Patients with adverse mood effects from combined oral contraceptives have lower levels of prepulse inhibition than healthy controls

BACKGROUND: Negative mood symptoms remain one of the major reasons for discontinuation of oral contraceptive pills. The aim of this study was to compare acoustic startle response and prepulse inhibition (PPI) in women with different experience of oral contraceptive pills. METHODS: Thirty women currently on combined oral contraceptives (COCs) with no reports of adverse mood symptoms, 28 women currently on COCs and experiencing mood-related side effects from treatment, 27 women who had discontinued COC use for reasons other than adverse mood symptoms and 32 women who had discontinued COC use due to adverse mood effects were included. The eyeblink component of the acoustic startle reflex was assessed using electromyographic measurements of musculus Orbicularis Oculi. Twenty pulse-alone trials (115dB 40ms broad-band white noise) and 40 prepulse-pulse trials were presented. The prepulse stimuli consisted of a 115dB 40ms noise burst preceded at a 100ms interval by 20ms prepulses that were 72, 74, 78, or 86dB. RESULTS: Patients with adverse mood effects of COCs exhibited lower levels of PPI with 86dB prepulse compared to COC users with no adverse effects of COCs (p<0.05). There was no difference in PPI between the two groups of prior COC users. No significant difference was found between the groups regarding acoustic startle response. CONCLUSION: Relative to COC users with no reports of adverse mood symptoms, subjects suffering from COC-induced negative mood displayed deficits in PPI of acoustic startle. The fact that there was no difference in PPI between the two groups of prior COC users indicates that deficient PPI is related to adverse mood effects caused by COCs.     

Prepulse inhibition of the startle response in risperidone-treated patients: comparison with typical antipsychotics

Individuals with schizophrenia are known to show deficits in prepulse inhibition (PPI) of the startle response. PPI refers to a response suppression in reaction to a strong startling stimulus, if preceded briefly by a weak non-startling stimulus and represents a well-established animal model to investigate information processing deficits in schizophrenia. This study examined PPI of the startle acoustic response in schizophrenic patients given typical antipsychotics or a second generation atypical antipsychotic, risperidone, using a naturalistic between-subjects design. Two groups of male schizophrenic patients: (i) stable on a range of typical antipsychotics (n = 20), and (ii) stable on risperidone (n = 10) were tested for PPI (prepulse-to-pulse intervals: 30, 60, and 120 ms, prepulses 15 dB above the background) of the acoustic startle response, and compared with a group of healthy male subjects (n = 20). Patients on typical antipsychotics showed significantly less PPI with 30 and 60 ms prepulse trials than healthy subjects. Risperidone-treated patients did not differ from healthy subjects for PPI with any prepulse trials. Further longitudinal within-subject studies are now required to examine whether risperidone is superior to typical antipsychotics in improving information processing functions, as assessed by PPI of the acoustic startle response, in treatment-responsive male patients with schizophrenia.     

Pharmacogenetics,pharmacogenomics and personalized psychiatry: Are we there yet?

Previous studies suggest an important role for serotonergic (5-HT) modulation of the acoustic startle reflex (ASR) and prepulse inhibition (PPI). Acute challenge of brain serotonin by means of tryptophan depletion test (TDT) represents an established human challenge tool for temporary reduction of tryptophan (-TRP) levels and central nervous serotonin. Under these experimental conditions, PPI was found attenuated in males, but greater biochemical effects of TDT in the central nervous system of females are known. Therefore, in order to explore influence of 5-HT on various standard startle parameters in females, 16 young healthy females participated in a double-blind, cross-over TDT study. Acoustic stimuli were presented in 15 pulse-alone trials (100 dB, 40 ms) randomly followed by 25 pulse-alone or prepulse (70 dB, 30 ms; 120 ms interval) trials alongside electromyographic eyeblink recordings and mood state assessments. During 81% depletion of free plasma TRP, mean ASR magnitudes were significantly reduced compared to control (+TRP) condition while there were no differences in habituation or PPI nor did startle parameters correlate with mood states. Changes of plasma TRP and mood states correlated in tendency negatively in (-TRP) for depression and positively in (+TRP) for fatigue. In conclusion, this first study of startle parameters after TDT in a homogenous female population demonstrates that depletion of brain 5-HT in women only influences ASR.     

