Parametric approaches towards understanding the effects of the preferential D3 receptor agonist pramipexole on prepulse inhibition in rats

The preferential dopamine D3 receptor agonist pramipexole (PRA) disrupts prepulse inhibition (PPI) of acoustic startle, an operational measure of sensorimotor gating, in rats. Drug effects on PPI are sensitive to numerous experimental variables; proceeding with in-depth analyses of drug effects without a clear understanding of these variables is inefficient. The present studies characterized the impact on PRA-induced PPI deficits by a range of experimental parameters. As shown previously, PRA reduced both PPI and startle magnitude beginning 5-15 min post-injection; PRA effects on PPI were statistically significant through 35 min post-injection, while those on startle magnitude were still significant 65 min post-injection. PRA-induced PPI deficits were evident under conditions that matched startle magnitude in vehicle and PRA conditions and were independent of PRA-induced changes in prepulse-elicited motor activity. Additionally, PRA-induced PPI deficits did not differ significantly between uni- vs. cross-modal stimuli or between male vs. female rats, with no robust effect of estrous phase in females. These findings demonstrate that PRA effects on PPI are observed across several different experimental conditions and are dissociable from changes in startle magnitude or prepulse-elicited responses. Recommendations are made regarding “optimal” experimental conditions for studying the neurobiology of PRA-induced changes in PPI in rats.     

Selective dopamine D4 receptor antagonists reverse apomorphine-induced blockade of prepulse inhibition

 Recent evidence suggests that the dopamine D₄ receptor may play a role in schizophrenia, and that the atypical properties of the antipsychotic clozapine may be attributable in part to its antagonistic actions at this receptor. In the present study, clozapine and three other compounds having D₄ dopamine receptor antagonist properties were examined for their effectiveness in reducing losses in prepulse inhibition (PPI) induced in rats by the dopamine receptor agonist apomorphine. Previously, activity in the PPI model has been shown to correlate highly with the antipsychotic potency of a number of neuroleptics. As previously reported, clozapine (1–5.6 mg/kg) significantly reduced apomorphine-induced PPI deficits. The three D₄-selective compounds, CP-293,019 (5.6–17.8 mg/kg), U-101,387 (3–30 mg/kg) and L-745,870 (1–10 mg/kg), also significantly blocked the losses in PPI produced by apomorphine. Taken together, these results suggest that dopamine receptor antagonists with selectivity for the D₄ dopamine receptor subtype may be effective in the treatment of schizophrenia, while being less likely to produce dyskinesias associated with D₂ receptor antagonists. Received: 13 May 1997/Final version: 15 July 1997     

D1 and D2 dopamine receptor antagonists reverse prepulse inhibition deficits in an animal model of schizophrenia

The amplitude of the acoustic startle response is decreased if the startle stimulus is preceded by a nonstartle eliciting stimulus. This sensorimotor gating phenomenon, known as prepulse inhibition, is diminished in schizophrenic individuals. In rats, the dopamine agonist apomorphine disrupts prepulse inhibition and this disruption is reversed by classical and atypical antipsychotics. Furthermore, the ability of antipsychotics to reverse the apomorphine disruption is correlated with clinical potency and D₂ receptor affinity. In the present study, the role of the D₁ receptor in prepulse inhibition of the acoustic startle response was studied; the effects of the D₁ receptor antagonist SCH 23390 were examined and compared to the effects of the D₂ receptor antagonist eticlopride. Male Sprague-Dawley rats were placed into a startle chamber and presented with auditory stimuli consisting of either 95 or 105 dB noise bursts presented alone or preceded by a 75 dB noise burst. Trials consisting of no stimulus and the 75 dB prepulse stimulus alone were also included. These six trial types (ten each) were randomly presented within a 35-min session. Rats treated with 2.0 mg/kg apomorphine (SC) demonstrated a significant disruption of prepulse inhibition compared to vehicle controls. Pretreatment with the D₁ antagonist SCH 23390 (0.01, 0.05, 0.1 mg/kg SC) or the D₂ antagonist eticlopride (0.01, 0.05, 0.1 mg/kg SC) attenuated the disruptive effects of apomorphine. These results indicate that selective blockade of either the D₁ or D₂ receptor subtype is sufficient in reversing the sensorimotor gating deficits produced by apomorphine. The effects of eticlopride and SCH 23390 on prepulse inhibition in saline-treated rats were also examined. Each antagonist produced a dose-related facilitation of prepulse inhibition, suggesting that endogenous DA acting at either receptor subtype plays a role in the tonic modulation of sensorimotor gating.     

