Effects of olanzapine treatment on prepulse inhibition in neurodevelopmental mice model of schizophrenia / 中华行为医学与脑科学杂志

Objective:To establish neurodevelopmental mice model of schizophrenia(SZ) with prepulse inhibition(PPI) deficits and investigate the effectiveness of olanzapine on PPI disruption.Methods:On the 9th day of pregnancy of SPF grade C57BL/6 mice, female mice were injected with polyinosinic acid poly (I∶C) (6 mg/kg) through tail vein for immune stimulation. The stress model was constructed by chronic unpredictable mild stress 30-40 d after birth (PND30-40). The offspring mice were divided into pregnancy immune stimulation + adolescent stress group (P + S + group), pregnancy immune stimulation group (P + S- group), adolescent stress group (P-S+ group) and non stimulation group (P-S-group), with 18 mice in each group. The mice in P+ S+ group were divided into OLZ intervention group (OLZ group) and non-OLZ intervention group (non-OLZ group), with 9 mice in each group. The PPI function of mice was detected by acoustic startle reflex test after modeling and OLZ intervention. Adopt StatView Version 5.0 software for data analysis, and multi factors analysis of variance was used to test the main effect, interactive effect and simple effect of each factor.Results:The main effects of maternal Poly(I: C) immune activation and pubertal chronic unpredictable stress were significant( F(1, 330)=47.72, P<0.01), and there was a significant interaction between the two factors( F(1, 330)=14.80, P<0.01), simple effect analysis showed that average percent prepulse inhibition (PPI%) in P+ S+ group((15.42±6.13)%) was significantly decreased compared with groups of P+ S-((27.33±4.58)%), P-S+ ((31.17±3.97)%) and P-S-((47.14±12.28)%)(all P<0.01). There was significant gender difference in Prepulse inhibition(PPI)score( F(1, 396)=61.94, P<0.01), in male and female mice, average startle reactivity of Pulse under Prepulse+ Pulse influence of distinct intensities was significantly different( F(1, 198)=18.68, 18.44, P<0.01), and the maternal Poly(I∶C) immune activation had a significant main effect( F(1, 198)=32.18, 12.58, P<0.01) and interaction with pubertal chronic unpredictable stress( F(1, 198)=34.54, 11.39, P<0.01), simple effect analysis suggested that the average startle reactivity of Prepulse+ Pulse in P+ S+ group(0.47±0.12) was significantly higher than other three groups(P+ S-: 0.36±0.11, P-S+ : (0.25±0.22), P-S-: (0.31±0.19)) in male mice( P<0.01) and in P-S+ group was significantly higher than the other three groups in female mice ( P<0.01). OLZ treatment could efficiently reverse the deficits on PPI by increasing PPI%( F(1, 165)=18.24, P<0.01), OLZ could reduce PPI score in male "dual-hit" model mice( F(1, 102)=21.81, P<0.01)and raise it in female( F(1, 102)=4.88, P<0.05). Conclusion:OLZ can reverse PPI deficits in schizophrenic neurodevelopmental model mice, and in the evaluation of PPI function in the model mice through PPI of acoustic startle reflex, PPI% has better stability and reactivity to OLZ intervention.

Prepulse Inhibition of Auditory Cortical Responses in the Caudolateral Superior Temporal Gyrus in Macaca mulatta / 神经科学通报·英文版

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. These findings 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.

Effects of 5HT1A Activation on Gating Profile Following 5HT Depletion in Rats Lacking Social Attachment Since Weanling

OBJECTIVE: Central 5-HT1A receptor is involved in the modulation of sensorimotor gating function. However, its precise role is not clearly defined in developmentally social deprived (isolation rearing, IR) rats featured with impaired sensorimotor gating ability. We therefore aimed to examine the effects of 5HT1A activation on acoustic startle response (ASR) and prepulse inhibition (PPI) in IR rats in a condition of compromised presynaptic 5-HT functions. METHODS: Social control (SOC) and IR rats received an intracerebraoventricular (ICV) injection of 5-HT depletor, 5,7-DHT. Seven days later rats entered a protocol of 8-OH-DPAT, a 5-HT1A agonist, in which locomotor activity, ASR and PPI and their tissue levels of 5-HT were measured. RESULTS: Our results found that both IR and 5,7-DHT decreased the tissue concentration of 5-HT. IR-induced hyperactivity and gating impairment were unaffected by 5-HT depletion. 8-OH-DPAT strengthened the ASR in IR but not SOC rats and the drug-reduced PPI could be adjusted by 5,7-DHT pretreatment. 8-OH-DPAT at 100 μg/kg enhanced PPI in 5-HT-depleted SOC rats. However for IR rats, 8-OH-DPAT strengthened PPI in sham rats but downgraded it in depletion condition. CONCLUSION: The integrity of central 5-HT system is important to 5-HT1A-modulated sensorimotor gating in isolation-reared rats.

