Prepulse inhibition predicts working memory performance whilst startle habituation predicts spatial reference memory retention in C57BL/6 mice.

Prepulse inhibition (PPI) of the acoustic startle reflex refers to the attenuation of the startle response to an intense pulse stimulus when it is shortly preceded by a weak non-startling prepulse stimulus. It is a well-established high-throughput translational measure of pre-attentive sensory gating, and its impairment is detected in several neuropsychiatric diseases including schizophrenia. It has been hypothesized that PPI might be associated with, or predictive of, cognitive deficiency in such diseases, and therefore provide an efficient assay for screening drugs with potential pro-cognitive efficacy. Free from any predetermined disease model, the present study evaluated in a homogeneous cohort of inbred C57BL/6 mice the presence of a statistical link between PPI expression and cognitive performance. Performance indices in a spatial reference memory test and a working memory test conducted in the Morris water maze, and contextual fear conditioning were correlated against pre-existing baseline PPI expression. A specific correlative link between working memory and PPI induced by weak (but not strong) prepulse was revealed. In addition, a correlation between habituation of the startle reflex and reference memory was identified for the first time: a stronger overt habituation effect was associated with superior spatial search accuracy. The PPI paradigm thus provides two independent predictors of dissociable cognitive traits in normal C57BL/6 mice; and they might serve as potential markers for high-throughput evaluation of potential cognitive enhancers, especially in the context of schizophrenia where deficits in startle habituation and PPI co-exist.

Nurr1 is not essential for the development of prepulse inhibition deficits induced by prenatal immune activation.

Inflammation-induced disruption of fetal neurodevelopmental processes has been linked to the precipitation of long-lasting behavioral abnormalities and associated neuropathology. Recent longitudinal investigations in prenatal immune activation models have revealed developmental correspondences between the ontogeny of specific dopaminergic neuropathology and the postnatal onset of distinct forms of dopamine-dependent functional abnormalities implicated in schizophrenia. Two examples of such developmental correspondences are increased expression of the orphan nuclear receptor Nurr1 (NR4A2) in ventral midbrain areas and disruption of prepulse inhibition of the acoustic startle reflex, with both the neuroanatomical and behavioral effects emerging only in adult but not pre-pubertal subjects exposed to prenatal maternal inflammation. In the present study, we tested the hypothesis that Nurr1 may be a critical molecular mediator of prepulse inhibition deficits induced by prenatal immune activation. To this end, we compared the effects of prenatal immune challenge on adult PPI in wild-type (wt) mice and mice with a heterozygous constitutive deletion of Nurr1 (Nurr1+/-) using a well established mouse model of maternal immune activation by exposure to the viral mimetic poly(I:C) (=polyriboinosinic-polyribocytidilic acid). We found that prenatal poly(I:C) treatment on gestation day 9 was similarly effective in disrupting prepulse inhibition in adult wt and Nurr1+/- mice. Prenatal poly(I:C) treatment also generally increased midbrain Nurr1-positive cells and counteracted the genetically driven Nurr1 deficit in the substantia nigra. Our data thus suggest that at least under the present experimental conditions, Nurr1 is not essential for the development of prepulse inhibition deficits induced by prenatal immune activation.

Modulation of sensorimotor gating in prepulse inhibition by conditional brain glycine transporter 1 deletion in mice.

Inhibition of glycine transporter 1 (GlyT1) augments N-methyl-D-aspartate receptor (NMDAR)-mediated transmission and represents a potential antipsychotic drug target according to the NMDAR hypofunction hypothesis of schizophrenia. Preclinical evaluation of GlyT1 inhibiting drugs using the prepulse inhibition (PPI) test, however, has yielded mixed outcomes. Here, we tested for the first time the impact of two conditional knockouts of GlyT1 on PPI expression. Complete deletion of GlyT1 in the cerebral cortices confers resistance to PPI disruption induced by the NMDAR blocker MK-801 (0.2mg/kg, i.p.) without affecting PPI expression in unchallenged conditions. In contrast, restricting GlyT1 deletion to neurons in forebrain including the striatum significantly attenuated PPI, and the animals remained sensitive to the PPI-disruptive effect of MK-801 at the same dose. These results demonstrate in mice that depending on the regional and/or cell-type specificity, deletion of the GlyT1 gene could yield divergent effects on PPI.

