"Early" and "late" effects of sustained haloperidol on apomorphine- and phencyclidine-induced sensorimotor gating deficits.

Both dopamine (DA) agonists and NMDA antagonists produce prepulse inhibition (PPI) deficits in rats that model PPI deficits in schizophrenia patients. While DA agonist effects on PPI are reversed by acute treatment with either "typical" high-potency D2 DA antagonists or "atypical" antipsychotics, PPI deficits produced by phencyclidine (PCP) are preferentially reversed by acute treatment with "atypical" antipsychotics. Acute effects of antipsychotics may not accurately model the more clinically relevant effects of these drugs that emerge after several weeks of continuous treatment. In the present study, sustained treatment with haloperidol via subcutaneous minipumps blocked the PPI-disruptive effects of apomorphine and attenuated the PCP-induced disruption of PPI. Restoration of PPI in apomorphine-treated rats was evident within the first week of sustained haloperidol administration. A partial reversal of PCP effects on PPI did not develop until the second week of sustained haloperidol treatment, followed a fluctuating course, but remained significant into the seventh week of sustained haloperidol administration. The delayed emergence of anti-PCP effects of haloperidol suggests that the brain substrates responsible for the DAergic and NMDA regulation of PPI are differentially sensitive to acute and chronic effects of antipsychotics.     

Seroquel, clozapine and chlorpromazine restore sensorimotor gating in ketamine-treated rats

Sensorimotor gating of the startle reflex – measured by prepulse inhibition (PPI) – is impaired in schizophrenia patients and in rats treated with either dopamine (DA) agonists or with N-methyl-D-aspartate (NMDA) antagonists. While both typical and atypical antipsychotics restore PPI in DA agonist-treated rats, studies thus far have demonstrated that only atypical antipsychotics restore PPI in rats treated with NMDA antagonists. This model for predicting atypical antipsychotic properties has been studied extensively in rats, and there is interest in moving these studies into humans, where the NMDA antagonist ketamine is also reported to significantly reduce PPI. In anticipation of such studies, and to facilitate the use of this model in humans, we examined the effects of high and low potency typical antipsychotics (haloperidol and chlorpromazine), the atypical antipsychotic clozapine, and the putative atypical antipsychotic, Seroquel, on ketamine-disrupted PPI in rats, across a range of ketamine that produced submaximal, as well as maximal disruptions of PPI. Ketamine dose-dependently reduced PPI, and this effect was significantly opposed by Seroquel, clozapine and chlorpromazine, but not haloperidol. The effects of chlorpromazine on ketamine-disrupted PPI demonstrate that the ability of antipsychotics to restore PPI in NMDA antagonist-treated rats is not specific to clinically atypical antipsychotics. Receptor properties shared by Seroquel, clozapine and chlorpromazine, but not haloperidol, may implicate critical substrates in the NMDA antagonist-induced disruption of PPI. Received: 31 December 1997/Final version: 11 March 1998     

Sensitivity to drug effects on prepulse inhibition in inbred and outbred rat strains

Genetic differences in the neurochemical regulation of PPI in rats may help clarify the neural basis of inherited PPI differences in neuropsychiatric disorders. We reported and characterized substantial heritable differences in sensitivity to PPI-disruptive effects of DA agonists in outbred Sprague Dawley (SDH) versus Long-Evans (LEH) rats. Other strains might yield large group separations and facilitate studies of the neural basis for these strain differences; inbred strains might also allow us to map genes associated with differential PPI sensitivity. Sensitivity to the PPI-disruptive effects of the DA agonist apomorphine (APO) and the NMDA antagonist phencyclidine (PCP) were compared across inbred and outbred strains. APO sensitivity was greatest in SDH and buffalo rats, but the effect in buffalo rats was complicated by significant APO-induced startle suppression. PPI APO sensitivity was least in ACI and LEH rats; F344s exhibited intermediate sensitivity and Lewis rats showed a nonlinear dose response (sensitivity at low but not higher doses). PPI APO insensitivity in ACI rats developed over time, with ACI pups exhibiting robust sensitivity. Substantial strain differences were observed in short-interval (10-30 ms) prepulse effects, and APO-induced increases in short-interval PPI occurred in SDH, LEH, and Lewis rats, but not in F344, ACI, or buffalo rats. Sensitivity to PPI-disruptive effects of PCP was generally greater in outbred than inbred rats. These findings identify strains suitable for comparisons of PPI neural circuitry and others for whom such comparisons would be complex and perhaps less informative.     

Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review

RATIONALE: Patients with schizophrenia exhibit deficits in an operational measure of sensorimotor gating: prepulse inhibition (PPI) of startle. Similar deficits in PPI are produced in rats by pharmacological or developmental manipulations. These experimentally induced PPI deficits in rats are clearly not animal models of schizophrenia per se, but appear to provide models of sensorimotor gating deficits in schizophrenia patients that have face, predictive, and construct validity. In rodents, disruptions in PPI of startle are produced by: stimulation of D2 dopamine (DA) receptors, produced by amphetamine or apomorphine; activation of serotonergic systems, produced by serotonin (5-HT) releasers or direct agonists at multiple serotonin receptors; and blockade of N-methyl-D-aspartate (NMDA) receptors, produced by drugs such as phencyclidine (PCP). Accordingly, dopaminergic, serotonergic, and glutamatergic models of disrupted PPI have evolved and have been applied to the identification of potential antipsychotic treatments. In addition, some developmental manipulations, such as isolation rearing, have provided non-pharmacological animal models of the PPI deficits seen in schizophrenia. OBJECTIVE: This review summarizes and evaluates studies assessing the effects of systemic drug administrations on PPI in rats. METHODS: Studies examining systemic drug effects on PPI in rats prior to January 15, 2001 were compiled and organized into six annotated appendices. Based on this catalog of studies, the specific advantages and disadvantages of each of the four main PPI models used in the study of antipsychotic drugs were critically evaluated. RESULTS: Despite some notable inconsistencies, the literature provides strong support for significant disruptions in PPI in rats produced by DA agonists, 5-HT2 agonists, NMDA antagonists, and isolation rearing. Each of these models exhibits sensitivity to at least some antipsychotic medications. While the PPI model based on the effects of direct DA agonists is the most well-validated for the identification of known antipsychotics, the isolation rearing model also appears to be sensitive to both typical and atypical antipsychotics. The 5-HT PPI model is less generally sensitive to antipsychotic medications, but can provide insight into the contribution of serotonergic systems to the actions of newer antipsychotics that act upon multiple receptors. The deficits in PPI produced by NMDA antagonists appear to be more sensitive to clozapine-like atypical antipsychotics than to typical antipsychotics. Hence, despite some exceptions to this generalization, the NMDA PPI model might aid in the identification of novel or atypical antipsychotic medications. CONCLUSIONS: Studies of drug effects on PPI in rats have generated four distinctive models that have utility in the identification of antipsychotic medications. Because each of these models has specific advantages and disadvantages, the choice of model to be used depends upon the question being addressed. This review should help to guide such decisions.     

Separable noradrenergic and dopaminergic regulation of prepulse inhibition in rats: implications for predictive validity and Tourette Syndrome

Introduction Startle inhibition by lead stimuli (prepulse inhibition, “PPI”), and the disruption of this process by dopamine agonists and N-methyl-d-aspartate (NMDA) antagonists, are used in predictive models for antipsychotic development. PPI is also disrupted by the norepinephrine α-1 agonist, cirazoline, and the PPI-disruptive effects of the indirect dopamine agonist amphetamine are opposed by the norepinephrine reuptake inhibitor, desipramine. The hypothesis that PPI may be regulated by norepinephrine, or by interactions between dopamine and norepinephrine substrates, was tested in a series of experiments with the α-2 agonist, clonidine, which is used clinically to treat Tourette Syndrome (TS).Materials and methods PPI was measured in male Sprague–Dawley rats after pretreatment with clonidine or the D2 antagonist haloperidol, and treatment with cirazoline, amphetamine, the D1/D2 agonist apomorphine, or the NMDA antagonist, phencyclidine.Results PPI was disrupted by cirazoline; this effect was prevented by clonidine but not haloperidol. PPI was disrupted by apomorphine; this effect was prevented by haloperidol but not clonidine. Clonidine also failed to oppose the PPI-disruptive effects of amphetamine and augmented the PPI-disruptive effects of phencyclidine. Over a range of prepulse intervals, clonidine enhanced PPI at short intervals and opposed the PPI-disruptive effects of cirazoline at long intervals.Conclusions PPI is regulated by both norepinephrine and dopamine substrates that are neurochemically separable. The PPI-protective effects of clonidine suggest that the noradrenergic regulation of PPI may have utility for predicting therapeutic benefit in TS for drugs other than antipsychotics. Clonidine’s failure to prevent the PPI-disruptive effects of apomorphine or phencyclidine further support the specificity of these PPI models for detecting drugs with antipsychotic properties.     