Update of studies about prepulse inhibition in psychiatric disorders / 中华行为医学与脑科学杂志

Prepulse inhibition ( PPI) is the suppression of the startle reflex when the startling stim-ulus is preceded by a non-startling stimulus ( the prepulse) . It is an operational measurement of sensorimotor gating mechanism to help the brain adapt to the complex environment,which could be top-down modulated by attention and other higher cognitive processes. Deficits of PPI and the top-down modulation of PPI are closely related to psychiatric diseases. Research papers published from January 2001 to October 2016 related to PPI in psychiatric disorders were searched in the Chinese and English databases. Results showed that schizo-phrenic patients and their relatives showed deficits in baseline PPI as well as the attentional modulation of PPI,and more importantly,the attentional modulation of PPI rather than the baseline PPI was more related to the symptom severity. Patients with Tourette'' s syndrome showed PPI impairment,while patients with obsess-ive compulsive disorder had lower levels of PPI. PPI deficits in bipolar disorder patients were gender-depend-ent. Studying PPI and the top-down modulation of PPI could provide a basis to study the interaction of senso-ry processing and attention,and facilitate the researches of neural mechanism underlying the deficits of senso-ry gating. To establish advanced paradigms of PPI,new cognitive components could be introduced,such as at-tention,emotion,motor control,compulsivity and so on,thus improving the specificity of PPI test and promo-ting the PPI test as new biomarker and endophenotype in various psychiatric disorders.

Effects of paliperidone on MK-801-induced hyperactivity and disruption prepulse inhibition in rats / 中国神经精神疾病杂志

Objective To investigate the effects of risperidone and its active metabolite, paliperidone (9-hydroxyrisperidone), on hyperactivity and deficient sensorimotor gating induced by MK-801 in rats. Methods Adult male Sprague-Dawley (SD) rats (n=96) were used in this study. The effects of risperidone (0.1 mg/kg) and paliperidone (0.05, 0.10 and 0.20 mg/kg) on MK-801-induced (0.40 mg/kg) hyperactivity were examined in 48 rats with with 8 animals per group.The effects of risperidone(0.5 mg/kg)and paliperidone(0.10,0.50,1.00 mg/kg)on MK-801-induced (0.25 mg/kg) deficit in prepulse inhibition (PPI) were examined in 48 rats with 8~10 animals per group. Results Risperidone (0.10 mg/kg) and paliperidone (0.05 mg/kg) diminished the MK-801-induced hyperactivity (P<0.05). But paliperidone (0.10, 0.20 mg/kg) group did not affect locomotor activity compared to the control group. Risperidone (0.10 mg/kg) and different doses of paliperidone (0.10, 0.50, 1.00 mg/kg) enhanced the PPI baseline in rats. However, only risperidone (0.10 mg/kg), but not paliperidone restored the MK-801-induced deficits in PPI. Conclusion Risperidone and paliperidone have different pharmacological actions on MK-801-induced hyperactivity and deficits in prepulse inhibition in rats, suggesting that pharmacological actions of paliperidone are different from those of risperidone, although paliperidone is the active metabolite of risperidone.

Correlation of catechol-O-methyl transferase Vall58Met polymorphism with prepulse inhibition of the auditorystartle reflex in patients with schizophrenia / 中国心理卫生杂志

Objective:To investigate the association between catechol-O-methyl transferase (COMT)Vall58Met polymorphism and prepulse inhibition of the auditory startle reflex (PPI) in patients with schizophrenia.Methods:Totally 178 patients with schizophrenia and 190 healthy volunteers were recruited.The auditory startle reflex was detected by using SR-HLAB monitoring system.The indexed of the auditory startle reflex included the amplitude,habituation％ and PPI30,PPI60,PPI120 (the lead interval was set 30 ms,60 ms,120 ms).COMT Vall58Met polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RELP).The differences of PPI among COMT genotypes were compared.Results:Compared to the healthy volunteers,patients with schizophrenia had a significant lower the amplitude of auditory startle reflex[(563± 460) mV vs (695 ± 447) mY,P ＜ 0.05] and habituation％ [(32 ± 46) vs (48 ± 33),P ＜ 0.01] as well as the ％PPI120[(27 ± 5) vs (35 ± 3),P ＜ 0.05].The significant differences in COMT allelic and genotypic distribions were observed between patients with schizophrenia and healthy volunteers (x2 =8.16,11.74,Ps ＜ 0.05).The significant main effect of COMT genotype on habituation％ was observed (P ＜0.05) but no interaction genotype by diagnosis on the amplitude of auditory startle reflex,habituation％ and ％ PPI120 was observed (Ps ＞ 0.05).Conclusions:There may be a correlation between COMT genotype and adaptability,but not between COMT genotype and PPI deficit present in patients with schizophrenia