Limited impact of social isolation on Alzheimer-like symptoms in a triple transgenic mouse model.

Gene-environment interactions are known to play a major role in the ethiopathology of several neuropsychiatric disorders, including Alzheimer's disease (AD). The present study investigates whether environmental manipulations, that is, social isolation, may affect the genetic predisposition to develop AD-related traits in a triple transgenic mouse model (3 x Tg-AD), as suggested by our previous study employing physical exercise (Pietropaolo et al., 2008). Mutant and wild type mice of both sexes were housed singly or in groups from weaning, and evaluated behaviorally at 6 to 7 months of age. Independent of sex, the 3 x Tg-AD genotype was associated with enhanced acoustic startle response, improved performance in the cued version of the water maze and a clear impairment in the Y maze. Notably, the female (but not male) mutant mice showed increased anxiety. Although social isolation was effective in modifying several behaviors, it did not exacerbate any of the AD-like symptoms. Our findings demonstrated the differential susceptibility of the 3 x Tg-AD mouse line to environmental manipulations, showing that social isolation did not induce remarkable effects on the genetically determined AD-like symptoms, in contrast to what previously observed with physical exercise.

Age-dependent phenotypic characteristics of a triple transgenic mouse model of Alzheimer disease.

The triple-transgenic mouse line (3 x Tg-AD) harboring PS1M146V, APPSwe, and taup301L transgenes represents the only transgenic model for Alzheimer's disease (AD) to date capturing both beta-amyloid and tau neuropathology. The present study provides an extensive behavioral characterization of the 3 x Tg-AD mouse line, evaluating the emergence of noncognitive and cognitive AD-like symptoms at two ages corresponding to the early (6-7 months) and advanced (12-13 months) stages of AD-pathology. Enhanced responsiveness to aversive stimulation was detected in mutant mice at both ages: the 3 x Tg-AD genotype enhanced acoustic startle response and facilitated performance in the cued-version of the water maze. These noncognitive phenotypes were accompanied by hyperactivity and reduced locomotor habituation in the open field at the older age. Signs of cognitive aberrations were also detected at both ages, but they were limited to associative learning. The present study suggests that this popular transgenic mouse model of AD has clear phenotypes beyond the cognitive domain, and their potential relationship to the cognitive phenotypes should be further explored.

On the influence of baseline startle reactivity on the indexation of prepulse inhibition.

Prepulse inhibition (PPI) of the startle reflex refers to the reduction of the reflexive startle response to an intense pulse stimulus when its presentation is shortly preceded by a weak prepulse stimulus. PPI is considered as a cross-species translational model of sensorimotor gating, and deficient PPI has been reported in a number of neuropsychiatric disorders. Although a part of the literature is based on the assumption that PPI is independent of the baseline startle reaction, there is accumulating evidence (Csomor et al., 2006; Sandner & Canal, 2007; Yee, Chang, Pietropaolo, & Feldon, 2005) that argues against such an independency. The authors systematically investigated whether PPI indexed as percentage or difference score is dependent on the magnitude of baseline startle reactivity in healthy human volunteers and in C57BL/6 mice. The results revealed that both indexations of PPI were affected by the magnitude of the baseline startle. The authors highlight the pitfalls of different methods to index PPI, especially when startle reactivity differs considerably between groups under comparison, and offer practical recommendations to satisfactorily deal with such baseline differences.

Nonphysical contact between cagemates alleviates the social isolation syndrome in C57BL/6 male mice.