Reversal of phencyclidine-induced prepulse inhibition deficits by clozapine in monkeys

Rationale Prepulse inhibition (PPI) of the acoustic startle reflex is a measure of sensorimotor gating, which occurs across species and is deficient in severe neuropsychiatric disorders such as schizophrenia. In monkeys, as in rodents, phencyclidine (PCP) induces schizophrenia-like deficits in PPI. In rodents, in general, typical antipsychotics (e.g. haloperidol) reverse PPI deficits induced by dopamine (DA) agonists (e.g. apomorphine), but not those induced by N-methyl-d-aspartate (NMDA) receptor antagonists [e.g. phencyclidine (PCP)], whereas atypical antipsychotics (e.g. clozapine) reverse PPI deficits induced by DA agonists and NMDA antagonists. However, some discrepancies exist with some compounds and strains of rodents.Objectives This study investigated whether a typical (haloperidol, 0.035 mg/kg) and an atypical (clozapine, 2.5 mg/kg) antipsychotic could be distinguished in their ability to reverse PCP-induced deficits in PPI in eight monkeys (Cebus apella).Methods First, haloperidol dose was determined by its ability to attenuate apomorphine-induced deficits in PPI. Then, haloperidol and clozapine were tested in eight monkeys with PCP-induced deficits of PPI. Experimental parameters were similar to standard human PPI procedures, with 115 dB white noise startle pulses, either alone or preceded by 120 ms with a prepulse 16 dB above the 70 dB background noise.Results Clozapine reversed PCP-induced PPI deficits. In contrast, haloperidol did not significantly attenuate PCP-induced PPI deficits even at doses that significantly attenuated apomorphine effects.Conclusions In this primate model, clozapine was distinguishable from haloperidol by its ability to attenuate PCP-induced deficits in PPI. The results provide further evidence that PPI in nonhuman primates may provide an important animal model for the development of novel anti-schizophrenia medications.     

Effects of acute versus chronic treatment with typical or atypical antipsychotics on d-amphetamine-induced sensorimotor gating deficits in rats

RATIONALE: Dopamine (DA) receptor agonists disrupt the prepulse inhibition (PPI) in rats which is considered to model PPI deficits observed in schizophrenic patients. Many laboratories have demonstrated that both "typical" and "atypical" antipsychotics reverse the disruptive effect of DA agonists on PPI in rats. These results are based on acute treatment with antipsychotics, which is different from clinical observations since humans receive treatment for months and the effects of antipsychotics only emerge after weeks of treatment. OBJECTIVES: We aimed to investigate the effect of chronic treatment with "typical" and "atypical" antipsychotics on the PPI model in rats. METHODS: We investigated the effect of acute versus sub-chronic (3 days) and chronic (21 days) treatment with haloperidol or two "atypical" antipsychotics (olanzapine; sertindole) on d-amphetamine-disrupted PPI in rats. RESULTS: We observed that all three antipsychotics dose-dependently reversed the disruptive effect of d-amphetamine after acute or sub-chronic treatment, but that this reversal effect disappeared after chronic treatment. We confirmed this effect in the same model using oral administration instead of mini-pumps, and in an additional model predictive of antipsychotic action, i.e. d-amphetamine-induced hyperactivity in rats. CONCLUSIONS: The d-amphetamine-disrupted PPI model highlighted a modification in the effects of antipsychotics after chronic treatment when compared to their acute effects, but only the acute treatment can be considered predictive of antipsychotic action in clinic.     

