Prepulse Inhibition Measures Research Articles

Neurophysiological differentiation of personality disorders

The neurophysiological objectification of intranosological differentiation of main clusters (schizoid/paranoid and hysterical/emotionally unstable) within the typology of personality disorders (PD), as well as the differentiation of schizoid/paranoid PD and schizophrenia. Two groups of patients with PD participated in the study: PD1 - with schizoid/paranoid pattern (n=16), and PD2 - with hysterical/emotionally unstable pattern (n=18). The data were compared with the control group of healthy volunteers (n=86) and the group of schizophrenic patients (Sz, n=67). The analysis of four neurophysiological endophenotypes (measures of prepulse inhibition (PPI) of acoustic startle response and of P50 suppression, P300 amplitude, percentage of antisaccade errors) was carried out. The decrease of PPI and P50 suppression (measures of sensorimotor and sensory gating) relative to the control group was found both for Sz (p<0.01) and PD1 (p<0.05) groups. The highest P300 amplitude was observed in the control group, while the lowest values were observed in the Sz group (p<0.001); the values of PD1 and PD2 groups were intermediate. In all clinical groups percent of antisaccade errors was significantly higher compared to the control group (Sz - p<0.001; PD1 - p<0.05; PD2 - p<0.01). However, the level of the fronto-central cortical activation during antisaccade performance (estimated by contingent negative variation amplitude) was significantly reduced only in the Sz group (p<0.01), which is consistent with the concept of «hypofrontality» in schizophrenia. The changes associated with increased emotional reactivity were found in PD2 group only (P300 amplitude frontal maximum, asymmetry of error percent in antisaccade task). The study showed that two personality patterns in PD patients are related to the individual specificity of functional brain networks.

Tinnitus development is associated with synaptopathy of inner hair cells in Mongolian gerbils.

Human hearing loss (HL) is often accompanied by comorbidities like tinnitus, which is affecting up to 15% of the adult population. Rodent animal studies could show that tinnitus may not only be a result of apparent HL due to cochlear hair cell damage but can also be a consequence of synaptopathy at the inner hair cells (IHCs) already induced by moderate sound traumata. Here, we investigate synaptopathy previously shown in mice in our animal model, the Mongolian gerbil, and relate it to behavioral signs of tinnitus. Tinnitus was induced by a mild monaural acoustic trauma leading to monaural noise induced HL in the animals, quantified by auditory brainstem response (ABR) audiometry. Behavioral signs of tinnitus percepts were detected by measurement of prepulse inhibition of the acoustic startle response in a gap-noise paradigm. Fourteen days after trauma, the cochleae of both ears were isolated, and IHC synapses were counted within several spectral regions of the cochlea. Behavioral signs of tinnitus were only found in animals with IHC synaptopathy, independent of type of HL. On the other hand, animals with apparent HL but without behavioral signs of tinnitus showed a reduction in amplitudes of ABR waves I&II but no significant changes in the number of synapses at the IHC. We conclude-in line with the literature-that HL is caused by damage to the IHC or by other reasons but that the development of tinnitus, at least in our animal model, is closely linked to synaptopathy at the IHC.

T39. IMPAIRED SENSORIMOTOR GATING USING THE ACOUSTIC PREPULSE INHIBITION PARADIGM IN INDIVIDUALS AT A CLINICAL HIGH RISK FOR PSYCHOSIS

