic agonist-induced PPI is reversed by dopamine D2 receptor antagonists and a dopaminergic partial agonist aripiprazole. However, in general, the glutamate receptor antagonist-induced PPI is reversed by atypical antipsychotics such as clozapine, but not by typical antipsychotics such as haloperidol. Therefore, PPI is believed to have face, construct, and predictive validity for the PPI disruption in schizophrenia, and it is widely used as a model to study the neurobiology of this disorder and for screening antipsychotics. Recently, various inbred mouse strains and genetically modified mouse lines have been examined and the studies using PPI indicated the involvement of various neurotransmitters such as dopamine, glutamate, serotonin, GABA and neuropeptide in the biological basis of sensorimotor gating. In addtition, mood stabilizers such as valproate and lamotrigine or alpha7 nicotinic receptor agonists have reported to reverse the PPI disruption.     

Examination of drug-induced and isolation-induced disruptions of prepulse inhibition as models to screen antipsychotic drugs

Prepulse inhibition (PPI) of an acoustic startle response is impaired in schizophrenics. PPI can also be studied in the rat, and is impaired by dopamine (DA) D_2/3 receptor agonists such as apomorphine. This disruption is reversed by DA antagonists, leading to proposals that this approach may be a useful means to identify novel antipsychotics. There is also evidence to suggest a role of serotonergic (5-HT) and glutamatergic systems in schizophrenia, and accordingly PPI can be disrupted by the 5-HT₂ agonist DOI, and the non-competitive NMDA antagonist, dizocilpine. In the present study we have examined the effect of four antipsychotic drugs, haloperidol (0.1–0.3 mg/kg), raclopride (0.03–0.3 mg/kg), risperidone (0.3–3 mg/kg) and clozapine (0.0001–10 mg/kg), against the PPI disruptions induced by apomorphine (0.5 mg/kg), DOI (3 mg/kg) and dizocilpine (0.15 mg/kg). Furthermore, these drugs have been examined for their ability to restore a PPI deficit produced by housing rats under conditions of social isolation. All drugs except clozapine reversed an apomorphine-induced disruption. However, clozapine and risperidone, but not raclopride and haloperidol, reversed a DOI-induced disruption. Only risperidone was effective in restoring a PPI deficit produced by dizocilpine. In contrast to the drug-induced disruptions which were differentially sensitive to the various neuroleptics, isolation-induced disruptions were restored by each drug. These results support the idea that non-drug induced disruptions of PPI, such as social isolation, may be a more viable approach to identify novel antipsychotics.     

The atypical antipsychotic,aripiprazole, blocks phencyclidine-induced disruption of prepulse inhibition in mice

Rationale The psychotomimetic drug, phencyclidine, induces schizophrenia-like behavioural changes in both humans and animals. Phencyclidine-induced disruption of sensory motor gating mechanisms, as assessed by prepulse inhibition of the acoustic startle, is widely used in research animals as a screening model for antipsychotic properties in general and may predict effects on negative and cognitive deficits in particular. Dopamine (DA) stabilizers comprise a new generation of antipsychotics characterized by a partial DA receptor agonist or antagonist action and have been suggested to have a more favourable clinical profile. Objective The aim of the present study was to investigate the ability of first, second and third generation antipsychotics to interfere with the disruptive effect of phencyclidine on prepulse inhibition in mice. Results Aripiprazole blocked the phencyclidine-induced disruption of prepulse inhibition. The atypical antipsychotic clozapine was less effective, whereas olanzapine, and the typical antipsychotic haloperidol, failed to alter the effects of phencyclidine on prepulse inhibition. Conclusions The somewhat superior efficacy of clozapine compared to haloperidol may be explained by its lower affinity and faster dissociation rate for DA D2 receptors possibly combined with an interaction with other receptor systems. Aripiprazole was found to be more effective than clozapine or olanzapine, which may be explained by a partial agonist activity of aripiprazole at DA D2 receptors. In conclusion, the present findings suggest that partial DA agonism leading to DA stabilizing properties may have favourable effects on sensorimotor gating and thus tentatively on cognitive dysfunctions in schizophrenia.     