Quinelorane, a dopamine D3/D2 receptor agonist, reduces prepulse inhibition of startle and ventral pallidal GABA efflux: time course studies

Startle is inhibited when the startling stimulus is preceded 30–300 ms by a weak prepulse. Prepulse inhibition (PPI), an operational measure of sensorimotor gating, is deficient in schizophrenia patients, and reduced in rats and humans by dopamine agonists. The neural basis for the PPI-disruptive effects of dopamine agonists in rats is studied to understand neural circuitry regulating PPI and its deficits in schizophrenia. Existing data suggest that ventral pallidal (VP) GABAergic transmission regulates PPI and its disruption by dopamine agonists. We measured changes in VP GABA efflux and PPI in rats in response to the D2/D3 agonist, quinelorane. Wistar rats were administered quinelorane (vehicle, 0.003 or 0.01 mg/kg). In some rats, VP dialysate was analyzed for GABA content. In others, PPI was assessed using 120 dB(A) startle pulses and prepulses 10 dB over a 70 dB(A) background. Quinelorane reduced GABA efflux, with significant effects for 0.01 but not 0.003 mg/kg, persisting for at least 100 min. Quinelorane reduced PPI for 50 min, an effect significant for both the 0.003 (p < 0.05) and 0.01 mg/kg doses (p < 0.015). Differences in time course and dose sensitivity of quinelorane effects on VP GABA efflux and PPI are discussed.     

Sensitization to amphetamine,but not phencyclidine,disrupts prepulse inhibition and latent inhibition

Rationale Schizophrenia has been linked to dysregulation of dopamine and glutamate transmitter systems. Attempts to model aspects of schizophrenia in animals have made use of treatments that primarily affect dopaminergic (e.g., amphetamine, Amp) and glutamatergic (e.g., phencyclidine, PCP) function. In addition to exerting short-term acute effects, these agents also induce long-term effects, as seen, for example, in neurochemical and behavioural sensitization.Objectives The goal of this work was to compare Amp- and PCP-sensitized states on two measures of information processing that are impaired in schizophrenia, prepulse inhibition (PPI) of the acoustic startle reflex and latent inhibition (LI).Methods Rats received injections of Amp, PCP or saline 3 days per week for 3 weeks. The Amp dose increased from 1 to 3 mg/kg, at the rate of 1 mg/kg each week. The PCP dose was 3 mg/kg throughout. After various periods of withdrawal rats were tested for PPI and LI.Results Repeated intermittent treatment with Amp or PCP resulted in augmented locomotor responses to challenge with each drug, providing an operational index that sensitization had occurred. Rats sensitized to Amp showed disrupted PPI when tested drug free at 3, 21 and 60 days of withdrawal. Amp-sensitized rats also showed abolition of the LI effect. Rats sensitized to PCP did not show deficits in any of these behaviours when tested drug free.Conclusions Because disrupted PPI and LI have both been reported in schizophrenic patients, these results suggest that the Amp-sensitized state may represent a useful model for investigating the neural bases of information processing deficits in schizophrenia.     

Amphetamine disruption of prepulse inhibition of acoustic startle is reversed by depletion of mesolimbic dopamine

Previous studies have demonstrated that dopamine (DA) agonists disrupt sensorimotor gating as measured by prepulse inhibition (PPI) of the acoustic startle response (ASR) in rats; other reports suggest that this stimulant-induced disruption of PPI may reflect drug-induced increases in ASR amplitude rather than changes in sensorimotor gating. In the current study, 6-hydroxydopamine lesions that depleted dopamine from the nucleus accumbens, olfactory tubercles and anterior striatum reversed the disruption of PPI caused by amphetamine (AMPH), but did not disrupt AMPH potentiation of ASR baseline. These findings strongly suggest that increased mesolimbic DA activity is one substrate of the AMPH-induced disruption of PPI; in contrast, AMPH potentiation of baseline startle amplitude may be independent of mesolimbic DA activation.     