BackgroundMany robust studies on prepulse inhibition (PPI) were conducted in patients with schizophrenia, and, increasingly, evidence has indicated individuals who are at clinical high risk for psychosis (CHR). The specificity of the PPI is insufficient with the classic paradigm. The current study investigated an improved perceived spatial separation PPI (PSSPPI) paradigm in CHR individuals, compared with patients of first-episode schizophrenia (FES) and healthy controls (HC), and the relationship between PPI, demographics, clinical characteristics, and cognitive performance.MethodsWe included 53 FESs, 55 CHR individuals, and 53 HCs. CHRs were rated on the Structured Interview for Prodromal Syndromes (SIPS). The prepulse inhibition measures of perceived spatial co-location PPI (PSCPPI) and PSSPPI paradigms were applied using 60- and 120-ms lead intervals. The MATRICS Consensus Cognitive Battery (MCCB) was used to assess neurocognitive functions.ResultsCompared with HC, the CHR group had lower PSSPPI level (ISI=60 ms, P<0.001; ISI=120 ms, P<.001). PSSPPI showed a large effect size (ES) between CHR and HC (ISI=60 ms, ES=0.91; ISI=120 ms, ES=0.98); on PSSPPI using 60-ms lead interval, ES ranged from small to large from CHR to FES. PPI deficits in CHR were unrelated to demographics, clinical characteristics, and cognition.DiscussionCHR individuals show a sensorimotor gating deficit similar to FES patients on PSSPPI of the startle response, with greater sensitivity than the classic PPI paradigm. PSSPPI appears a promising objective approach for identifying individuals at clinical high risk for psychosis related to a high risk of transition to schizophrenia.

Deficits of perceived spatial separation-induced prepulse inhibition in patients with bipolar disorder compared to healthy controls

ObjectiveThis study aimed to assess sensorimotor gating deficits in patients with bipolar disorder (BD) using a modified perceived spatial separation-induced prepulse inhibition (PSS-PPI) paradigm. The relationships between PSS-PPI, demographic and clinical characteristics, and cognitive functioning were also analyzed. MethodsIn this cross-sectional study, 30 patients with BD were compared to 33 healthy controls (HC) with respect to prepulse inhibition measures of PSS-PPI using a 120 ms lead interval. The Young Mania Rating Scale, Hamilton Depression Scale, and Hamilton Anxiety Scale were used to assess manic, depressive, and anxiety symptoms. Cognition was evaluated using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Stroop color-word test. ResultsCompared with HC, patients with BD had a lower PSS-PPI level. PSS-PPI showed medium effect size (ES) between patients with BD and HC (ES = 0.65). Among patients with BD, PSS-PPI was positively correlated with the language domain of RBANS and negatively correlated with double word time and color interference time. There were no differences in PSS-PPI levels between patients with and without psychotic symptoms or between those euthymic patients or depressive patients with BD. ConclusionsPatients with BD show a sensorimotor gating deficit as measured by perceived spatial separation-induced PPI of the startle response, which was more sensitive compared to the classic PPI paradigm. Euthymic bipolar patients and depressive bipolar patients show similar PPI level. PPI deficit in patients with BD is related to cognition, but not with demographic and clinical characteristics.

Progression of temporal processing deficits in the HIV-1 transgenic rat.

The HIV-1 transgenic (Tg) rat, which expresses 7 of the 9 HIV-1 genes, was used to investigate the effect(s) of long-term HIV-1 viral protein exposure on chronic neurocognitive deficits observed in pediatric HIV-1 (PHIV). A longitudinal experimental design was used to assess the progression of temporal processing deficits, a potential underlying dimension of neurocognitive impairment in HIV-1. Gap prepulse inhibition (gap-PPI), a translational experimental paradigm, was conducted every thirty days from postnatal day (PD) 30 to PD 180. HIV-1 Tg animals, regardless of sex, displayed profound alterations in the development of temporal processing, assessed using prepulse inhibition. A differential sensitivity to the manipulation of interstimulus interval was observed in HIV-1 Tg animals in comparison to control animals. Moreover, presence of the HIV-1 transgene was diagnosed with 90.8% accuracy using measures of prepulse inhibition and temporal sensitivity. Progression of temporal processing deficits in the HIV-1 Tg rat affords a relatively untapped opportunity to increase our mechanistic understanding of the role of long-term exposure to HIV-1 viral proteins, observed in pediatric HIV-1, in the development of chronic neurological impairment, as well as suggesting an innovative clinical diagnostic screening tool.

Effects of acute memantine administration on MATRICS Consensus Cognitive Battery performance in psychosis: Testing an experimental medicine strategy.