The role of serotonin receptors in the action of atypical antipsychotic drugs

The main class of atypical antipsychotic drugs (APDs) in current use includes the protypical atypical APD, clozapine, as well as aripiprazole, asenapine, iloperidone, lurasidone, olanzapine, quetiapine, risperidone, and ziprasidone. At clinically effective doses, these agents produce extensive blockade of serotonin (5-HT)(2A) receptors, direct or indirect stimulation of 5-HT(1A) receptors, and to a lesser extent, reduction in dopamine (DA) D(2) receptor-mediated neurotransmission. This contrasts with typical APDs, for example haloperidol and perphenazine, which are mainly DA D(2/)D(3) receptor antagonists and have weaker, if any, potency as 5-HT(2A) receptor antagonists. Some, but not all, atypical APDs are also effective 5-HT(2C) receptor inverse agonists or neutral antagonists, 5-HT(6) or 5-HT(7) receptor antagonists. This diverse action on 5-HT receptors may contribute to significant differences in efficacy and tolerability among the atypical APDs. There is considerable preclinical and some clinical evidence that effects on 5-HT receptors contribute to the low risk of producing extrapyramidal side effects, which is the defining characteristic of an atypical APD, the lack of elevation in plasma prolactin levels (with risperidone and 9-hydroxyrisperidone being exceptions), antipsychotic action, and ability to improve some domains of cognition in patients with schizophrenia. The serotonergic actions of the atypical APDs, especially 5-HT(2A) receptor antagonism, are particularly important to the differential effects of typical and atypical APDs to overcome the effects of acute or subchronic administration of N-methyl-d-aspartate (NMDA) receptor antagonists, such as phencyclidine, ketamine, and dizocipline (MK-801). 5-HT(1A) receptor stimulation and 5-HT(6) and 5-HT(7) receptor antagonism may contribute to beneficial effects of these agents on cognition. In particular, 5-HT(7) receptor antagonism may be the basis for the pro-cognitive effects of the atypical APD, amisulpride, a D(2)/D(3) receptor antagonist, which has no effect on other 5-HT receptor. 5-HT(2C) receptor antagonism appears to contribute to the weight gain produced by some atypical APDs and may also affect cognition and psychosis via its influence on cortical and limbic dopaminergic activity.     

Role of different monoamine receptors controlling MK-801-induced release of serotonin and glutamate in the medial prefrontal cortex: relevance for antipsychotic action

Several studies have demonstrated that systemically administered N-methyl-d-aspartate (NMDA) receptor antagonists increase serotonin (5-HT) and glutamate release in the medial prefrontal cortex (mPFC). Previously we showed that the perfusion of clozapine in the mPFC prevented the MK-801-induced increase in extracellular glutamate and 5-HT whereas haloperidol blocked only the effect of MK-801 on glutamate. To study the contribution of different monoaminergic receptors (for which clozapine and haloperidol exhibit distinct affinities) to these effects, here we used in-vivo microdialysis to examine the role of local blockade of dopamine D2, 5-HT2A and alpha1-adrenergic receptors as well as agonism at dopamine D1 and 5-HT1A receptors in the mPFC on the increased efflux of glutamate and 5-HT elicited by MK-801. The results show that M100907 (5-HT2A antagonist), BAY x 3702 (5-HT1A agonist) and prazosin (alpha1-adrenergic antagonist) blocked the MK-801-induced increase of 5-HT and glutamate in the mPFC. However, raclopride, eticlopride (dopamine D2 antagonists) and SKF-38393 (dopamine D1 agonist) were able to prevent the increased efflux of glutamate (but not that of 5-HT) elicited by MK-801. We propose that D2 receptor antagonists and D1 agonists would act predominantly on a subpopulation of GABAergic interneurons of the mPFC, thus leading to an enhanced cortical inhibition that would prevent an excessive glutamatergic transmission. On the other hand, atypical antipsychotic drugs might further act upon 5-HT2A, 5-HT1A and alpha1-adrenoceptors present in pyramidal cells (including those projecting to the dorsal raphe nucleus), which would directly inhibit an excessive excitability of these cells.     