A preliminary study of single prolonged stress influence acoustic startle reflex and prepulse inhibition in rats / 中华行为医学与脑科学杂志

ObjectiveTo explore the deficits of acoustic startle reflex (ASR) and prepulse inhibition (PPI) of acoustic startle reflex in single prolonged stress rats.MethodsSixty Sprague Dawley rats were randomly divided into control 1,7,14 d groups and stress 1,7,14 d groups.All stressed rats received single prolonged stress while all control rats were left in their home cage.Behavioral changes in these rats were analyzed in ASR and PPI paradigm.ASR and PPI were carried out on day 2,8,15,respectively.ResultsThere were no differences of ASR and PPI among control 1,7,14 d groups (P ＞ 0.05).ASR of stress 1 d group ( (92.49 ± 31.54) g) was higher than that of control 1 d group((64.48 ± 17.95)g,P＜0.05) while PPI of stress 1 d group((28.60 ±29.02)％) was lower than that of control 1 d group( (41.60 ± 15.10)％,P ＜ 0.05 ).There were no differences of ASR between control 7 d group and stress 7 d group,control 14 d group and stress 14 d group (P＞ 0.05 ).Compared with control 7 d group ( (41.30 ± 12.79) ％ ),PPI in stress 7 d group ( ( 17.95 ± 31.79) ％ ) was reduced (P ＜ 0.05 ).Compared with control 14 d group ( (41.16 ± 12.25 ) ％ ),PPI in stress 14 d group( ( 13.71 ± 32.48) ％ ) was reduced (P ＜ 0.05).ConclusionEffects of stress on ASR in rats increased in early period,while the impaired PPI may last for a long time.

Comparative study on prepulse inhibition of the startle reflex between pure cerebral concussion and multiple cerebral concussion model rats / 中华行为医学与脑科学杂志

ObjectiveTo observe the prepulse inhibition(PPI) ot the startle reflex of pure cerebral concussion (PCC) suffered from one concussion and multiple cerebral concussion (MCC) suffered from three concussions in rats,and to explore accumulate effect upon cognitive dysfunction of MCC.MethodsA metallic pendulum striker device for closed head injury was employed to duplicate PCC and MCC models in Stragu-Dawley rats.The MCC rats were hit three times on rats'head and it is interval 24 hours for every hit.According to the criteria of cerebral concussion,the investigated animals were divided into PCC group and MCC group at freedom.One control group was used.Each group included 10 animals.Each experience mental animal was tested from 3 days pre-injury to 28 days post-concussion.Startle reflex amplitude (for P values),pre-stimulation induced reflex amplitude on three standard stimulations,that was,67dB,69dB and 73dB (for PP67,PP69 and PP73 values) and prepulse inhibition of the startle reflex (PPI) were collected.ResultsThe P values and three PP values in the first three days of pre-replication experiment,there was no statistical significance in each group.However the P values and PP67,PP69 and PP73 values declined until to the 16th day after injury (P＜0.05),then recovered in PCC group.The P value and PP67,PP69 and PP73 values changes of MCC group declined and not recovered until to test end (P＜0.05 ) and they were more lower than PCC.The three PPI values were a little bit increase in both groups,there were statistics significance at some test points (P＜0.05) compared with control.ConclusionThe startle reflex amplitude and pre-stimulation induced reflex amplitude weaken after cerebral concussion and there is damaging accumulate effect to injury times,the PPI is enlanced by cerebral concussion.

Iptakalim Preferentially Decreases Nicotine-induced Hyperlocomotion in Phencyclidine-sensitized Rats: A Potential Dual Action against Nicotine Addiction and Psychosis

OBJECTIVE: Iptakalim is a putative ATP-sensitive potassium (KATP) channel opener. It is also a novel nicotinic acetylcholine receptor (nAChR) blocker and can antagonize nicotine-induced increase in dopamine release in the nucleus accumbens. Our recent work also shows that iptakalim exhibits a clozapine-like atypical antipsychotic profile, indicating that iptakalim may possess a dual action against nicotine addiction and schizophrenia. METHODS: The present study examined the potential therapeutic effects of iptakalim on nicotine use in schizophrenia. We created an animal model of comorbidity of nicotine addiction and schizophrenia by injecting male Sprague-Dawley rats with nicotine (0.40 mg/kg, subcutaneously[sc]) or saline, in combination with phencyclidine (PCP, 3.0 mg/kg, sc) or saline daily for 14 consecutive days. RESULTS: During the PCP/nicotine sensitization phase, PCP and nicotine independently increased motor activity over time. PCP also disrupted prepulse inhibition (PPI) of acoustic startle response. Acute nicotine treatment attenuated the PCP-induced hyperlocomotion and PCP-induced disruption of PPI, whereas repeated nicotine treatment potentiated these effects. Importantly, pretreatment with iptakalim (10-20 mg/kg, intraperitoneally) reduced nicotine-induced hyperlocomotion in a dose-dependent fashion. This reduction effect was highly selective: it was more effective in rats previously sensitized to the combination of PCP and nicotine, but less effective in rats sensitized to saline, nicotine alone or PCP alone. CONCLUSION: To the extent that the combined nicotine and PCP sensitization mimics comorbid nicotine addiction in schizophrenia, the preferential inhibitory effect of iptakalim on nicotine-induced hyperlocomotion suggests that iptakalim may be a potential useful drug for the treatment nicotine abuse in schizophrenia.