Ontogeny of phencyclidine and apomorphine-induced startle gating deficits in rats

NMDA antagonists and dopamine (DA) agonists produce neuropathological and/or behavioral changes in rats that may model specific abnormalities in schizophrenia patients. In adult rats, NMDA antagonists and DA agonists disrupt sensorimotor gating-measured by prepulse inhibition (PPI)-modeling PPI deficits in schizophrenia patients. In addition, high doses of NMDA antagonists produce limbic system pathology that may model neuropathology in schizophrenia patients. We examined these behavioral and neuropathological models across development in rats. Both the NMDA antagonist phencyclidine (PCP) and the DA agonist apomorphine disrupted PPI in 16 day pups, demonstrating early developmental functionality in substrates regulating these drug effects on PPI. In contrast, PCP neurotoxicity was evident only in adult rats. Brain mechanisms responsible for the PCP disruption of PPI, and PCP-induced neurotoxicity, are dissociable across development.     

Clozapine enhances disruption of prepulse inhibition after sub-chronic dizocilpine- or phencyclidine-treatment in Wistar rats

Sensitisation (i.e. progressive enhancement) of behavioural abnormalities induced by repeated treatment with non-competitive NMDA receptor antagonists in animals is considered an animal model for schizophrenia. Here, male Wistar rats were treated for 11 days with either dizocilpine (0.1 mg/kg), phencyclidine (PCP, 2 mg/kg), or saline and tested for prepulse inhibition (PPI) of the acoustic startle response (ASR). The aims of this study were twofold: First, we tested whether sensitisation of PPI deficits previously found in Sprague-Dawley rats were also found in Wistar rats, and, second, whether these effects can be ameliorated by the atypical antipsychotic clozapine. PPI is a paradigm for the assessment of sensorimotor gating (and its deficits) and is impaired in schizophrenic patients. After the sub-chronic treatment the rats were tested drug-free (day 12), and on the following days after drug challenge by PCP (2 mg/kg), combinations of PCP (2 mg/kg) and clozapine (5 and 10 mg/kg), or clozapine (5 mg/kg) alone. PPI was significantly reduced by both NMDA receptor antagonists. This effect was not further enhanced by the daily treatment. Startle magnitude was increased after eight days of dizocilpine-treatment only, indicating sensitisation of startle-potentiation by this drug. Testing the rats drug-free on day 12 revealed enhanced PPI and reduced startle (compared to the matching test on day 0) irrespective of previous treatment. Drug challenge with PCP (2 mg/kg) again reduced PPI in all groups. Clozapine (5 and 10 mg/kg) failed to antagonise the PPI-disruptive effects of PCP and even enhanced the PCP-induced PPI-deficits in rats pretreated with PCP or dizocilpine. These findings suggest: (1) that PPI and startle are influenced differently by non-competitive NMDA receptor antagonists, (2) that PCP and dizocilpine reduce PPI in Wistar rats, but do not lead to a sensitisation of this effect; and (3) that under the present schedule of treatments, the antipsychotic compound clozapine does not antagonise but rather enhances PPI-disruptive effects of non-competitive NMDA receptor antagonists, pointing towards a complex interaction of the brain processes underlying the action of psychotomimetic and atypical antipsychotic drugs.     

Iloperidone reduces sensorimotor gating deficits in pharmacological models, but not a developmental model, of disrupted prepulse inhibition in rats

Iloperidone is a novel atypical antipsychotic which acts as a broad spectrum dopamine/serotonin/norepinephrine receptor antagonist. To compare iloperidone behaviorally to other known antipsychotics, we evaluated the drug in three pharmacological models and one developmental model of disrupted prepulse inhibition (PPI) in rats. Firstly, 0.5 mg/kg apomorphine induced PPI deficits that were prevented by pretreatment with iloperidone (1 and 3 mg/kg). Secondly, treatment with the N-methyl-D-aspartate (NMDA)-receptor antagonist phencyclidine (PCP) produced robust deficits in PPI. Both doses of iloperidone (1 and 3 mg/kg) prevented the PPI-disruptive effects of treatment with 1 mg/kg PCP. Thirdly, treatment with the alpha1-adrenoceptor agonist cirazoline (0.6 mg/kg) disrupted PPI, and produced a concurrent large increase in startle magnitude. A relatively low dose of iloperidone (0.3 mg/kg) prevented cirazoline-induced PPI deficits, independent of its effects on startle magnitude. Finally, iloperidone (1 mg/kg) did not reverse PPI deficits in the isolation-rearing model of schizophrenia. These results indicate that iloperidone exerts behavioral effects in pharmacological models of disrupted sensorimotor gating consistent with "atypical" antipsychotics, mediated by antagonism of dopaminergic and noradrenergic receptors. The absence of effect in isolation-reared rats may be due to the relatively small effect size of isolation rearing on PPI or dose of iloperidone.     