Pro-cognitive agents for chronic psychotic disorders (CPDs) might be detected via experimental medicine models, in which neural targets engaged by the drug predict sensitivity to the drug's pro-cognitive effects. This study aims to use an experimental medicine model to test the hypothesis that "target engagement" predicts pro-cognitive effects of the NMDA antagonist, memantine (MEM), in CPDs. MATRICS Consensus Cognitive Battery (MCCB) performance was assessed in CPD (n = 41) and healthy subjects (HS; n = 41) in a double-blind, randomized cross-over design of acute (single dose) MEM (placebo vs. 10 or 20mg p.o.). Measures of prepulse inhibition (PPI) and mismatch negativity previously reported from this cohort substantiated target engagement. Biomarkers predicting MEM neurocognitive sensitivity were assessed. Testing confirmed MCCB deficits associated with CPD diagnosis, age, and anticholinergic exposure. MEM (20mg p.o.) reduced MCCB performance in HS. To control for significant test order effects, an "order-corrected MEM effect" (OCME) was calculated. In CPD subjects, greater age, positive MEM effects on PPI, and SNP rs1337697 (within the ionotropic NMDA receptor gene, GRIN3A) predicted greater positive OCME with 20mg MEM. An experimental medicine model to assess acute pro-cognitive drug effects in CPD subjects is feasible but not without challenges. A single MEM 20mg dose had a negative impact on neurocognition among HS. In CPD patients, age, MEM effects on PPI, and rs1337697 predicted sensitivity to the neurocognitive effects of MEM. Any potential clinical utility of these predictive markers for pro-cognitive effects of MEM in subgroups of CPD patients cannot be inferred without a validating clinical trial.

Impaired prepulse inhibition of acoustic startle in Chinese patients with first-episode, medication-naïve schizophrenia

Background Patients with schizophrenia have prominent abnormality in information processing that can be observed by measures of prepulse inhibition (PPI) of acoustic startle reflex and PPI deficits have been considered as a candidate endophenotypic marker of schizophrenia. However, there has been little information on PPI and related measures in Chinese patients with schizophrenia. The research was to explore the deficits of acoustic startle reflex that might exist in Chinese patients with schizophrenia. Methods Startle response to acoustic stimuli, habituation, and PPI were examined in 31 Chinese patients with first-episode, medication-naïve schizophrenia and 30 age- and sex- matched healthy Chinese controls. At the same day of startle testing, psychopathological symptoms of the patients were assessed with the Positive and Negative Syndrome Scale (PANSS). Results Compared with healthy controls, patients exhibited the significant reduction in startle response and PPI deficits at 60 milliseconds (ms) intervals (PPI60, P &lt;0.05) but not at 30 or 120 ms intervals. Furthermore, there was a relatively strong correlation between PPI60 (P &lt;0.05) and scores of positive scale of PANSS in patients with schizophrenia. Conclusion Our findings confirmed impaired PPI in Chinese patients with schizophrenia and suggested that a relationship between sensorimotor gating deficits and clinical symptoms of patients with schizophrenia might exist.

Prepulse inhibition and genetic mouse models of schizophrenia

Mutant mouse models related to schizophrenia have been based primarily on the pathophysiology of schizophrenia, the known effects of antipsychotic drugs, and candidate genes for schizophrenia. Sensorimotor gating deficits in schizophrenia patients, as indexed by measures of prepulse inhibition of startle (PPI), have been well characterized and suggested to meet the criteria as a useful endophenotype in human genetic studies. PPI refers to the ability of a non-startling “prepulse” to inhibit responding to the subsequent startling stimulus or “pulse.” Because of the cross-species nature of PPI, it has been used primarily in pharmacological animal models to screen putative antipsychotic medications. As techniques in molecular genetics have progressed over the past 15 years, PPI has emerged as a phenotype used in assessing genetic mouse models of relevance to schizophrenia. In this review, we provide a selected overview of the use of PPI in mouse models of schizophrenia and discuss the contribution and usefulness of PPI as a phenotype in the context of genetic mouse models. To that end, we discuss mutant mice generated to address hypotheses regarding the pathophysiology of schizophrenia and candidate genes (i.e., hypothesis driven). We also briefly discuss the usefulness of PPI in phenotype-driven approaches in which a PPI phenotype could lead to “bottom up” approaches of identifying novel genes of relevance to PPI (i.e., hypothesis generating).