In rodents, social isolation during the early postweaning phase induces several behavioral abnormalities, commonly referred to as the isolation syndrome. We attempted to identify the contribution of the selective deprivation of physical contact to the emergence of the isolation syndrome. To this end, we devised a pseudoisolated housing condition in which male 3-week-old C57BL/6 mice were caged in pairs, but were separated by a transparent perforated partition allowing only nonphysical contact, and compared it with the classical isolation procedure and standard laboratory group housing. Locomotor activity, acoustic startle reactivity, and amphetamine-induced hyperactivity were enhanced by isolation, but neither anxiety nor prepulse inhibition of the acoustic startle response was affected. Pseudoisolated mice were comparable to grouped controls in their acoustic startle response and locomotor reactivity to amphetamine, but they were as active as isolated animals in the predrug sessions of the open field. Furthermore, pseudoisolation also exerted its own unique effects, namely, anxiolysis. Our results demonstrated for the first time the relevance of nonphysical contact including its ability to undermine the emergence of the isolation syndrome in mice.

Haloperidol differentially modulates prepulse inhibition and p50 suppression in healthy humans stratified for low and high gating levels.

Schizophrenia patients exhibit deficits in sensory gating as indexed by reduced prepulse inhibition (PPI) and P50 suppression, which have been linked to psychotic symptom formation and cognitive deficits. Although recent evidence suggests that atypical antipsychotics might be superior over typical antipsychotics in reversing PPI and P50 suppression deficits not only in schizophrenia patients, but also in healthy volunteers exhibiting low levels of PPI, the impact of typical antipsychotics on these gating measures is less clear. To explore the impact of the dopamine D2-like receptor system on gating and cognition, the acute effects of haloperidol on PPI, P50 suppression, and cognition were assessed in 26 healthy male volunteers split into subgroups having low vs high PPI or P50 suppression levels using a placebo-controlled within-subject design. Haloperidol failed to increase PPI in subjects exhibiting low levels of PPI, but attenuated PPI in those subjects with high sensorimotor gating levels. Furthermore, haloperidol increased P50 suppression in subjects exhibiting low P50 gating and disrupted P50 suppression in individuals expressing high P50 gating levels. Independently of drug condition, high PPI levels were associated with superior strategy formation and execution times in a subset of cognitive tests. Moreover, haloperidol impaired spatial working memory performance and planning ability. These findings suggest that dopamine D2-like receptors are critically involved in the modulation of P50 suppression in healthy volunteers, and to a lesser extent also in PPI among subjects expressing high sensorimotor gating levels. Furthermore, the results suggest a relation between sensorimotor gating and working memory performance.

Adult brain and behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice.

Maternal infection during pregnancy increases the risk for neurodevelopmental disorders such as schizophrenia and autism in the offspring. This association appears to be critically dependent on the precise prenatal timing. However, the extent to which distinct adult psychopathological and neuropathological traits may be sensitive to the precise times of prenatal immune activation remains to be further characterized. Here, we evaluated in a mouse model of prenatal immune challenge by the viral mimic, polyriboinosinic-polyribocytidilic acid (PolyIC), whether prenatal immune activation in early/middle and late gestation may influence the susceptibility to some of the critical cognitive, pharmacological, and neuroanatomical dysfunctions implicated in schizophrenia and autism. We revealed that PolyIC-induced prenatal immune challenge on gestation day (GD) 9 but not GD17 significantly impaired sensorimotor gating and reduced prefrontal dopamine D1 receptors in adulthood, whereas prenatal immune activation specifically in late gestation impaired working memory, potentiated the locomotor reaction to the NMDA-receptor antagonist dizocilpine, and reduced hippocampal NMDA-receptor subunit 1 expression. On the other hand, potentiation of the locomotor reaction to the dopamine-receptor agonist amphetamine and reduction in Reelin- and Parvalbumin-expressing prefrontal neurons emerged independently of the precise times of prenatal immune challenge. Our findings thus highlight that prenatal immune challenge during early/middle and late fetal development in mice leads to distinct brain and behavioral pathological symptom clusters in adulthood. Further examination and evaluation of in utero immune challenge at different times of gestation may provide important new insight into the neuroimmunological and neuropathological mechanisms underlying the segregation of different symptom clusters in heterogeneous neuropsychiatric disorders such as schizophrenia and autism.