Effects of experimental acute tryptophan depletion on acoustic startle response in females

Previous studies suggest an important role for serotonergic (5-HT) modulation of the acoustic startle reflex (ASR) and prepulse inhibition (PPI). Acute challenge of brain serotonin by means of tryptophan depletion test (TDT) represents an established human challenge tool for temporary reduction of tryptophan (−TRP) levels and central nervous serotonin. Under these experimental conditions, PPI was found attenuated in males, but greater biochemical effects of TDT in the central nervous system of females are known. Therefore, in order to explore influence of 5-HT on various standard startle parameters in females, 16 young healthy females participated in a double-blind, cross-over TDT study. Acoustic stimuli were presented in 15 pulse-alone trials (100 dB, 40 ms) randomly followed by 25 pulse-alone or prepulse (70 dB, 30 ms; 120 ms interval) trials alongside electromyographic eyeblink recordings and mood state assessments. During 81% depletion of free plasma TRP, mean ASR magnitudes were significantly reduced compared to control (+TRP) condition while there were no differences in habituation or PPI nor did startle parameters correlate with mood states. Changes of plasma TRP and mood states correlated in tendency negatively in (−TRP) for depression and positively in (+TRP) for fatigue. In conclusion, this first study of startle parameters after TDT in a homogenous female population demonstrates that depletion of brain 5-HT in women only influences ASR.     

Phencyclidine (PCP)-induced deficits of prepulse inhibition in monkeys

Prepulse inhibition (PPI) of the acoustic startle reflex is a measure of sensorimotor gating which occurs in both rodents and humans. PPI is deficient in severe neuropsychiatric disorders such as schizophrenia. We investigated PPI in 10 adult monkeys (Cebus apella). Stimuli were 115 dB white noise startle pulses, either alone or preceded by 120 ms with a prepulse of either 8 or 16 dB above the 70 dB background noise. Experiments included a pretreatment baseline session and a session following treatment with either phencyclidine (PCP, 0.12 mg/kg, i.m.) or saline. Comparison of peak amplitudes indicated a significant intensity-dependent decrease in startle response that was similar to that observed in humans under similar experimental conditions. PCP treatment significantly disrupted PPI, but did not reduce responses to startle pulses alone. These results provide the first demonstration of PPI in monkeys. The ability of PCP to induce schizophrenia-like deficits in PPI suggests that PPI in nonhuman primates may provide an important animal model for the development of novel anti-schizophrenia medications.     

Prepulse inhibition of acoustic startle response in mild cognitive impairment and mild dementia of Alzheimer type

Amnestic mild cognitive impairment (MCI) describes the condition of memory-impaired individuals who otherwise function well and do not meet the clinical criteria for dementia. Such individuals are considered to represent a transitional stage between normal aging and dementia of Alzheimer type (DAT). Neurobiologic changes in amnestic MCI, and their significance for psychophysiologic function, are poorly understood. In this study, the authors compared acoustic prepulse inhibition (PPI) between subjects with amnestic MCI and mild DAT to characterize sensorimotor gating. The acoustic startle reflex, which the authors measured using an accelerometer and electromyogram, involves whole-body movement and eye blink in response to a sudden loud noise (115 dB). PPI is inhibition of this reflex by a softer noise (prepulse; 85 dB) preceding the startle stimulus by 30 ms. PPI was examined in 30 controls, 20 subjects with amnestic MCI, and 20 subjects with mild DAT. Neither amnestic MCI nor mild DAT affected startle movement amplitude. Subjects with amnestic MCI showed significantly enhanced PPI (gating facilitation), while subjects with mild DAT exhibited significantly less PPI than controls (gating deficit). This pattern of PPI changes suggests that neuropathologic changes in the limbic cortex, mainly the entorhinal cortex, at the earliest stage of DAT might be responsible for PPI abnormalities via disturbed regulation of the limbic cortico-striato-pallido-pontine circuitry. Startle PPI changes could be used as a biologic marker for amnestic MCI and mild DAT.     

