Prepulse inhibition (PPI) of tactile startle response in recombinant congenic strains of mice:QTL mapping and comparison with acoustic PPI

Prepulse inhibition （PPI） of the startle response is a psychophysiological measure of sensorimotor gating believed to be cross-modal between different sensory systems. We analyzed the tactile startle response （TSR） and PPI of TSR （tPPI）, using light as a prepulse stimulus, in the mouse strains A/J and C57BL/6J and 36 recombinant congenic strains derived from them. Parental strains were significantly different for TSR, but were comparable for tPPI. Among the congenic strains, variation for TSR was significant in both genetic backgrounds, but that of tPPI was significant only for the C57BL/6J background. Provisional mapping for loci modulating TSR and tPPI was carried out. Using mapping data from our previous study on acoustic startle responses （ASR） and PPI of ASR （aPPI）, no common markers for aPPI and tPPI were identified. However, some markers were significantly associated with both ASR and TSR, at least in one genetic background. These results indicate cross-modal genetic regulation for the startle response but not for PPI, in these mouse strains.

Roles of 5-HT2 receptors in effects of DOM,ketamine and methamphetamine on prepulse inhibition in Sprague Dawley rats

OBJECTIVE Prepulse inhibition(PPI)of the acoustic startle response provides a measure of sensorimotor gating system mecha⁃nisms,which is known to be impaired in schizo⁃phrenia patients.We assessed the effects of the 5-HT2A/2C receptor agonist(±)2,5-dimethoxy-4-methylamphetamine(DOM),the NMDA receptor antagonist ketamine,the dopamine receptor ago⁃nist methamphetamine(Meth)on PPI and the startle magnitude in SD rats.METHODS AND RESULTS Systemic administration of the three compounds all dose-dependently reduced PPI.However,as far as startle magnitude,only DOM at the doses of 3 mg·kg-1 reduced that,while both ketamine and Meth did not change the startle magnitudes.Furthermore,to determine whether 5-HT2A receptor mediate this effect,the non-spe⁃cific 5-HT2 receptor antagonist cyproheptadine,specific 5-HT2A receptor antagonist ketanserin and specific 5-HT2C receptor antagonist SB242084 were tested.Cyproheptadine,ketan⁃serin and SB242084 did not alter startle ampli⁃tude by themselves in SD rats and only ketanserin slightly increased PPI at higher dose(3 mg·kg-1).PPI impairment induced by DOM was restored by pretreatment of cyproheptadine(1 mg·kg-1)and ketanserin(1 mg·kg-1),while not by pretreat⁃ment of SB242084(1 mg·kg-1).Damage of PPI induced by ketamine and Meth was not reversed by cyproheptadine(1 and 5 mg·kg-1).CONCLU⁃SION The receptor mechanisms underlying the disruption of PPI caused by DOM,ketamine and Meth were different from each other,at least 5-HT2A receptor was not the junction receptor for which the three chemicals acted.

Impaired prepulse inhibition of acoustic startle in Chinese patients with first-episode, medication-naive 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-naive 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 （PP160, P 〈0.05） but not at 30 or 120 ms intervals. Furthermore, there was a relatively strong correlation between PPI60 （P 〈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.

Differences in P50 and prepulse inhibition of the startle reflex between male smokers and non-smokers with first episode schizophrenia without medical treatment

Backgorund Nicotine may improve schizophrenia patient＇s cognitive deficit symptoms.This study was to explore the chronic effects of smoking on prepulse inhibition of the startle reflex （PPI） and P50 in the patients with first-episode schizophrenia （FES）.Methods The event-related potentials （ERP） recording and analysis instrument made by Brain Products,Germany,was used to detect PPI and P50 in 49 male FES patients （FES group,n=21 for smokers and n=28 for non-smokers） and 43 normal male controls （control group,n=19 for smokers and n=24 for non-smokers）.Results Compared with normal controls,the FES group had prolonged PPI latency when elicited by single stronger stimulus （P ＜0.05）; the FES group had prolonged PPI latency and increased PPI amplitude （P ＜0.05,0.01） when elicited by weak and strong stimuli.The FES group had lower PPI inhibition rate than normal controls （P ＜0.05）.Compared with normal controls,the FES group had increased P50-S2 amplitude and increased amplitude ratio S2/S1 （both P ＜0.05）.In the control group,the smokers had a tendency of increase in P50-S2 amplitude （P ＞0.05） and shorter P50-S2 latency （P ＜0.05） than the non-smokers.The smokers had higher PPI amplitude than the non-smokers （P ＜0.05）.In the FES group,the smokers had higher P50-S1 amplitude,shorter P50-S2 latency,and higher amplitude ratio S2/S1 than the non-smokers （P ＜0.05,0.01）.The smokers had higher PPI amplitude than the non-smokers （P ＜0.05）.Conclusions There is obvious PPI and P50 deficits in schizophrenic patients.However,these deficits are relatively preserved in the smokers compared with the non-smokers,which suggests that long-term smoking might partially improve the sensory gating in schizophrenic patients.Whether this conclusion can be deduced to female patients requires further follow-ups.