Correlation between prepulse inhibition and cortical perfusion during an attentional test in schizophrenia: A pilot study

Background Processes underlying cortical hypoactivation in schizophrenia are poorly understood but some evidence suggests that a deficient sensory filtering is associated with the condition. This filtering deficit can be studied by using measures of prepulse inhibition (PPI) of the startle reflex. Objective To evaluate the contribution of sensory filtering deficits to cortical hypoperfusion during an attention test in schizophrenia. Method Measurements of PPI of the startle reflex and perfusion during the performance of a Stroop test (assessed with single photon emission tomography) were obtained in 10 acutely treated schizophrenia patients (6 with recent onset, RO) and 16 control subjects. These measurements were compared between patients and controls and the correlation between PPI and perfusion was evaluated within each group, using Statistical Parametric Mapping. Results In comparison with normal subjects, the patients exhibited lower PPI, although the difference was not statistically significant. Perfusion was significantly lower in the prefrontal and premotor regions of the patients. In the patient group, a statistically significant difference was observed between PPI and perfusion in the parietal, premotor, and cingulate regions. When the associations were analyzed in the RO patients alone, a positive correlation was also found between prefrontal perfusion and PPI, while anterior hippocampal perfusion was inversely related to PPI. Conclusions These results support the notion that deficient sensory-motor filtering is associated with decreased cortical task-related activation in schizophrenia.

Modality-Specific Attention Under Imminent But Not Remote Threat of Shock

Theories of animal defensive behavior postulate that imminent, predictable threat elicits highly focused attention toward the threat source, whereas remote, unpredictable threat elicits distributed attention to the overall environment. We used threat of shock combined with measurement of prepulse inhibition of the startle reflex to test these claims in humans. Twenty-seven participants experienced periods of threat and safety. Threat and safe periods were short or long, with the short threat periods conveying relatively predictable, imminent shocks and the long threat periods conveying unpredictable shocks. Startle reflexes were elicited with equal numbers of acoustic probes presented alone, preceded by a tactile prepulse, or preceded by an auditory prepulse. We observed enhanced tactile relative to auditory prepulse inhibition during short threat periods only. This finding supports the notion that imminent threat, but not remote threat, elicits attention focused toward the relevant modality, potentially reflecting preparatory activity to minimize the impact of the noxious stimulus.

The chakragati mouse shows deficits in prepulse inhibition of acoustic startle and latent inhibition

The chakragati ( ckr) mouse, which was serendipitously created as a result of a transgenic insertional mutation, has been proposed as a model of aspects of schizophrenia. The mice exhibit circling, hyperactivity, reduced social interactions, and enlarged lateral ventricles, which parallel aspects of the pathophysiology of schizophrenia. Deficits in sensorimotor gating and processing of the relevance of stimuli are core features of schizophrenia, which underlie many of the symptoms presented. Measures of prepulse inhibition (PPI) and latent inhibition (LI) can assess sensorimotor gating and processing of relevance in both humans and animal models. We investigated PPI of acoustic startle and LI of aversive conditioning in wild-type, heterozygous, and ckr mice. The ckr mice, which are homozygous for the transgene insertion, but not heterozygous littermates, showed impaired PPI in the absence of any difference in acoustic startle amplitude and showed deficits in LI of conditioning of a light stimulus to footshock, measured as suppression of licking for water in water-restricted mice. Together with the previous evidence for hyperactivity, reduced social interactions, and enlarged lateral ventricles, these data lend further support to the suggestion that the ckr mouse has utility as an animal model of aspects of schizophrenia.

Initial heritability analyses of endophenotypic measures for schizophrenia: the consortium on the genetics of schizophrenia.