Sex differences in prepulse inhibition deficits in chronic schizophrenia

Recent years have seen a dramatic growth in the number of studies using prepulse inhibition (PPI) paradigms to index information processing deficits in schizophrenia. There are, however, robust sex differences in PPI in healthy subjects, with women exhibiting less PPI than men in the absence of any psychopathology. To investigate the role of sex in prepulse modification deficits in the long-term course of schizophrenia, we assessed PPI (response inhibition with the prepulse preceding the pulse by 30-150 ms) and prepulse facilitation (PPF; response facilitation with the prepulse preceding the pulse by 1000 ms) of the acoustic startle response in 42 chronic schizophrenia patients (27 men; all 42 on typical antipsychotics) and 35 controls (15 men). The results revealed that healthy women showed less PPI than healthy men. Men with schizophrenia showed less PPI compared to healthy men, but women with schizophrenia did not differ in PPI from healthy women. Age of illness onset negatively correlated to PPI in male patients. There was no significant effect of sex in PPF, and although patients (regardless of sex) showed less PPF relative to controls, this effect was abolished when the current age was co-varied for. These findings indicate sex differences in PPI deficits in schizophrenia. Future studies of schizophrenia patients need to take sex and age of subjects into account to optimise the investigation of PPI deficits, and their clinical, neural, and pharmacological correlates.     

A large single ethnicity study of prepulse inhibition in schizophrenia: Separate analysis by sex focusing on effect of symptoms

Deficits in sensorimotor gating, as measured with prepulse inhibition (PPI), have been considered an endophenotype of schizophrenia. However, the question remains whether these deficits are related to current symptoms. This single site study aimed to explore clinical features related to the modulation of startle reflex in a large sample of Japanese patients with schizophrenia (DSM-IV). The subjects comprised 181 patients and 250 healthy controls matched for age and sex. Schizophrenia symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). Startle reflex to acoustic stimuli was recorded using a startle stimulus of 115 dB and a prepulse of four different conditions (intensity: 86 dB or 90 dB; lead interval: 60 ms or 120 ms). Patients exhibited significantly reduced startle magnitude (p < 0.001), habituation (p = 0.001), and PPI (90 dB, 60 ms, p = 0.016; 90 dB, 120 ms, p = 0.001) compared with controls. Patients of both sexes exhibited significantly lower habituation and PPI (90 dB, 120 ms) compared with the same sex controls. We could not detect a significant correlation with any clinical variable in the entire patients, however, when men and women were examined separately, there was a negative correlation with the PANSS cognitive domain (ρ = −0.33, p = 0.008) in men, but not in women. Moreover, when patients were subdivided into four clusters, two clusters with high positive symptoms showed significant PPI deficits in men. Our results suggest that sensorimotor gating is impaired in schizophrenia of both sexes, and PPI deficits may be related to thought disturbance and disorganization in male patients with schizophrenia.     

Lipopolysaccharide produces dose-dependent reductions of the acoustic startle response without impairing prepulse inhibition in male rats

This study examined the dose-dependent effects of Lipopolysaccharide (LPS) on the acoustic startle response and prepulse inhibition (PPI) in male Long-Evans rats. LPS is known to stimulate the innate immune system and result in behavior modifications referred to as "sickness behaviors". The purpose of this study was to assess the ability of LPS to modulate sensorimotor reflexes (Startle-Only trials) and/or sensory processing (PPI trials). Rats were injected intraperitoneally with LPS (50, 100 or 200 microg/kg LPS, n=9/group) or saline vehicle (n=14) on 2 test days 72 h apart. Subjects were placed in a familiar startle box apparatus where startle response magnitudes were recorded following 115 dB Startle-Only trials and PPI trials (with prepulses at +3, +6 and +12 dB above background noise). Analysis of Startle-Only trials indicated a significant dose-dependent effect of LPS on Test Day 1. The 200 microg/kg LPS group exhibited significantly reduced startle response magnitude relative to all other treatments. On the PPI trials no LPS groups displayed significantly different performance from vehicle controls. Also, DayxDrug interactions for both Startle-Only and PPI trial types indicated behavioral tolerance to LPS. LPS reduced the acoustic startle response in a dose-dependent manner on Test Day 1. From the PPI data, it is evident that all treatment groups elicited near-normal inhibition levels indicating adequate sensory function. In combination, the results suggest that the range of sickness behaviors following LPS-administration to adult rats includes decreased non-voluntary motor activity as reflected by reduced startle magnitude.     