Effects of acute treatment with antidepressant drugs on sensorimotor gating deficits in rats

Rationale Schizophrenic patients have a deficit in prepulse inhibition (PPI) which can be modelled in rats by administration of direct or indirect dopamine (DA) receptor agonists and N-methyl-d-aspartate (NMDA) receptor antagonists. Moreover, antipsychotics reverse the disruptive effect of DA agonists and NMDA receptor antagonists in this rat model. Consequently, this model is considered as predictive of antipsychotic action in the clinic. However, the effect of compounds, such as antidepressants, used for other psychiatric disorders but also administered to patients with schizophrenia has not been well investigated in this model. Antidepressants have been suggested not to affect PPI in humans. Thus, antidepressants are not expected to antagonise PPI disruption in rats, and should normally be used as negative controls in this model.Objectives To investigate the effects of three antidepressant compounds, a serotonin reuptake inhibitor, a dopamine reuptake inhibitor, and a noradrenaline reuptake inhibitor in the rat PPI model.Methods The effect of acute treatment with citalopram, bupropion and desipramine on d-amphetamine-disrupted and phencyclidine (PCP)-disrupted PPI in rats was investigated. Ziprasidone was tested as a positive control.Results None of the antidepressants, in contrast to ziprasidone, reversed PCP-disrupted PPI in rats. Both desipramine and ziprasidone normalised d-amphetamine-disrupted PPI, while citalopram and bupropion were inactive.Conclusions PCP-disrupted PPI in rats was less sensitive to false positives than the d-amphetamine-disrupted PPI model, based on the antidepressants tested in this study.     

The effects of subchronic haloperidol on intact and dizocilpine-disrupted sensorimotor gating

Rationale: Reversal of deficits in prepulse inhibition (PPI) of the startle reflex in rats is considered a preclinical screen for potential antipsychotics. Whereas acutely administered antipsychotics consistently reverse apomorphine-induced deficits in PPI, some antipsychotics, including haloperidol, are unable to reverse deficits in PPI produced by non-competitive NMDA antagonists such as phencyclidine or dizocilpine (MK-801). Acute administration of antipsychotics tends to facilitate baseline PPI. However, the effect is generally not large enough in magnitude nor reliable enough to be considered a useful preclinical screen for antipsychotic activity. Objective: Because the clinical effects of antipsychotics typically require subchronic administration, this study tested the hypothesis that reversal of NMDA antagonist-induced deficits in PPI by antipsychotics require subchronic administration. A second aim of this study was to determine if subchronic administration of an antipsychotic produces a more potent facilitation of baseline PPI than acute administration. Methods: Rats received a subcutaneous injection of 0, 0.025, 0.1 or 0.5 mg/kg haloperidol for 16 consecutive days. On day 16, half the rats in each haloperidol dose group received a second subcutaneous injection consisting of either dizocilpine (0.1 mg/kg) or saline. Results: None of the haloperidol doses tested had a significant effect on baseline PPI. The 0.1 mg/kg dose of haloperidol diminished but did not completely reverse dizocilpine-induced disruption of PPI. The other doses had no significant effect. Conclusions: These results suggest that time course factors may partially modify the effects of haloperidol on dizocilpine-induced disruption of PPI but not its effect on baseline PPI. Received: 4 December 1998 / Final version: 19 April 1999     

Antipsychotic effects on prepulse inhibition in normal 'low gating' humans and rats.