Prenatal dexamethasone exposure, postnatal development, and adulthood prepulse inhibition and latent inhibition in Wistar rats.

Prenatal stress is an important risk factor in schizophrenia, and the aetiological factors mediating this relationship are central to the neurodevelopmental hypothesis of schizophrenia. The glucocorticoid receptor (GR) agonist dexamethasone (DEX) is commonly prescribed for prenatal conditions, and results in GR activation, which is part of the stress response. To investigate animal evidence for whether prenatal DEX leads to development of schizophrenia-like phenotypes, Wistar rats were prenatally exposed to DEX (0.1mg/kg/day) between the gestational days 15 and 21, and tested in two paradigms known to be disrupted in schizophrenia patients: prepulse inhibition (PPI) and latent inhibition (LI). A cross-fostering design was used to allow dissociation of any direct prenatal effects on offspring from effects dependent on DEX exposure of the rearing dam. Pup birth weight was reduced by prenatal DEX treatment. DEX-treated dams demonstrated increased pup-directed behaviour. There were additive effects of prenatal DEX treatment and DEX treatment of rearing dam in terms of reduced body weight in adulthood. In one of two replications, PPI was increased by prenatal DEX in males only and specific to the highest prepulse intensity. There was no evidence that LI was disrupted by prenatal DEX treatment. This study does not provide support for the hypothesis that prenatal DEX exposure leads to schizophrenia-like deficits in PPI or LI, suggesting that GR prenatal programming is not a mechanism of direct relevance to the neurodevelopmental hypothesis of schizophrenia.

The monotonic dependency of prepulse inhibition of the acoustic startle reflex on the intensity of the startle-eliciting stimulus.

Prepulse inhibition (PPI) of the acoustic startle reflex is a translational behavioural paradigm for the assessment of sensorimotor gating deficit which has been demonstrated in a number of neuropsychiatric conditions. PPI refers to the reduction of the reflexive startle response to a 'pulse' stimulus when its presentation is shortly preceded by a weak 'prepulse' stimulus. We have recently examined the expression of PPI as a function of the startle-eliciting 'pulse' stimulus intensity in mice and in humans. One major discrepancy that emerged was the finding that healthy human subjects, unlike normal mice, did not show a clear monotonic reduction of PPI magnitude (as indexed by % reduction in startle reactivity) with increasingly intense pulse stimulus. This lack of correspondence between species may potentially weaken the translational power of the PPI paradigm. Here, we re-examined this issue in 31 healthy subjects across three levels of pulse stimulus intensity (95, 105 and 115 dB). A clear linear reduction of PPI as a function of pulse intensity was revealed when subjects failing to respond to the lowest pulse stimulus were excluded. Inclusion of such non-responders, on the other hand, resulted in a trend towards an inverted U-shape function as reported previously. The present study thus clarifies an apparent divergence between mouse and man, and provides important qualification to the "First Law of Reflex Modification" proposed by Hoffman and Ison which suggests that the absolute reduction in startle reactivity resulting from a prepulse stimulus preceding the startle-eliciting pulse stimulus is fixed by the prepulse intensity regardless of the pulse stimulus intensity.

Prenatal and postnatal maternal contributions in the infection model of schizophrenia.