Female schizophrenia patients have prepulse inhibition deficits.

BACKGROUND: Prepulse inhibition (PPI) of startle shows sexual dimorphism: women have lower levels of PPI than do men, and have menstrual cycle shifts in PPI. Many studies report PPI deficits in male schizophrenia patients; one recent report identified PPI deficits in male but not female patients. This study was designed to determine whether female schizophrenia patients have lower levels of PPI than normal females. METHODS: Twenty-five female schizophrenia patients, and 26 normal females were tested in a startle paradigm using 115 dB startle pulses and prepulses of 8 and 16 dB above a 70 dB background, with 30 and 120 msec prepulse intervals. RESULTS: Female patients had significantly less PPI compared with normal females, particularly when 16 dB prepulses were utilized. Patients also exhibited a nonsignificant trend towards lower levels of habituation compared to normal subjects. CONCLUSIONS: Under the present paradigmatic and subject acquisition conditions, female schizophrenia patients had PPI deficits compared to normal females.     

Primary and secondary neural networks of auditory prepulse inhibition: a functional magnetic resonance imaging study of sensorimotor gating of the human acoustic startle response

Feedforward inhibition deficits have been consistently demonstrated in a range of neuropsychiatric conditions using prepulse inhibition (PPI) of the acoustic startle eye-blink reflex when assessing sensorimotor gating. While PPI can be recorded in acutely decerebrated rats, behavioural, pharmacological and psychophysiological studies suggest the involvement of a complex neural network extending from brainstem nuclei to higher order cortical areas. The current functional magnetic resonance imaging study investigated the neural network underlying PPI and its association with electromyographically (EMG) recorded PPI of the acoustic startle eye-blink reflex in 16 healthy volunteers. A sparse imaging design was employed to model signal changes in blood oxygenation level-dependent (BOLD) responses to acoustic startle probes that were preceded by a prepulse at 120 ms or 480 ms stimulus onset asynchrony or without prepulse. Sensorimotor gating was EMG confirmed for the 120-ms prepulse condition, while startle responses in the 480-ms prepulse condition did not differ from startle alone. Multiple regression analysis of BOLD contrasts identified activation in pons, thalamus, caudate nuclei, left angular gyrus and bilaterally in anterior cingulate, associated with EMG-recorded sensorimotor gating. Planned contrasts confirmed increased pons activation for startle alone vs 120-ms prepulse condition, while increased anterior superior frontal gyrus activation was confirmed for the reverse contrast. Our findings are consistent with a primary pontine circuitry of sensorimotor gating that interconnects with inferior parietal, superior temporal, frontal and prefrontal cortices via thalamus and striatum. PPI processes in the prefrontal, frontal and superior temporal cortex were functionally distinct from sensorimotor gating.     

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.     

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.     

Failure of haloperidol to block the effects of phencyclidine and dizocilpine on prepulse inhibition of startle.

Prepulse inhibition of acoustic or tactile startle (PPI), a form of sensorimotor gating, occurs when a weak prestimulus precedes a startling stimulus and inhibits the startle response. Studies of PPI have revealed that schizophrenic patients exhibit a deficit in this form of sensorimotor gating. In rats, PPI is blocked by dopamine agonists such as apomorphine or quinpirole, effects that are antagonized by haloperidol. Phencyclidine (PCP) has been suggested as a possible model psychotogen and produces a deficit in PPI that is similar to what is observed in schizophrenic patients. Dizocilpine is an anticonvulsant drug that, like PCP, is a noncompetitive antagonist of N-methyl-D-aspartate (NMDA)-induced excitations in brain and also disrupts PPI. In the present study, PPI of acoustic and tactile startle was measured in male Sprague-Dawley rats after injections of 5.0 mg/kg PCP with or without pretreatment with 0.02 or 0.1 mg/kg haloperidol, or with 0.5 mg/kg dizocilpine with or without pretreatment with 0.1 mg/kg haloperidol. The 0.1 mg/kg dose of haloperidol blocks the effects of apomorphine or quinpirole on PPI in rats. Startle was elicited by noise bursts at 105 or 120 dB or by air-puffs (tactile) and was inhibited by 75 or 85 dB prepulse stimuli presented 100 msec before the startle stimuli. The different eliciting stimuli produced different levels of startle in both control and drug-treated animals. Both NMDA antagonists significantly reduced the amount of PPI induced by the 75 dB prestimulus, independently of the level of startle responses elicited by the startle stimuli. Haloperidol did not block the disruption of PPI induced by either PCP or dizocilpine. In addition, PCP was unable to block PPI when the 85 rather than the 75 dB prepulse was used to inhibit either acoustic or tactile startle. These results confirm that putative NMDA antagonists inhibit sensorimotor gating in rats and suggest that these effects are not mediated by the activation of central dopamine systems.     