Effects of tryptophan deficiency on prepulse inhibition of the acoustic startle in rats

Rationale Serotonin (5-HT) plays a key role in the pathophysiology of psychotic disorders, presumably through a modulation of dopamine (DA) transmission. Reduction of 5-HT signaling has been suggested to enhance dopaminergic responses in animal models of psychosis. An intriguing naturalistic strategy to reduce 5-HT brain content is afforded by the dietary restriction to its precursor, l-tryptophan (TRP). Objective We investigated the impact of a TRP-deficient diet in rats on the prepulse inhibition of the startle (PPI), a measure of sensorimotor gating which is typically impaired by psychotomimetic substances. Materials and methods After either short-term (6 h) or long-term (14 days) TRP deprivation, rats were tested for startle reflex and PPI. Moreover, we assessed the impact of both TRP deprivation regimens on PPI reduction induced by the psychotomimetic substance d-amphetamine (AMPH). Results Both TRP-deficient regimens failed to significantly affect PPI responses. However, chronic, but not short-term, TRP-deficient diet induced a significant sensitization to the effects of AMPH (1.25–2.5 mg/kg, subcutaneous). The enhanced predisposition to PPI disruption elicited by prolonged TRP deprivation was completely reversed 24 h after reinstatement of TRP in the diet, as well as pretreatment with antipsychotic drugs haloperidol (0.1 mg/kg, intraperitoneal) and clozapine (5 mg/kg, intraperitoneal), which exert their therapeutic action mostly through blockade of DA D₂ receptors. Conclusions The present results confirm and extend previous findings on the impact of serotonergic signaling in the modulation of DA transmission in schizophrenia and point to chronic TRP deprivation as a potential model of environmental manipulation that may produce a sensitization to psychotic-like symptoms induced by dopaminergic activation. Fabio Fadda and Roberto Stancampiano contributed equally to the study.     

Realistic expectations of prepulse inhibition in translational models for schizophrenia research

INTRODUCTION: Under specific conditions, a weak lead stimulus, or "prepulse", can inhibit the startling effects of a subsequent intense abrupt stimulus. This startle-inhibiting effect of the prepulse, termed "prepulse inhibition" (PPI), is widely used in translational models to understand the biology of brainbased inhibitory mechanisms and their deficiency in neuropsychiatric disorders. In 1981, four published reports with "prepulse inhibition" as an index term were listed on Medline; over the past 5 years, new published Medline reports with "prepulse inhibition" as an index term have appeared at a rate exceeding once every 2.7 days (n=678). Most of these reports focus on the use of PPI in translational models of impaired sensorimotor gating in schizophrenia. This rapid expansion and broad application of PPI as a tool for understanding schizophrenia has, at times, outpaced critical thinking and falsifiable hypotheses about the relative strengths vs. limitations of this measure. OBJECTIVES: This review enumerates the realistic expectations for PPI in translational models for schizophrenia research, and provides cautionary notes for the future applications of this important research tool. CONCLUSION: In humans, PPI is not "diagnostic"; levels of PPI do not predict clinical course, specific symptoms, or individual medication responses. In preclinical studies, PPI is valuable for evaluating models or model organisms relevant to schizophrenia, "mapping" neural substrates of deficient PPI in schizophrenia, and advancing the discovery and development of novel therapeutics. Across species, PPI is a reliable, robust quantitative phenotype that is useful for probing the neurobiology and genetics of gating deficits in schizophrenia.     