Epidemiological studies have indicated that the risk of schizophrenia is enhanced by prenatal maternal infection with viral or bacterial pathogens. Recent experimentation in rodents has yielded additional support for a causal relationship between prenatal immune challenge and the emergence of psychosis-related abnormalities in brain and behaviour in later life. However, little is known about the putative roles of maternal postnatal factors in triggering and modulating the emergence of psychopathology following prenatal immunological stimulation. Here, we aimed to dissect the relative contributions of prenatal inflammatory events and postnatal maternal factors in precipitating juvenile and adult psychopathology in the resulting offspring with a cross-fostering design. Pregnant mice were exposed to the viral mimic, polyriboinosinic-polyribocytidilic acid (PolyI:C; at 5 mg/kg, intravenously), or vehicle treatment on gestation day 9, and offspring born to PolyI:C- and vehicle-treated dams were then simultaneously cross-fostered to surrogate rearing mothers, which had either experienced inflammatory or vehicle treatment during pregnancy. Prenatal PolyI:C administration did not affect the expression of latent inhibition (LI) at a juvenile stage of development, but led to the post-pubertal emergence of LI disruption in both aversive classical and instrumental conditioning regardless of the postnatal rearing condition. In addition, deficits in conditioning as such led to a pre- and post-pubertal loss of LI in prenatal control animals that were adopted by PolyI:C-treated surrogate mothers. Our findings thus indicate that the adoption of prenatally immune-challenged neonates by control surrogate mothers does not possess any protective effects against the subsequent emergence of psychopathology in adulthood. At the same time, however, the present study highlights for the first time that the adoption of prenatal control animals by immune-challenged rearing mothers is sufficient to precipitate learning disabilities in the juvenile and adult offspring.

Withdrawal from continuous amphetamine administration abolishes latent inhibition but leaves prepulse inhibition intact.

RATIONALE: Schizophrenia has been associated with dysregulation of dopamine (DA) transmission and impairment in a number of experimental tasks, including sensorimotor gating assessed using prepulse inhibition (PPI) and selective attention assessed using latent inhibition (LI). We have demonstrated in previous studies that after withdrawal from escalating (ESC) dosages of amphetamine (AMPH), animals exhibited disruption of LI but no alteration of PPI. Moreover, these animals always showed behavioural sensitization to an AMPH challenge. OBJECTIVE: In this study, we were interested in testing whether a different administration schedule would elicit disruption of both LI and PPI. METHODS: Animals were treated with continuous AMPH release (via osmotic mini-pumps at a dosage of 10 mg kg(-1) day(-1) for 7 days) and tested for their performance in L and PPI during withdrawal in a drug free state. Rats received AMPH treatment during the induction phase in their home cages or in the activity chambers. Following withdrawal, the expression of behavioural sensitization to an AMPH challenge was tested in both cases in the activity chambers. RESULTS: Animals pretreated with AMPH from both groups did not exhibit behavioural sensitization. Withdrawal from continuous administration induced LI attenuation with no effect on PPI. CONCLUSIONS: These findings are similar to what was previously found with respect to an ESC AMPH regime. The only difference between the schedules was that the ESC AMPH schedule led to behavioural sensitization whereas the continuous AMPH did not. It is suggested that the expression of sensitization may not be a prerequisite for observed LI disruption.

The expression of prepulse inhibition of the acoustic startle reflex as a function of three pulse stimulus intensities, three prepulse stimulus intensities, and three levels of startle responsiveness in C57BL6/J mice.

Using the acoustic startle reflex, prepulse inhibition (PPI) is typically demonstrated by the interaction between two auditory stimuli presented in close temporal proximity. When a startle-eliciting pulse stimulus is shortly preceded by a weak prepulse stimulus, the reaction to the former is attenuated in comparison to when the pulse stimulus is presented alone. The present experiment evaluated the influence of different prepulse and pulse intensities upon the expression of PPI by additionally taking into account individual differences in startle reactivity. To this end, we subdivided a cohort of 102 mice into three subsets of equal size differing in startle responsiveness, and evaluated PPI using three levels of prepulse stimulus in combination with three intensities of pulse stimulus. Our results revealed additive as well as complex interactive effects amongst individual's reactivity, pulse intensity and prepulse intensity. At the same time, additional issues concerning the quantification of PPI are highlighted, especially when startle reactivity differs considerably between comparison groups. We concluded that the variation in pulse intensity represents a valuable addition to PPI assessment in general, and especially in genetically modified mice.

On the feasibility to detect and to quantify prepulse-elicited reaction in prepulse inhibition of the acoustic startle reflex in humans.