Development of new antipsychotics and their novel applications may be facilitated through the use of physiological markers in clinically normal individuals. Both genetic and neurochemical evidence suggests that reduced prepulse inhibition of startle (PPI) may be a physiological marker for individuals at-risk for schizophrenia, and the ability of antipsychotics to normalize PPI may reflect properties linked to their clinical efficacy. We assessed the effects of the atypical antipsychotic quetiapine (12.5 mg p.o.) on PPI in 20 normal men with a 'low PPI' trait, based on PPI levels in the lowest 25% of a normal PPI distribution. The effects of quetiapine (7.5 mg/kg s.c.) on PPI were then assessed in rats with phenotypes of high PPI (Sprague Dawley (SD)) and low PPI (Brown Norway (BN)); effects of clozapine (7.5 mg/kg i.p.) and haloperidol (0.1 mg/kg s.c.) on PPI were also tested in SD rats. At a time of maximal psychoactivity, quetiapine significantly enhanced PPI to short prepulse intervals (20-30 ms) in 'low gating' human subjects. Quetiapine increased PPI in low gating BN rats for prepulse intervals <120 ms; this effect of quetiapine was limited to 20 ms prepulse intervals in SD rats, who also exhibited this pattern in response to clozapine but not haloperidol. In both humans and rats, normal 'low gating' appears to be an atypical antipsychotic-sensitive phenotype. PPI at short intervals may be most sensitive to pro-gating effects of these drugs.     

Clozapine and olanzapine, but not haloperidol, suppress serotonin efflux in the medial prefrontal cortex elicited by phencyclidine and ketamine

N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) and ketamine can evoke psychotic symptoms in normal individuals and schizophrenic patients. Here, we have examined the effects of PCP (5 mg/kg) and ketamine (25 mg/kg) on the efflux of serotonin (5-HT) in the medial prefrontal cortex (mPFC) and their possible blockade by the antipsychotics, clozapine, olanzapine and haloperidol, as well as ritanserin (5-HT2A/2C receptor antagonist) and prazosin (alpha1-adrenoceptor antagonist). The systemic administration, but not the local perfusion, of the two NMDA receptor antagonists markedly increased the efflux of 5-HT in the mPFC. The atypical antipsychotics clozapine (1 mg/kg) and olanzapine (1 mg/kg), and prazosin (0.3 mg/kg), but not the classical antipsychotic haloperidol (1 mg/kg), reversed the PCP- and ketamine-induced increase in 5-HT efflux. Ritanserin (5 mg/kg) was able to reverse only the effect of PCP. These findings indicate that an increased serotonergic transmission in the mPFC is a functional consequence of NMDA receptor hypofunction and this effect is blocked by atypical antipsychotic drugs.     

Time course of the attenuation effect of repeated antipsychotic treatment on prepulse inhibition disruption induced by repeated phencyclidine treatment

Antagonism of prepulse inhibition (PPI) deficits produced by psychotomimetic drugs has been widely used as an effective tool for the study of the mechanisms of antipsychotic action and identifying potential antipsychotic drugs. Many studies have relied on the acute effect of a single administration of antipsychotics, whereas patients with schizophrenia are treated chronically with antipsychotic drugs. The clinical relevance of acute antipsychotic effect in this model is still an open question. In this study, we investigated the time course of repeated antipsychotic treatment on persistent PPI deficit induced by repeated phencyclidine (PCP) treatment. After a baseline test with saline, male Sprague-Dawley rats were repeatedly injected with either vehicle, haloperidol (0.05 mg/kg), clozapine (5.0 or 10.0 mg/kg), olanzapine (2.0 mg/kg), risperidone (1.0 mg/kg) or quetiapine (10 mg/kg), followed by PCP (1.5 mg/kg, sc) and tested for PPI once daily for 6 consecutive days. A single injection of PCP disrupted PPI and this effect was maintained with repeated PCP injections throughout the testing period. Acute clozapine, but not other antipsychotic drugs, attenuated acute PCP-induced PPI disruption at both tested doses. With repeated treatment, clozapine and quetiapine maintained their attenuation, while risperidone enhanced its effect with a significant reduction of PCP-induced disruption toward the end of treatment period. In contrast, repeated haloperidol and olanzapine treatments were ineffective. The PPI effects of these drugs were more conspicuous at a higher prepulse level (e.g. 82 dB) and were dissociable from their effects on startle response and general activity. Overall, the repeated PCP-PPI model appears to be a useful model for the study of the time-dependent antipsychotic effect, and may help identify potential treatments that have a quicker onset of action than current antipsychotics.     