Effects of anticholinergic drugs selective for muscarinic receptor subtypes on prepulse inhibition in mice

The effects of anticholinergic drugs selective for muscarinic receptor subtypes on prepulse inhibition of acoustic startle response were determined in mice. The prepulse inhibition is associated with sensorimotor information processing in the brain. The anticholinergic agent scopolamine (0.3 mg/kg, s.c.) significantly attenuated prepulse inhibition, while the drug (1-10 mg/kg, s.c.) had no effects on startle amplitude as an indicator of startle response. The muscarinic M(1) receptor antagonist pirenzepine (0.1-10 microg/mouse, i.c.v.) and the muscarinic M(2) receptor antagonist AF-DX116 (11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one) (0.1-10 microg/mouse, i.c.v.) had no effects on prepulse inhibition or startle amplitude. The muscarinic M(3) receptor antagonist 4-DAMP (1,1-dimethyl-4-diphenylacetoxy-piperidinium iodide) (30 microg/mouse, i.c.v.) and the muscarinic M(4) receptor antagonist tropicamide (0.1 microg/mouse, i.c.v.) significantly attenuated prepulse inhibition, while tropicamide (0.01 microg/mouse, i.c.v.) but not 4-DAMP (10 and 30 microg/mouse, i.c.v.) produced a significant increase in startle amplitude. These results suggest that the blockade of muscarinic M(3) and M(4) receptors leads to the disruption of prepulse inhibition.     

The involvement of sigma and phencyclidine receptors in the action of antipsychotic drugs.

An atypical antipsychotic drug clozapine and a selective sigma antagonist BMY 14802 were significantly less effective in the behavioural experiments (against apomorphine, d-amphetamine and MK-801), as well in the radioligand binding studies against 3H-spiperone (dopamine2-receptors) and 3H-haloperidol (sigma receptors) in the rat brain, as compared to a typical antipsychotic compound haloperidol. Contrary to haloperidol and BMY 14802, clozapine was a relatively selective antagonist of MK-801-induced motor excitation in the mouse. A nearly 3-fold lower dose of clozapine was needed to block the effect of MK-801 (6.4 mumol/kg) as compared to the action of amphetamine (17 mumol/kg). Haloperidol and clozapine, but not BMY 14802, antagonized apomorphine-induced aggressiveness in the rat. After long-term treatment (for 15 days) with BMY 14802 (10 mg/kg daily), haloperidol (0.5 mg/kg daily) and clozapine (10 mg/kg daily) the motor depressant effect of apomorphine (0.15 mg/kg) was reversed. Chronic haloperidol treatment, but not administration of BMY 14802 and clozapine, increased the number of dopamine2-receptors in the rat brain. BMY 14802 caused upregulation of sigma receptors in frontal cortex, whereas haloperidol induced the opposite change in cerebellum. Repeated treatment with clozapine significantly augmented the motor stimulating effect of MK-801 in rats. Simultaneously with a behavioural change the density of 3H-TCP binding sites in the rat forebrain was elevated after long-term treatment with clozapine, probably indicating the involvement of PCP binding sites at NMDA channel in the action of clozapine.     

Dopamine D1 receptors and adenosine A1 receptors in the rat nucleus accumbens regulate motor activity but not prepulse inhibition