Neonatal domoic acid treatment produces alterations to prepulse inhibition and latent inhibition in adult rats

Schizophrenia is a complex and severe mental disorder characterized by positive, negative and cognitive symptoms. Characteristic behavioral alterations reflecting these categories of symptoms have been observed in many animal models of this disorder, and are consistent with those manifested in the clinical population. The purpose of this study was to determine whether early alterations in glutamate signaling would result in alterations to prepulse inhibition (PPI) and latent inhibition (LI); two assessments used for evaluating putative novel animal models with relevance to schizophrenia. In the present experiment, daily subcutaneous (s.c.) injections of 20 μg/kg of domoic acid (DOM) were administered to rat pups from postnatal days (PND) 8-14. When tested as adults, DOM treated rats displayed deficits in PPI that were dependant on both sex and time of day. No differences in startle amplitude, habituation, or movement were found during any test, indicating that the PPI deficits seen could not be attributed to baseline startle differences. Deficits in LI were also apparent when adult rats were tested using a conditioned taste aversion task, with DOM-treated animals displaying a significantly suppressed LI. These results suggest that early treatment with DOM may serve as a useful tool to model schizophrenia which in turn may lead to a better understanding of the contribution of glutamate, and in particular, kainate receptors, to the development and/or manifestation of schizophrenia or schizophrenia-like symptoms in the clinical population.     

Long-term evaluation of isolation-rearing induced prepulse inhibition deficits in rats: an update

Rationale Rats reared in social isolation from weaning show prepulse inhibition (PPI) deficits which are thought to model the sensorimotor gating deficits seen in schizophrenia and other psychiatric disorders. We have previously reported that ten cohorts of Lister Hooded rats reared in isolation showed robust and reliable PPI deficits.Objective Our methodology differed from those used by others (Weiss and Feldon in Psychopharmacology 156(2–3):305–326, 2001), most notably in the weaning of pups at postnatal day (PND) 28 compared with PND20-22. Since our initial report, we have studied 18 more cohorts weaned at PND28 and one cohort weaned at PND21.Method At weaning, male Lister Hooded pups were singly (isolates) or group (n=5) housed (grouped). Eight weeks later, startle and PPI responses of isolates and grouped rats were investigated using conditions of fixed inter-stimulus interval (ISI) (pulse=110 dB/50 ms; prepulse (PP)=75–80 dB/30 ms; ISI=100 ms).Results Isolates from 14 of the subsequent 18 cohorts demonstrated PPI deficits, giving an overall success rate of 86% for all 28 cohorts. %PPI ranged from 12 to 26% in the isolates and from 26 to 47% in the grouped for the successful cohorts, compared to 16–30% (isolates) and 19–35% (grouped) for those that failed. Only five out of the 19 subsequent cohorts demonstrated startle hyperreactivity, which was unrelated to PPI response. The isolates from the cohort weaned at PND21 did not show a significant deficit in PPI, suggesting, in our hands at least, a requirement for weaning at PND28.Conclusion The data presented here reinforce our original findings that isolation-rearing of Lister Hooded rats provides a viable, non-pharmacological model of impaired PPI.     

Effects of typical and atypical antipsychotics on prepulse inhibition in schizophrenia: a critical evaluation of current evidence and directions for future research

Prepulse inhibition (PPI) of the startle response refers to an attenuation in response to a strong stimulus (pulse) if this is preceded shortly by a weak non-startling stimulus (prepulse). PPI provides a simple operational measure of sensorimotor gating, serving to prevent the interruption of ongoing perceptual and early sensory analysis. In accord with postulated deficits in early stages of information processing, there is ample evidence that PPI is disrupted in individuals with schizophrenia. PPI in animals is thought to represent a well-validated model for evaluating potential new treatments for schizophrenia. Currently, available data on the differential effects of typical and atypical antipsychotics suggest that atypical antipsychotics, in particular clozapine and risperidone, may be more effective than typical antipsychotics in improving PPI deficits in schizophrenia. However, studies have so far used small samples and/or between-subjects designs, and not examined the effects of other concomitant medications that may also influence PPI. The directions are identified for further applications of this model using within-subjects longitudinal designs and reasonable sample sizes to establish superiority of particular atypical antipsychotics over typical antipsychotics in improving PPI in schizophrenic populations.     