Rat strain differences in startle gating-disruptive effects of apomorphine occur with both acoustic and visual prepulses

Prepulse inhibition of startle (PPI) is an operational measure of sensorimotor gating that is impaired in schizophrenia and is disrupted in rats by dopamine (DA) agonists like apomorphine (APO). Using acoustic prepulses and acoustic startle pulses, previous studies have demonstrated heritable strain differences between Sprague Dawley (SD) and Long Evans (LE) rats in the sensitivity to the PPI-disruptive effects of APO. As PPI deficits in schizophrenia are evident with both uni- and cross-modal stimuli, we tested whether strain differences in the gating-disruptive effects of APO occur with a cross-modal visual and acoustic stimulus combination. APO caused a dose-dependent disruption of both acoustic and visual PPI in SD rats. Compared to LE rats, SD rats were more sensitive to the PPI-disruptive effects of APO with both acoustic and visual PPI. These findings suggest that SD vs. LE strain differences in PPI APO sensitivity are mediated outside of the auditory system, within higher circuitry that regulates or processes multi-modal information. The present findings provide further validation for this heritable model of impaired sensorimotor gating in schizophrenia, which can be detected across multiple sensory modalities.     

Heritable differences in the effects of amphetamine but not DOI on startle gating in albino and hooded outbred rat strains

Sensorimotor gating, measured by prepulse inhibition (PPI) of the startle reflex, is reduced in schizophrenia patients and in rats treated with dopamine (DA) agonists. Strain and substrain differences in the sensitivity to the PPI-disruptive effects of DA agonists may provide insight into the basis for human population differences in sensorimotor gating. We reported heritable differences in sensitivity to the PPI-disruptive effects of the D1/D2 agonist apomorphine (APO) in Harlan Sprague-Dawley (SDH) and Long-Evans (LEH) rats, offspring (F1) of an SDHxLEH cross, and subsequent offspring (N2) of an SDHxF1 cross. In this study, we assessed the neurochemical specificity of this heritable phenotype across parental SDH and LEH strains, and their F1 and N2 offspring, based on their sensitivity to the PPI-disruptive effects of the indirect DA agonist D-amphetamine (AMPH) and the 5HT2A agonist DOI. AMPH sensitivity followed a gradient of SDH>N2>F1>LEH, consistent with past findings with APO. DOI sensitivity did not differ across strains or generations. These findings demonstrate that the heritable phenotype in this model is not specific to a particular compound (APO), and reflects physiological differences in the DAergic, but not serotonergic, regulation of PPI.     

Sensitivity to the dopaminergic regulation of prepulse inhibition in rats: evidence for genetic, but not environmental determinants.

Prepulse inhibition (PPI), a measure of sensorimotor gating, is reduced in schizophrenia patients and in rats treated with dopamine (DA) agonists. Reported strain and supplier-based differences in sensitivity to PPI-disruptive effects of DA agonists presumably reflect the differential impact of genetics and/or environment on DAergic substrates regulating PPI. In 2000, Harlan Laboratories established a Texas Sprague-Dawley line (SDHt; facility 211) using breeders from Indianapolis (SDHi; facility 202A). SDHi rats had been used, approximately 11 years earlier, to establish a colony in San Diego (SDHsd; facility 235). SDHt and SDHi rats are thus genetically similar, but raised in distinct environments; approximately 11 years of genetic "drift" separates SDHsd rats from both SDHi and SDHt rats. Harlan Long-Evans hooded rats (LEH; Madison, WI; facility 207) are genetically distinct from albino SDH. All except SDHsd rats were shipped to our facility by air freight. We used SDHt, SDHi, SDHsd, and LEH rats to assess genetic and environmental contributions to the DAergic regulation of PPI. Acoustic startle/PPI were assessed in rats treated with the D1/D2 agonist apomorphine (APO), the D2 agonist quinpirole, or the D1 agonist SKF 82958. The relative sensitivities to the PPI-disruptive effects were: APO: SDHt=SDHsd=SDHi>LEH; SKF 82958: SDHt=SDHsd=SDHi (LEH not sensitive); quinpirole: SDHt=SDHsd=SDHi; SDHi>LEH. Strain/supplier differences in sensitivity to drug effects on startle magnitude did not correspond to patterns of PPI sensitivity. In these rats, strain differences in the DAergic regulation of PPI are most easily explained by genetic, rather than environmental influences that differentially impact both D1 and D2 substrates. This finding is consistent with published reports in other strains. Pharmacogenetic studies of PPI in rats may identify a genetic basis for a model of deficient sensorimotor gating in schizophrenia.     

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.     

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.