Stability of the acoustic startle reflex, prepulse inhibition, and habituation in schizophrenia

Prepulse inhibition (PPI) of the acoustic startle reflex has been proposed as a neurophysiological measure of sensorimotor gating. There is high test-retest reliability of both startle magnitude and PPI in non-psychiatric subjects. The present study examined the stability of the acoustic startle reflex and its modulation in patients with schizophrenia. Startle measurements were performed in 19 chronic schizophrenic patients on stable medications and 24 healthy control subjects, three times at one-month intervals. PPI trials with various intervals between the prepulse and the startle stimulus (30, 60. 120, 240, and 2000 ms) were used. Intraclass correlation coefficients (ICC) were computed to assess stability. There was a good test-retest reliability of PPI in both schizophrenic patients (Mean ICC: 0.75) and control subjects (Mean ICC: 0.71). Acoustic startle magnitude was the most stable measure across sessions (Mean ICC schizophrenics: 0.89; Mean ICC controls: 0.89). In both groups, a good test-retest reliability was found in the startle latencies. Habituation and prepulse-induced shortening of latencies exhibited moderate stability. Schizophrenic patients exhibited significantly less PPI than control subjects in the 60 ms prepulse condition. This PPI deficit was evident in all three sessions. These results indicate that PPI is a stable neurobehavioral measure in chronic schizophrenic patients in the absence of changes in clinical state.     

Attentional modulation of prepulse inhibition: a new startle paradigm

There is increasing evidence for an influence of directed attention on prepulse inhibition (PPI) of the acoustic startle reflex. However, the existing paradigms for the assessment of this effect have methodological problems and pitfalls. In particular, most previous studies used a paradigm which directed the attention of subjects to the prepulse only. In the present study, we used a modified paradigm which directed the attention of the subjects both to the prepulse and the pulse. Twenty healthy male subjects were instructed trial by trial either to relax or to attend to the startle stimulus and decide whether it was a 'simple' (prepulse alone or pulse alone) or a 'composite' trial (pulse plus a prepulse or postpulse). Directed attention enhanced PPI at the lead interval of 240 ms, but not at the lead interval of 100 ms. This finding is in line with the idea that attention contributes to PPI when there is enough time for the attentional mechanisms to exert an influence. This new paradigm offers a valuable tool for the study of attentional modulation of sensorimotor gating in humans.     

Amphetamine dose dependently disrupts prepulse inhibition of the acoustic startle response in rats within a narrow time window

Prepulse inhibition (PPI) of the acoustic startle response refers to the reduction in startle amplitude when a weak prepulse precedes a startle-inducing pulse. Prepulse inhibition has been shown to be disrupted by amphetamine at doses that also stimulate locomotor activity, and it has been suggested that the same neuroanatomical substrate, mesolimbic dopamine activation, mediates the effects of amphetamine on locomotor activity and PPI. Amphetamine stimulates locomotor activity and mesolimbic dopamine release over a 1- to 3-h period, whereas PPI is typically measured within the first 30 min following amphetamine treatment. The present study therefore determined whether delays in testing would alter the PPI-disruptive effect of amphetamine in male Wistar rats. Amphetamine dose dependently disrupted PPI when the test session occurred 10 min following amphetamine treatment and only when the prepulse intensity was 5-10 dB above background. Delays of 40 and 60 min post-amphetamine injection, however, resulted in a loss of the ability of amphetamine to disrupt PPI although locomotor activity was significantly stimulated by amphetamine at these time points. The data from the present study therefore do not readily fit with the notion that the effects of amphetamine on locomotion and PPI are mediated by the same substrate.     