Prepulse Inhibition of Auditory Cortical Responses in the Caudolateral Superior Temporal Gyrus in Macaca mulatta

Prepulse inhibition(PPI) refers to a decreased response to a startling stimulus when another weaker stimulus precedes it. Most PPI studies have focused on the physiological startle reflex and fewer have reported the PPI of cortical responses. We recorded local field potentials(LFPs) in four monkeys and investigated whether the PPI of auditory cortical responses(alpha, beta, and gamma oscillations and evoked potentials) can be demonstrated in the caudolateral belt of the superior temporal gyrus(STGcb). We also investigated whether the presence of a conspecific, which draws attention away from the auditory stimuli, affects the PPI of auditory cortical responses. The PPI paradigm consisted of Pulse-only and Prepulse + Pulse trials that were presented randomly while the monkey was alone(ALONE) and while another monkey was present in the same room(ACCOMP). The LFPs to the Pulse were significantly suppressed by the Prepulse thus, demonstrating PPI of cortical responses in the STGcb. The PPI-related inhibition of the N1 amplitude of the evoked responses and cortical oscillations to the Pulse were not affected by the presence of a conspecific. In contrast, gamma oscillations and the amplitude of the N1 response to Pulse-only were suppressed in the ACCOMP condition compared to the ALONE condition. Thesefindings demonstrate PPI in the monkey STGcb and suggest that the PPI of auditory cortical responses in the monkey STGcb is a pre-attentive inhibitory process that is independent of attentional modulation.

Acoustic startle reflex and pre-pulse inhibition in tinnitus patients

Gap induced pie-pulse inhibition(Gap-PPI) of acoustic startle reflex has been used as a measurement of tinnitus in animal models.However,whether this test is sensitive to detect tinnitus in humans is still unclear.Based on the testing procedure used in animal studies,a human subject testing method was formulated and conducted to investigate if a similar result could be found in tinnitus patients.Audiologic and tinnitus assessments and acoustic startle reflex measurements were performed on seven tinnitus subjects and nine age matched subjects without tinnitus.There was no significant difference found between the control and tinnitus group on the Gap-PPl across the frequencies evaluated.The amplitude of the startle response in the tinnitus group with normal hearing thresholds was significantly higher than the control group and those with tinnitus and hearing loss.This preliminary result suggests that hyperexcitability in the central auditory system may be involved in tinnitus.There was no correlation between hearing thresholds and the increased amplitude of startle response.

Genetic Rat Models of Schizophrenia-Relevant Symptoms

It is recognized that developing valid animal models is essential for the research on the neurobiological mechanisms of (and treatments for) psychiatric disorders, even when these are as complex as schizophrenia. To be considered a valid analogue of the disorder, a given model should present good face validity (i.e. similarity of symptoms), good predictive validity (i.e. similarity of treatment effects and potential for discovering novel treatments) and enough construct validity (i.e. the model should help discover neurobiological mechanisms underlying the disorder or some relevant symptoms). The complexity of symptoms (positive, negative and cognitive) of schizophrenia makes it a very difficult task for a model to mimic all the main features of the disorder, but some rodent (mouse and rat) models have behavioural and even neurobiological phenotype characteristics resembling positive-like symptoms, cognitive symptoms and some neurochemical features of schizophrenia. As several recent works have already reviewed the main behavioural and developmental models, as well as the most used drug-induced, lesion-induced and genetic mouse models, the present review focuses on describing the most relevant genetically-based rat models of schizophrenia-relevant symptoms. Thus, we discuss several selective breeding programs leading to rat lines/strains which present impaired prepulse inhibition (PPI) of the acoustic startle response and (in some cases) latent inhibition deficits (both of which may be considered as endophenotypes of schizophrenia related with pre-attentive processes and attention, respectively), as well as other schizophrenia-relevant symptoms (e.g. learning deficits). Evidence is presented for the effects of genetic background on PPI (and other symptoms/phenotypes), as well as for environmental influences on genetic predisposition to enhanced apomorphine (mixed dopamine receptor agonist) effects. Some of the described rat models appear to present face validity and, to a certain extent, construct validity. While efforts should be made to evaluate the predictive validity of these genetic rat models, we propose that they have the advantage (over mouse knockouts, for example) of better representing “normal” genetic, neurobiological and phenotype variation, thus allowing the study of associations among them by means of genetic mapping or gene expression studies.

A Study on the Effect of Risperidone on PPI and P50 Deficit in FirstEpisode and Chronic Patients with Schizophrenia

Objective To investigate the effect of atypical antipsychotics risperidone on prepulse inhibition of the startle reflex(PPI) and P50 deficit in first-episode and chronic patients with schizophrenia. Methods PPI and P50 were tested and compared in 81 first-episode acute schizophrenia patients and 92 chronic schizophrenia patients before and after the risperidone. Results There was no significant difference in PPI and P50 indices between the two groups before treatment(P>0. 05); 2) there was no significant correlation between PPI & P50 inhibition indices and PANSS score, onset frequency and disease course(P>0.05); 3) Except the significant group main effect for S2 amplitude in P50(P=0. 02), there was no significant change for main effect and interaction of the other P50 and PPI inhibition ratio indices after treatment(P>0. 05). The effect of risperidone on PPI and P50 measurement index had nothing to do with the curative effect. Conclusion There exists a deficit in sensory gating inhibition in both first-episode schizophrenia and chronic schizophrenia, which is relatively independent from disease course. The risperidone is not effective in improving PPI and P50 inhibition deficit.