Exploration of the genetic architecture of specific endophenotypes may be a powerful strategy for understanding the genetic basis of schizophrenia. To characterize the genetic architecture of some key endophenotypic measures selected for their reported heritabilities in schizophrenia. Family-based heritability study. Seven sites across the United States. At the time of these initial data analyses, the members of 183 nuclear families ascertained through probands with schizophrenia had been assessed for these endophenotypes. Variance component models were used to assess the heritability of and the environmental and genetic correlations among the endophenotypes. The Consortium on the Genetics of Schizophrenia assesses the neurophysiologic measures of prepulse inhibition of acoustic startle, P50 event-related potential suppression, and the antisaccade task for eye movements and the neurocognitive measures of the Continuous Performance Test (Degraded Stimulus version), the California Verbal Learning Test, the Letter-Number Sequencing test, and 6 measures from the University of Pennsylvania Computerized Neurocognitive Battery. The heritabilities of these 12 measures are the focus of this article. All of the endophenotypes and the University of Pennsylvania Computerized Neurocognitive Battery measures were found to be significantly heritable (P < or = .005), with heritabilities ranging from 24% to 55%. Significant environmental and genetic correlations were also observed between many of the endophenotypic measures. This is the first large-scale, multisite, family-based heritability study of a collection of endophenotypes for schizophrenia and suggests that endophenotypes are important measures to consider in characterizing the genetic basis of schizophrenia.

Disrupted sensory gating in pathological gambling

Background Some neurochemical evidence as well as recent studies on molecular genetics suggest that pathologic gambling may be related to dysregulated dopamine neurotransmission. Methods The current study examined sensory (motor) gating in pathologic gamblers as a putative measure of endogenous brain dopamine activity with prepulse inhibition of the acoustic startle eye-blink response and the auditory P300 event-related potential. Seventeen pathologic gamblers and 21 age- and gender-matched healthy control subjects were assessed. Both prepulse inhibition measures were recorded under passive listening and two-tone prepulse discrimination conditions. Results Compared to the control group, pathologic gamblers exhibited disrupted sensory (motor) gating on all measures of prepulse inhibition. Sensory motor gating deficits of eye-blink responses were most profound at 120-millisecond prepulse lead intervals in the passive listening task and at 240-millisecond prepulse lead intervals in the two-tone prepulse discrimination task. Sensory gating of P300 was also impaired in pathologic gamblers, particularly at 500-millisecond lead intervals, when performing the discrimination task on the prepulse. Conclusions In the context of preclinical studies on the disruptive effects of dopamine agonists on prepulse inhibition, our findings suggest increased endogenous brain dopamine activity in pathologic gambling in line with previous neurobiological findings.

Impact of prepulse characteristics on the detection of sensorimotor gating deficits in schizophrenia

Schizophrenia patients have prominent deficits in information processing that can be detected by measures of prepulse inhibition (PPI) of the startle response. Deficient PPI in schizophrenia is thought to reflect a failure of brain-based information ‘protective’ mechanisms that normally inhibit responsivity for 30–500 ms after a weak prepulse stimulus. The relationship between specific prepulse stimulus characteristics and PPI deficits in this study was examined in 31 schizophrenia patients and 34 normal comparison subjects. Schizophrenia patients had overall deficits in PPI across four conditions where the prepulse was either discrete (abrupt) or continuous (sustained) and consisted of either white noise or a pure tone. On inspection and analysis of the data, it appears that the white noise conditions, rather than tone conditions, account for the group differences. Thus, the discrete white noise prepulse was most effective in eliciting PPI deficits, resulting in a large effect size between groups ( d=0.85; P<0.01). Deficits in information-protective mechanisms in schizophrenia may be differentially sensitive to specific stimulus characteristics; this observation may be relevant both to the neurobiology of information processing deficits in schizophrenia and to the methodologies for studying these deficits experimentally.