PHNO, a selective dopamine D2 receptor agonist, does not reduce prepulse inhibition of the startle reflex in rats

RATIONALE: Dopamine agonists nonselective for dopamine receptor subtypes, such as apomorphine, reduce prepulse inhibition of the startle reflex. It has been suggested that either D2 or D3 dopamine receptors mediate this action of apomorphine. OBJECTIVE: The present study investigated whether a selective D2 agonist with relatively low affinity for D3 receptors can reduce prepulse inhibition. METHODS: Rats (n=48) were treated with vehicle or one of three doses ( 15, 30 or 60 microg/kg, s.c.) of the specific dopamine D2 receptor agonist (+)-4-propyl-9-hydroxynaphthoxazine (PHNO) for 11 days. On days 1, 6 and 11 of treatment, the rats (n=12 in each group) were tested for their acoustic startle reflexes (105-dB, 40-ms white noise) and for prepulse inhibition (5-kHz tone, 5 dB above a 65 dB background white noise). Prepulses were presented with a range of stimulus onset asynchronies (SOAs: 5-160 ms) or lead times between the onset of the prepulse and the onset of the startle stimulus. In a second experiment, two groups of rats (n=10 in each group) were tested in a similar manner after vehicle or apomorphine (0.8 mg/kg, s.c.) to verify the sensitivity of the present procedure to agonist-induced reductions in prepulse inhibition. RESULTS: At doses that increased motor activity, PHNO increased prepulse inhibition at SOAs less than 80 ms and had no effect on prepulse inhibition at SOAs of 80 ms or above. However, all doses decreased startle amplitudes on trials in which only the startle-eliciting stimulus was presented. Apomorphine reduced prepulse inhibition under the same conditions. CONCLUSIONS: These findings with PHNO are in contrast to the less-specific D2 agonist, quinpirole, which has been reported to decrease prepulse inhibition. It is concluded that activation of D2 dopamine receptors alone is not sufficient to attenuate prepulse inhibition of the startle reflex.     

Subnanomolar dopamine D3 receptor antagonism coupled to moderate D2 affinity results in favourable antipsychotic-like activity in rodent models: I. neurochemical characterisation of RG-15

RG-15 (trans-N-{4-[2-[4-(3-cyano-5-trifluoromethyl-phenyl)-piperazine-1-yl]-ethyl]-cyclohexyl}-3-pyridinesulfonic amide dihydrochloride) displayed subnanomolar affinity to human and rat dopamine D₃ receptors (pKi 10.49 and 9.42, respectively) and nanomolar affinity to human and rat D₂ receptors (pKi 8.23 and 7.62, respectively). No apparent interactions were found with the other 44 receptors and four channel sites tested in this study. RG-15 inhibited dopamine-stimulated [³⁵S]GTPγS binding in membranes from rat striatum, in murine A9 cells expressing human D_2L receptors and in CHO cells expressing human D₃ receptors (IC₅₀ values were 21.2, 36.7 and 7.2 nM, respectively). In these tests RG-15 showed the highest affinity toward D₃ receptors when compared to amisulpride, haloperidol and SB-277011. RG-15, similar to haloperidol and amisulpride, dose-dependently inhibited in vivo [³H]raclopride binding in mouse striatum, enhanced dopamine turnover and synthesis rate in mouse and rat striatum and olfactory tubercle. SB-277011 did not change [³H]raclopride binding in mouse striatum nor biosynthesis or turnover rates in either region in mice or rats. RG-15 and haloperidol, but not SB-277011, antagonised dopamine synthesis inhibition induced by the D₃/D₂ full agonist 7-OH-DPAT in GBL-treated mice. RG-15, but not SB-277011, elevated plasma prolactin levels. In vitro receptor binding and functional experiments demonstrated that RG-15 had an antagonist profile on both D₃ and D₂ receptors. with high selectivity for dopamine D₃ receptors over D₂ receptors. However, in vivo, its neurochemical actions were similar to those of D₂ receptor antagonists. Neurochemical comparison of RG-15 with antagonists having a different affinity and selectivity toward D₃ and D₂ receptors indicate that D₃ receptors have little, if any, role in the control of presynaptic dopamine biosynthesis/release in dopaminergic terminal regions.     