Effects of background and prepulse characteristics on prepulse inhibition and facilitation: implications for neuropsychiatric research.

BACKGROUND: Both prepulse inhibition (PPI) and prepulse facilitation (PPF) deficits have been reported in schizophrenia patients, but the use of different experimental parameters across laboratories makes direct comparisons of results difficult. We assessed the effects of different parameters on PPI and PPF in normal subjects. METHODS: Eyeblink startle was measured in 14 healthy male subjects, using 115 dB[A] white noise startle pulses and 86 dB[A] prepulses. Analyses compared the effects of: 1) background noise level (ambient 54 vs. 70 dB[A]) on PPI and PPF, 2) prepulse duration (discrete 20 msec vs. continuous) on PPF, 3) prepulse frequency (1000 Hz vs. white noise) on PPI and PPF, and 4) prepulse interval (2000 vs. 4500 msec) on PPF. RESULTS: Compared to an experimentally delivered 70 dB[A] background, ambient 54 dB[A] background led to significantly more PPI (with discrete white noise prepulses), and more PPF (with continuous prepulses). Continuous and longer (4500 msec) prepulses induced more PPF than did discrete and shorter (2000 msec) prepulses. CONCLUSIONS: Paradigmatic differences appear likely to be responsible for divergent findings in studies of PPI and PPF in normal and schizophrenia subjects. The present study should guide investigators in the selection of parameters for assessing PPI and PPF in studies of normal subjects and schizophrenia patients. Attention to the 4 factors of 1) background noise, 2) prepulse duration, 3) frequency, and 4) interval will facilitate comparability of results across different laboratories, especially when using PPI/PPF in schizophrenia research as neural substrate probes, as biomarkers, and as endophenotypes.     

Sensorimotor gating of schizophrenia patients depends on Catechol O-methyltransferase Val158Met polymorphism

It has been recently shown that Catechol O-methyltransferase (COMT) Val(158)Met polymorphism strongly influences prepulse inhibition (PPI) of the acoustic startle response (ASR) in healthy human volunteers. Given that schizophrenia patients exhibit impairment in PPI and that COMT is a putative susceptibility gene for schizophrenia, we investigated the impact of the COMT Val(158)Met polymorphisms on PPI in schizophrenic inpatients. We analyzed COMT Val(158)Met polymorphisms and assessed startle reactivity, habituation, and PPI of ASR in 68 Caucasian schizophrenia inpatients. Clinical symptoms were measured with the Positive and Negative Syndrome Scale (PANSS). Patients carrying the Val(158)Met Met/Met allele showed elevated PPI levels whereas startle reactivity and habituation did not differ from the other two genotypes. These preliminary results imply that PPI is influenced by COMT Val(158)Met genotype in schizophrenia as well. In concert with other findings, our data suggest that PPI is a polygenic trait.     

Prepulse inhibition of the acoustic startle reflex in pigs and its disruption by d-amphetamine

Prepulse inhibition (PPI) of the startle reflex is an operational measure of sensorimotor gating. The dopamine receptor agonist-mediated disruption of PPI in rats is widely used as a model of the sensorimotor gating deficiencies demonstrated in schizophrenia patients. As a possible tool for validation of a pig model of psychosis, we wished to verify the existence of PPI in landrace pigs and investigate the potential disruption of PPI by d-amphetamine (AMPH) in these animals. PPI of the acoustic startle reflex and its potential disruption by AMPH were investigated using three doses 0.5-1.5mg/kg with a paradigm including two levels of prepulses (82 and 88dB) and a prepulse (PP) interval of 60 and 120ms. We found an average PPI of the startle reflex of 25.6% and both of the investigated PP intensities and PP intervals were equally effective in this PP-inhibitive paradigm. AMPH significantly disrupted PPI and, in spite of only the 0.5mg/kg dose proved statistically significant, the results indicate this to be dose-related. We have demonstrated the phenomenon of PPI of the startle reflex in landrace pigs and its disruption by d-amphetamine. Studies of sensorimotor gating defects could be a valuable additional tool in assessing pig models of neuropsychiatric disorders.