The possibility that the prepulse stimulus typically employed in the studies of prepulse inhibition (PPI) can produce observable response has been questioned recently. Conflicting reports range from observations of prepulse-elicited startle reaction to a complete lack of detectable prepulse-elicited reactions in healthy volunteers. This controversy is subjected to critical examination in the present study. The ability of prepulse stimuli to induce PPI and to elicit measurable responses was examined in two separate experiments using prepulses ranging from 6 to 18dB above background (experiment 1), or 1 to 5dB above background (experiment 2). Three levels of pulse stimulus were employed: 95, 105 and 115dBA. Clear PPI and prepulse-elicited reaction were obtained in experiment 1, while neither effect was evident in experiment 2. Non-startle-eliciting prepulses that are of sufficient intensities to induce reliable PPI are associated with detectable and quantifiable response, confirming that direct evaluation of prepulse-processing is feasible and practical. This provides an additional measure of theoretical and potentially clinical relevance to PPI, and it ought to be included in future studies in patients as well as healthy subjects.

Acoustic startle response, prepulse inhibition, and spontaneous locomotor activity in MPTP-treated mice.

Parkinson's disease (PD) is marked by characterised motor deficits and is accompanied by a severe degeneration of the nigrostriatal dopamine (DA) pathway. It has also been reported that PD patients exhibited additional behavioural deficits, including a deficiency in sensorimotor gating mechanisms. We therefore examined whether the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD in mice could lead to a sensorimotor gating deficit in the prepulse inhibition (PPI) of the acoustic startle response (ASR) paradigm. Two MPTP treatment schedules were separately examined here in male C57BL/6 mice. Post-mortem HPLC analysis confirmed that they were effective in depleting DA in the dorsal striatum (75-88%). PPI was evaluated on days 2, 9 and 16 after the last MPTP treatment; spontaneous locomotor activity was assessed 24 h before each PPI test. No significant change in the expression of PPI was detected across the three time points. On the other hand, the MPTP treatment reduced activity on post-treatment day 1. This effect subsided on post-treatment day 8, and was reversed on day 15. The possibility remains therefore that the reported sensorimotor gating deficits in PD patients might stem from structural or neurochemical aberrations beyond those induced by MPTP treatment.

The prenatal methylazoxymethanol acetate treatment: a neurodevelopmental animal model for schizophrenia?

The prenatal methylazoxymethanol acetate (MAM) treatment has been proposed as a suitable model for the neurodevelopmental aspects of schizophrenia since the morphological abnormalities it induces in the brain are subtle and in line with most reports of neuropathology in schizophrenic brains. However, the functional aspects of this treatment have not been investigated with behavioural paradigms that are relevant for the psychopathology of the symptoms of schizophrenia. In the present study, we investigated the validity of the prenatal MAM treatment as a developmental model for schizophrenia with a prepulse inhibition of the acoustic startle reflex, latent inhibition, locomotor activity, and cognition and emotionality with freezing in fear conditioning paradigms. We have conducted two studies: in Study I, MAM was injected from E09 to E12, and in Study II MAM was administered at later stages in the embryonic development, from E12 to E15. Morphologically, the prenatal MAM treatment induced mild to severe reduction in brain weights and in the entorhinal cortex, prefrontal cortex and striatum volumes, the severity of the effects depending on the timing of administration. However, despite the morphological abnormalities induced by the MAM treatments, no behavioural deficits were observed in the MAM-treated animals when compared to Controls in prepulse inhibition, latent inhibition with the two-way active avoidance, and in the freezing paradigms. Therefore, due to the consistent lack of treatment effect observed in the present investigation, we conclude that the prenatal MAM treatment has no validity as a behavioural model for schizophrenia.

The Effects of dizocilpine and phencyclidine on prepulse inhibition of the acoustic startle reflex and on prepulse-elicited reactivity in C57BL6 mice.