Regulation of Sensorimotor Gating of the Startle Reflex by Serotonin 2A Receptors: Ontogeny and Strain Differences

Sensorimotor gating of the startle reflex can be assessed via measures of prepulse inhibition (PPI), which is the reduction in startle magnitude when the startling stimulus is preceded immediately by a weak prepulse. PPI is reduced in humans with specific neuropsychiatric disorders and in rats after treatment with certain classes of drugs, including serotonin (5-HT) agonists. Because of the relative loss of PPI in inherited, neurodevelopmental disorders such as schizophrenia, there is great interest in understanding the inherited and developmental features of the neurochemical regulation of PPI in animals. In the present study, PPI was disrupted significantly by the 5-HT2A agonist 2,5-dimethoxy-4 iodopheny-lisopropylamine (DOI) in Sprague Dawley (SDH) and Wistar rat strains (WH). While it was demonstrated that the DOI effects in SDH rats reflected an unequivocal disruption of sensorimotor gating, in WH rats, reduced PPI was observed in the context of a trend for a DOI-induced reduction in startle magnitude. This effect of DOI in SDH rats was evident at the earliest date tested (17 days of age) in male pups, but was not statistically significant in female pups. Thus, the regulation of sensorimotor gating by 5-HT2A receptor stimulation in rats may exhibit subtle differences across strains, and within SDH rats, between sexes. Most importantly, the 5-HT2A regulation of sensorimotor gating in male SDH rats is a “phenotype” that is expressed very early in life, and is sustained through adulthood.

Animal models of deficient sensorimotor gating: what we know, what we think we know, and what we hope to know soon.

Sensorimotor gating of the startle reflex can be studied in humans and laboratory animals using measures of prepulse inhibition (PPI) of the startle reflex. PPI is reduced in patients with specific neuropsychiatric disorders and in rats after manipulation of the limbic cortex, striatum, pallidum or pontine tegmentum. Studies are rapidly identifying the neurochemical and neuroanatomical substrates regulating PPI in laboratory animals; this detailed circuit information has been used as a 'blueprint' to identify possible candidate substrates responsible for PPI deficits in psychiatrically disordered humans. In parallel, studies have also begun to assess the homology of pharmacological effects on PPI across species, as an initial step towards translating detailed neural circuit information from rats to humans. Despite this rapid progress, there is an increasing danger of overlooking important methodological and interpretative issues that could impact either positively or negatively on the ultimate utility of models based on measures of PPI. Some of these issues--ranging from the cross-species methods for quantifying specific variables to the relevance of genetic drift to animal and human studies of PPI--and their implications for future studies are the focus of this review.

Sensorimotor gating and thought disturbance measured in close temporal proximity in schizophrenic patients.

Sensorimotor gating abnormalities have been previously correlated with thought disturbance in schizophrenic patients. These correlative studies have led to the hypothesis that sensorimotor gating abnormalities may underlie thought disturbance. Several authors have cautioned, however, that this and similar hypotheses are supported by data recorded at different times or during resting states" and therefore incorrectly assume that the observed association represents a concurrent relationship. To address this issue, sensorimotor gating and thought disturbance were measured in close temporal proximity, thus strengthening the evidence for the association of these 2 abnormalities in schizophrenic patients. Twenty-one schizophrenic men were assessed on measures of sensorimotor gating and thought disturbance. Sensorimotor gating was examined operationally via the use of prepulse inhibition. Thought disturbance was assessed via the Rorschach test measures of perceptual inaccuracy, disordered cognition, and the expression of normally repressed contents. Symptom rating scales (the Scale for the Assessment of Positive Symptoms and the alogia subscale of the Scale for the Assessment of Negative Symptoms) were also used. Deficient prepulse inhibition correlated significantly with 2 of the 3 Rorschach-derived thought disturbance measures. Prepulse inhibition was not correlated significantly with symptom rating scales. The Rorschach measure of impaired perceptual accuracy independently accounted for 60% of the variance in prepulse inhibition measures and contributed 35% of the unique variance beyond the effect attributable to the Scale for the Assessment of Positive Symptoms. Assessment of information processing and thought disturbance measures in close temporal proximity resulted in strong evidence that gating deficits correlate highly with measures of perceptual and reasoning disturbances. This relationship may form an important basis for the cognitive dysfunction observed among schizophrenic patients.