Locomotor activity and sensorimotor gating (measured as prepulse inhibition of startle) are regulated by mesoaccumbal dopamine. Recent evidence indicated antagonistic interactions between adenosine A(1) receptors and dopamine D(1) receptors, as well as between adenosine A(2) receptors and dopamine D(2) receptors in the nucleus accumbens. Therefore, it is conceivable that accumbal dopamine and adenosine are both involved in the regulation of prepulse inhibition and locomotion. We tested whether accumbal adenosine A(1) and dopamine D(1) receptors control locomotor activity and prepulse inhibition using the following four treatments. (1) Injections of the selective adenosine A(1) receptor agonist N(6)-cyclopentanyladenosine (CPA 1.5 and 3 microg/microl per side) into the nucleus accumbens. (2) Stimulation of the ventral tegmental area by local infusion of the GABA(A) receptor antagonist picrotoxin (25-100 ng/0.5 microl bilaterally). (3) Picrotoxin injections into the ventral tegmental area (100 ng/0.5 microl) and simultaneous bilateral injections of CPA (3 microg/microl per side) into the nucleus accumbens. (4) Injections of the selective dopamine D(1) receptor antagonist SCH 23390 (3 microg/0.5 microl per side) into the nucleus accumbens and ventral tegmental area stimulation by picrotoxin. Intra-accumbal CPA infusion reduced locomotor activity but had no effect on prepulse inhibition. Picrotoxin stimulation of the ventral tegmental area increased locomotor activity which was antagonized by co-administration of CPA or SCH 23390 into the nucleus accumbens. An enhancement of prepulse inhibition was observed after stimulation of the ventral tegmental area and co-administration of SCH 23390 into the nucleus accumbens. These findings demonstrate that adenosine A(1) and dopamine D(1) receptors are involved in the regulation of locomotor activity mediated by the mesoaccumbal dopamine system. The finding that locomotor effects induced by stimulation of the mesoaccumbal dopamine system were not accompanied by a prepulse inhibition-deficit suggests a dissociation of the neuronal substrates involved in the control of locomotion and the regulation of sensorimotor gating.     

Role of serotonin type 1A receptors in fluvoxamine-induced inhibition of marble-burying behavior in mice

This study examined the roles of presynaptic and postsynaptic serotonin type 1A receptors in fluvoxamine-induced inhibition of marble-burying behavior in mice. The effect of fluvoxamine was attenuated by the serotonin type 1A receptor antagonist WAY100635 at 1 mg/kg, while it was enhanced by the antagonist at 0.1 mg/kg. Fluvoxamine (30 mg/kg) and WAY100635 (0.1 and 1 mg/kg) did not affect spontaneous locomotor activity. These results suggest that the effect of fluvoxamine is mediated by postsynaptic serotonin type 1A receptors and it is enhanced by an inhibition of presynaptic serotonin type 1A receptors.     

Impaired action of anxiolytic drugs in mice deficient in cannabinoid CB1 receptors

The role of cannabinoid CB(1) receptors in the action of anxiolytics was examined. Deletion of CB(1) receptors resulted in increased anxiety-like behaviours in light/dark box, elevated plus maze and social interaction tests. Mutant mice presented basal low corticosterone concentrations and low proopiomelanocortin gene expression in the anterior lobe of the pituitary gland compared to wild-type mice. Ten minutes of restraint stress resulted in a twofold increase in corticosterone concentrations in the plasma of mutant mice, compared to wild-type mice. Bromazepam (50 or 100 microg/kg) markedly increased the time spent in light area in wild-type animals, though both doses were without effect in mutant mice. Administration of buspirone (1 or 2 mg/kg) produced anxiolytic effects in wild-type mice. In contrast, only the highest dose of buspirone had anxiolytic results in mutant mice. Our findings reveal that CB(1) receptors are involved in the regulation of emotional responses, and play a pivotal role in the action mechanism of anxiolytics. They suggest that alterations in the functional activity of the CB(1) receptor may be related to the emergence of anxiety disorders, and may affect treatment with anxiolytics.     

Potentiation of prepulse inhibition of the startle reflex in rats: pharmacological evaluation of the procedure as a model for detecting antipsychotic activity