Prepulse inhibition (PPI) of the acoustic startle response refers to the reduction in startle reaction to a startle-eliciting stimulus when it is shortly preceded by a subthreshold prepulse stimulus. Here, we evaluated the possible effects on prepulse-elicited reactivity by dizocilpine (MK-801) and phencyclidine (PCP) in the PPI of acoustic startle paradigm in C57BL6/J mice. The aim was to ascertain whether these two drugs would affect prepulse-elicited reactivity in a manner similar to apomorphine, which enhances prepulse-elicited reactivity at doses that disrupt PPI. In two dose-response studies, we showed that both drugs exhibited a tendency to attenuate prepulse-elicited reaction at higher doses when PPI was severely disrupted. On the other hand, at lower doses when PPI was marginally disrupted, reaction to the prepulse, if anything, tended to increase. It is concluded that PPI disruption induced by noncompetitive NMDA receptor antagonists can be distinguished from apomorphine-induced PPI disruption by their concomitant effects on prepulse-elicited reactivity. Our data support the suggestion that dopamine receptor agonists and NMDA receptor antagonists disrupt PPI via interference with distinct neural pathways or neuronal systems.

Apomorphine-induced prepulse inhibition disruption is associated with a paradoxical enhancement of prepulse stimulus reactivity.

Prepulse inhibition (PPI) refers to the reduction in startle reaction to a startle-eliciting stimulus when it is shortly preceded by a subthreshold prepulse stimulus. PPI has been extensively employed as an assay for sensorimotor gating, and its disruption has been characterized in specific disease conditions, including schizophrenia. In animals, dopamine agonists disrupt PPI, and this disruption can be antagonized by antipsychotic drug treatment. The present study extended these fundamental findings to C57BL6 mice, and further evaluated the subjects' reaction to the prepulse stimulus alone in relation to the expression of PPI. Not only did apomorphine (2.0 mg/kg, intraperitoneal (i.p.)) attenuate PPI but it also enhanced reactivity to the prepulse stimulus. The dual effects of apomorphine appear paradoxical in view of the positive correlation, detectable in both the control and apomorphine groups, between prepulse reactivity and PPI magnitude. The present findings contradict the hypothesis that apomorphine disrupts PPI via reduced detectability or perception of the prepulse, and we further propose that enhanced distractibility may provide a parsimonious account for the dual effects of apomorphine. Moreover, haloperidol pretreatment (0.4 mg/kg, i.p.) fully antagonized the effects of apomorphine upon prepulse reactivity as well as on PPI. The present results add to our understanding of the relevance and applicability of the PPI paradigm in modeling schizophrenia-like symptoms in animals.

Prepulse inhibition during withdrawal from an escalating dosage schedule of amphetamine.

RATIONALE: Psychomotor stimulants can induce psychotic states in humans that closely resemble those observed in patients with idiopathic schizophrenia. Attentional and sensorimotor gating impairments are observed in schizophrenic patients using the latent inhibition (LI) and prepulse inhibition (PPI) behavioral assays, respectively. Our previous studies demonstrated that after 4 days of withdrawal from a period of amphetamine (AMPH) administration, animals exhibited disrupted LI but normal PPI. OBJECTIVE: The aim of the present study was to test PPI in AMPH-withdrawn rats under experimental conditions similar to those used to best demonstrate locomotor sensitization following AMPH withdrawal. METHODS: We examined the effects on PPI of (1) pairing drug injections with PPI test-associated cues, (2) administration of a low-dose dopamine agonist challenge and (3) testing following longer withdrawal periods (23, 30, 60 days). RESULTS: Although none of these conditions revealed a disruption of PPI in AMPH-withdrawn rats, we did observe that the acoustic startle response was reduced during a restricted time period following AMPH withdrawal. Similar to our previous findings, AMPH-withdrawn animals showed disrupted LI on day 16 of withdrawal and locomotor sensitization to a challenge injection of AMPH after 62 days of withdrawal. CONCLUSION: We conclude that the effects of repeated AMPH on PPI are not modulated by the same experimental parameters known to be important for eliciting locomotor sensitization and that withdrawal from the schedule of AMPH administration used in this study models only specific cognitive dysfunctions linked to schizophrenic symptoms, since LI was disrupted but PPI was not affected.