Blockage of histamine H1 receptor attenuates social isolation-induced disruption of prepulse inhibition: a study in H1 receptor gene knockout mice

Rationale Histaminergic neurotransmission has been implicated in the pathophysiology of stress-related psychiatric diseases. Although several atypical antipsychotics are potent H1 anagonists, the clinical significance of interaction between atypical antipsychotics and H1 receptors is still unknown.Objective In this study, we investigated the effects of H1 receptors blockage on social isolation-induced behavioral changes in H1 receptor gene knockout (H1KO) mice and their wild-type (WT) mice.Methods Both H1KO and their WT mice were subjected to 4-week social isolation rearing after weaning (21 postnatal days). After the 4-week isolation period, mice behavioral changes were evaluated using behavioral tests.Results Locomotor activity in home cages was significantly lower in isolation-reared WT mice than in socially reared WT mice. However, no change in locomotor activity was observed between socially and isolation-reared H1KO mice. Social isolation significantly impaired prepulse inhibition (PPI) of startle response in WT mice but not in H1KO mice. In addition, social isolation significantly impaired spatial learning and memory in WT mice but not in H1KO mice. Furthermore, H1KO mice treated with methamphetamine (METH) showed no enhancement in isolation-induced disruption of PPI. A neurochemical study revealed that isolation-reared WT mice had significantly lower dopamine (DA) levels and slightly increased DA turnover in the cortex than socially reared WT mice. Conversely, isolation-reared H1KO mice showed significantly higher DA contents as compared with socially reared H1KO mice. Conclusion: The results of our study indicate that blockage of H1 receptor-mediated neurotransmission attenuates social isolation-induced behavioral changes and that the therapeutic effects of atypical antipsychotics are mediated, at least in part, by interaction with H1 receptors in the brain.     

Interaction of corticosterone and nicotine in regulation of prepulse inhibition in mice

The aim of the present study was to investigate if different levels of circulating corticosterone (CORT) modulate the effect of nicotine on prepulse inhibition (PPI), a measure of sensorimotor gating that is disrupted in schizophrenia and other mental illnesses. Four groups of mice were investigated: sham-operated, adrenalectomized (ADX) and implanted with a cholesterol pellet, ADX and implanted with a 10 mg CORT pellet, or ADX and 50 mg of CORT. Different CORT levels or doses of nicotine did not significantly affect startle responses. Baseline PPI was significantly reduced in mice implanted with the highest dose of CORT. In ADX mice implanted with cholesterol, nicotine treatment influenced PPI depending on the prepulse intensity. In ADX mice implanted with 50 mg of CORT, treatment with 10 mg/kg of nicotine caused a significant increase in PPI at all prepulse intensities. Binding studies showed that corticosterone treatment had significantly affected nicotinic acetylcholine receptor (nAChR) density in the mouse brain. Treatment with 50 mg CORT decreased 125I-epibatidine binding in the globus pallidus and 125I-alpha-bungarotoxin binding in the claustrum. These results suggest a possible interaction of corticosterone and nicotine at the level of the alpha4- and alpha7-type nAChR in the regulation of PPI. In situations of high circulating levels of corticosterone, nicotine may be beneficial to restore disruption of PPI.     