Involvement of the medial geniculate body in prepulse inhibition of acoustic startle

Prepulse inhibition of acoustic startle is the normal reduction in startle response to an intense auditory stimulus when this stimulus is immediately preceded by a weaker prestimulus. Previous studies have shown that several neuroanatomical structures and pathways in the brain are involved in the modulation of prepulse inhibition. In the present study, the functional importance of the medial geniculate body (MG) in the modulation of prepulse inhibition was investigated. To this end, in vivo brain microdialysis probes were used to infuse drugs locally into the MG of awake, freely moving rats simultaneously with startle response and prepulse inhibition measurements in the same animals. Intrageniculate infusion of the sodium channel blocker, tetrodotoxin, significantly reduced prepulse inhibition without affecting baseline startle amplitude. A similar effect was obtained after intrageniculate infusion of the GABA(B) receptor agonist, baclofen. In addition, intrageniculate infusion of muscimol, an agonist at the GABA(A) receptor complex, reduced prepulse inhibition, although this effect was obtained at a higher concentration of the drug compared to that of baclofen. These studies suggest that the MG is involved in the modulation of prepulse inhibition and that auditory signals relayed via the MG may be subjected to inhibitory control at this level, involving GABA neurotransmission.

The nitric oxide synthase inhibitor. L-NAME, blocks certain phencyclidine-induced but not amphetamine-induced effects on behaviour and brain biochemistry in the rat

1. 1. The present experiments examined the effects of the nitric oxide synthase (NOS) inhibitor, N G-nitro-L-arginine methyl ester (L-NAME), on some behavioural and biochemical effects of phencyclidine (PCP) and d-amphetamine (AMPH) in rats. Observation of behaviour was performed using a subjective scoring system. 2. 2. PCP (4 mg/kg) increased locomotor activity, rearing, sniffing, grooming and stereotyped behaviour, and decreased stillness. PCP also increased forepaw myoclonus, forepaw treading, head weaving, licking and chewing behaviour. Most of these behaviours were significantly suppressed by pretreatment with L-NAME (10 mg/kg). 3. 3. AMPH (1 mg/kg) exerted different effects on behaviour. It increased locomotor activity, rearing, sniffing, and stereotyped behaviour, and decreased stillness and grooming, but failed to affect the other behavioural items observed. Pretreatment with L-NAME did not counteract these effects. 4. 4. Ex vivo biochemical analysis indicated that PCP increased the tissue concentration of the dopamine (DA) metabolites, dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA), in the ventral striatum (i.e., the nucleus accumbens and olfactory tubercles) and frontal cortex but not in the dorsal striatum. DA was not significantly affected in any of these regions. Furthermore, PCP increased the tissue concentration of the serotonin (5-HT) metabolite, 5-hydroxyindole acetic acid (5-HIAA), in a similar manner, while 5-HT was not affected. These biochemical effects were significantly counteracted by pretreatment with L-NAME. 5. 5. AMPH decreased tissue DOPAC concentration in the dorsal striatum, an effect which was not sensitive to pretreatment with L-NAME. However, the combined treatment with L-NAME and AMPH increased tissue DA concentration in all three regions investigated. 6. 6. The neurochemical and behavioural effects of PCP and AMPH were further investigated in an experimental model which allowed measurement of prepulse inhibition (PPI) of acoustic startle in parallel with in vivo microdialysis sampling of extracellular DA concentration in the brain of awake, freely moving animals. 7. 7. Both PCP (2 mg/kg) and AMPH (2 mg/kg) caused a significant decrease in PPI of similar magnitude and duration. These behavioural effects were accompanied by a significant increase in extracellular DA concentration in the nucleus accumbens (PCP: 213 ± 21% of basal concentration; AMPH: 563±117%). 8. 8. The decrease in PPI caused by PCP was blocked by pretreatment with L-NAME, but the change in DA concentration was not. Neither of these measures were significantly affected by L-NAME in AMPH-treated rats. 9. 9. In conclusion, this study shows that several behavioural and biochemical effects of PCP are prevented by pretreatment with the NOS inhibitor, L-NAME, while the effects of AMPH are less sensitive to this pretreatment. These observations emphasise the involvement of nitric oxide in the pharmacological effects of PCP.