Prepulse inhibition (PPI) of the startle reflex – whereby presentation of a weak prepulse preceding a startling pulse diminishes the amplitude of the startle reflex – is disrupted by dopamine (DA) agonists; this disruption can be reversed by antipsychotics. There are also some indications in the literature that a few antipsychotics (most notably clozapine and haloperidol) may, on their own, have effects opposite to those of DA agonists, i.e. may enhance PPI. In order to explore these antipsychotic-induced potentiations of PPI more thoroughly, we assessed, in Sprague-Dawley rats, the effects of IP administration of various clinically effective antipsychotics in a PPI procedure with levels of PPI (ranging from 5 to about 40%) low enough to facilitate detection of PPI-potentiating effects of drugs. Both clozapine (5–20 mg/kg) and haloperidol (0.25–1 mg/kg) robustly and dose-dependently potentiated PPI. A similar effect was not seen with risperidone (0.1–1 mg/kg) or with the three substituted benzamides amisulpride (10–60 mg/kg), raclopride (0.1–3 mg/kg) and remoxipride (1–10 mg/kg). As risperidone is known to have prominent 5-HT₂ antagonistic activity, these results do not indicate a role for 5-HT₂ receptors in the clozapine and haloperidol PPI-enhancing effects. The absence of effects with the benzamides and with risperidone, at doses with known anti-dopaminergic activity, suggests that DA antagonist activity is not involved. The demonstration that prazosin (3–20 mg/kg), a non-antipsychotic with α₁ adrenoceptor antagonistic properties, dose-dependently potentiated PPI indicates that α₁ receptors might mediate the clozapine and haloperidol PPI-enhancing activity. Additionally, the finding that diazepam (1–10 mg/kg) did not enhance, but on the contrary reduced PPI, argues against a sedation- or general depressant-mediated effect of clozapine, haloperidol and prazosin. The negative results with four clinically active antipsychotics (risperidone and the benzamides), and the positive result with the non-antipsychotic prazosin, indicate that this PPI-enhancing procedure has poor predictive validity as a screening tool for potential antipsychotics. Received: 14 November 1996/Final version: 6 February 1997     

Effects of scopolamine in comparison with apomorphine and phencyclidine on prepulse inhibition in rats

The potential involvement of the muscarinic cholinergic system in the underlying mechanisms of prepulse inhibition of the acoustic startle reflex was evaluated in male Sprague-Dawley rats under conditions of varying dose, prepulse intensity, and interstimulus interval. The effects of scopolamine on prepulse inhibition were also directly compared with the effects observed using apomorphine and phencyclidine under the same test parameters. Scopolamine (0. 03-1.0 mg/kg) produced a significant dose-dependent decrease in prepulse inhibition, but had no effect on startle amplitude over the dose range tested. Apomorphine (0.03-1.0 mg/kg) and phencyclidine (0. 1-5.6 mg/kg) produced significant dose-dependent decreases in prepulse inhibition and changes in startle amplitude. The scopolamine-induced decrease in prepulse inhibition varied with prepulse intensity in that the changes produced by scopolamine became smaller in magnitude as the prepulse intensity was increased from 9 to 30 dB above background. On the other hand, apomorphine and phencyclidine decreased prepulse inhibition to approximately the same magnitude across all prepulse intensities tested. The observed decreases in prepulse inhibition produced by scopolamine, apomorphine, and phencyclidine were also dependent on interstimulus interval duration. Scopolamine produced marked decreases in prepulse inhibition at the 100- and 300-ms interstimulus interval durations, but had little or no effect on prepulse inhibition at the 30- and 1000-ms interstimulus interval durations. In contrast, apomorphine decreased prepulse inhibition across all interstimulus interval durations while phencyclidine decreased prepulse inhibition across the 30- to 300-ms interstimulus interval durations. The present findings support the hypothesis that the muscarinic cholinergic system, like the dopaminergic and glutamatergic systems, is directly involved in the mechanisms of prepulse inhibition. However, these three neurotransmitter systems appear to modulate different aspects of prepulse inhibition.     

Antagonism of phencyclidine-induced deficits in prepulse inhibition by the putative atypical antipsychotic olanzapine

Prepulse inhibition (PPI) of the startle reflex provides an operational measure of sensorimotor gating. Deficits in PPI are observed in schizophrenia patients and can be modelled in animals by administration of noncompetitive NMDA antagonists such as phencyclidine (PCP) or dizocilpine (MK-801). Previous studies indicate that the atypical antipsychotic clozapine restores PPI in PCP-treated animals while the typical antipsychotic haloperidol does not. Olanzapine (LY170053) is a novel putative atypical antipsychotic that shares many pharmacological and behavioral properties with clozapine. The present study assessed the ability of olanzapine (0, 1.25, 2.5, 5.0 or 10.0 mg/kg) to antagonize deficits in PPI produced by PCP (1.5 mg/kg) and dizocilpine (0.1 mg/kg). At the two highest doses, olanzapine significantly increased PPI in PCP- and dizocilpine-treated animals without affecting PPI or baseline startle reactivity by itself. These results support the notion that olanzapine is functionally similar to clozapine and may have utility as an atypical antipsychotic agent.