Caffeine and prepulse inhibition of the acoustic startle reflex

Rationale: A stimulus presented immediately prior to a startle reflex-eliciting stimulus inhibits the startle reflex. This is termed prepulse inhibition (PPI) and is postulated to index automatic and controlled attentional processing of the prepulse. Objective: Two experiments investigated the effect of 0, 2, and 4 mg/kg oral caffeine on PPI of the acoustic startle eyeblink reflex across stimulus onset asynchronies (SOAs) ranging from 30 to 420 ms. In experiment 1, acoustic prepulses were used and automatic attention was investigated, whereas in experiment 2, acoustic and tactile prepulses were used and automatic and controlled attention was investigated. Controlled attention was investigated by instructing the subjects to attend to one stimulus (attended stimulus) and not to another stimulus (non-attended stimulus). Methods: Caffeine was administrated to human subjects in within-subjects designs (n=24 and n=18). Startle reflexes to 100 dB noise were recorded by electromyography. A mood scale and readings of blood pressure indexed arousal. Results: Caffeine increased the indexes of arousal. There were, however, no significant main effects of caffeine on startle, nor did caffeine significantly interact with any other variable. Attended acoustic prepulses increased PPI at the 120 ms and longer SOAs. Caffeine 4 mg/kg abolished this difference between attended and non-attended stimuli. Attended tactile prepulses facilitated startle at short SOAs, and caffeine reduced facilitation of startle by tactile prepulses. Conclusions: Caffeine did not facilitate automatic attention. Caffeine 4 mg/kg abolished the effect of controlled attention on PPI. Facilitation of startle by attended acoustic prepulses is best explained by facilitation of motoneurons in the facial nucleus. Received: 11 May 1999 / Final version: 1 July 1999     

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.     

Repeated administration of amphetamine induces sensitisation to its disruptive effect on prepulse inhibition in the rat

 Male Sprague-Dawley rats were repeatedly treated with amphetamine (AMP, 1 mg/kg, SC) at 3- day intervals for 15 days and tested for prepulse inhibition of acoustic startle after each treatment. This treatment regimen induced sensitisation in the animals as evidenced by a progressive increase in the disruptive effect of AMP on prepulse inhibition. Persistent changes in brain function was indicated, since an increase in disruptive effect was observed in sensitised animals also after a 22-day-long drug- and test-free period. The development of sensitisation was blocked by pretreatment with haloperidol (HPD, 0.1 mg/kg, SC), which suggests that sensitisation to the disruptive effect of AMP was dependent on dopamine (DA) D₂ receptor activation. Furthermore, the development of sensitisation was blocked by adrenalectomy, which suggests that sensitisation was dependent also on circulating adrenal hormones. Increased DA-ergic activity has been implicated in the pathophysiology of schizophrenia and AMP-induced sensitisation to the neuronal functions that modulate prepulse inhibition may be an experimental model to investigate this hypothesis. Received: 20 May 1997 / Final version: 14 August 1997     

Effects of single and repeated exposure to apomorphine on the acoustic startle reflex and its inhibition by a visual prepulse

The acoustic startle reflex (ASR) is inhibited by startle-irrelevant stimuli that briefly precede reflex elicitation. This effect, prepulse inhibition (PPI), is reduced in strength for animals that have received dopamine agonists, such as apomorphine (APO). Reduction in PPI is most evident for weak masked noise prepulses, thus suggesting that APO disrupts the reception of stimuli to the extent that they present a low signal-to-noise ratio. Here we examine the effect of APO on PPI produced by non-masked visual prepulses. Light flashes were given at two intensities, 40, 70, 110, or 220 ms before ASR elicitation. In phase 1 (5 weeks in duration) half of the animals received one weekly injection of APO (0.5 mg/kg, IP) and one of vehicle (VEH), while the other half received two injections of VEH. Within these groups, half were tested 30 min after the injections, the other half kept test naive (four groups total). In phase 2, following a 4-week rest, all groups were tested after a low dose of APO (0.1 mg/kg) and VEH, 1 week apart. APO eliminated PPI for a dim flash and reduced PPI for a brighter flash to a level normally obtained with the dim flash, while increasing both ASR control values and activity. The bright light was maximally effective at a lead time of 70 ms and APO did not alter this value. Because in general the time of maximal inhibition varies with prepulse intensity for visual stimuli, the finding that the time of the peak remained constant reveals that APO has its effect on inhibition rather than on effective stimulus intensity. In phase 2, APO reduced PPI with no sign of sensitization from past drug exposure. However, APO increased the ASR only in groups previously exposed to APO, indicating behavioral sensitization. The differential effects of repeated exposure on these response measures suggest that neural substrates for the several behavioral effects of APO function at least in part independently.This research was supported by USPHS Research Grants MH00859 and AG09524, and a Center Support Grant to the Center for Visual Science at the University of Rochester, EY01319. A preliminary report of these data was presented at the Meeting of the Society for Neuroscience, Washington DC, November 1993     

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.