Effects of the Antioxidant Sulforaphane on Hyperlocomotion and Prepulse Inhibition Deficits in Mice after Phencyclidine Administration

OBJECTIVE: Accumulating evidence suggests that oxidative stress plays a role in the pathophysiology of schizophrenia and that the potent antioxidants may be potential therapeutic drugs for schizophrenia. This study was undertaken to examine the effects of the potent antioxidant sulforaphane (SFN), found in cruciferous vegetables, on behavioral abnormalities (e.g., hyperlocomotion and prepulse inhibition [PPI] deficits) in mice after a single administration of the N-methyl-D-aspartate (NMDA)-receptor antagonist phencyclidine (PCP). METHODS: Effects of SFN (3, 10, and 30 mg/kg, intraperitoneally [i.p.]) on hyperlocomotion and PPI deficits in the adult male ddY mice after administration of PCP (3.0 mg/kg, subcutaneously [s.c.]) were examined. RESULTS: Administration of SFN (30 mg/kg, intraperitoneally [i.p.]), but not low doses (3 and 10 mg/kg, i.p.), significantly attenuated hyperlocomotion in mice after PCP administration (3.0 mg/kg, subcutaneously [s.c.]). Furthermore, administration of SFN (3, 10, and 30 mg/kg, i.p.) attenuated the PPI deficits in mice after PCP administration (3.0 mg/kg, s.c.) in a dose-dependent manner. CONCLUSION: These results suggest that SFN has antipsychotic activity in an animal model of schizophrenia. Therefore, it is likely that SFN may be a potential therapeutic drug for schizophrenia.

Dopamina, óxido nítrico e suas interações em modelos para o estudo da esquizofrenia / Dopamine, nitric oxide and their interactions in models for the study of schizophrenia

Modelos experimentais baseados no aumento da neurotransmissão dopaminérgica mimetizam aspectos comportamentais e neuroquímicos característicos da esquizofrenia. Psicoestimulantes, como a anfetamina, são utilizados com esta finalidade, pois aumentam os níveis de dopamina extracelular nas vias mesocorticolímbica e mesoestriatal. As limitações da manipulação direta do sistema dopaminérgico nos modelos animais incentivam abordagens complementares. O óxido nítrico (NO), um neurotransmissor atípico que inibe a recaptação de dopamina e estimula sua liberação, parece modular comportamentos controlados pelo sistema dopaminérgico. O teste de inibição pré-pulso revela uma deficiência no filtro sensório-motor, verificada em esquizofrênicos ou após tratamentos com psicotomiméticos, podendo ser prevenida pela inibição do NO. Esta revisão apresenta evidências da interação do NO com o sistema dopaminérgico em modelos para o estudo da esquizofrenia como uma nova ferramenta de investigação desta patologia.

Experimental models based on the increase of dopaminergic neurotransmission mimic behavioral and neurochemical schizophrenia-like aspects. Psychostimulants, as amphetamine, are used with this purpose because they increase extracellular dopamine levels in mesocorticolimbic and mesostriatal pathways. The limitations of direct manipulation uniquely based on the dopamine system in animal models have encouraged the use of new approaches. Nitric oxide (NO), an atypical neurotransmitter which inhibits dopamine reuptake and stimulates its release, seems to modulate dopamine-controlled behaviors. The prepulse inhibition test reveals deficits on the sensorimotor filter found in schizophrenics or after psichotomimetic treatments. This review presents evidences for the interaction between NO and DA systems on schizophrenia models as a new tool for the investigation of this pathology.

Effects of a New Antipsychotic Drug (YKP1447) on Impaired Prepulse Inhibition Induced by Apomorphine and Phencyclidine in Rats / 대한정신약물학회지

OBJECTIVE: Schizophrenia, a devastating mental disorder, displays a wide range of cognitive impairments including attentional impairment. Prepulse inhibition (PPI), in which a startle response to a loud acoustic noise is reduced by a preceding auditory stimulus of a lower intensity, is impaired in schizophrenic patients and rats injected with apomorphine (APO) or phencyclidine (PCP) mimicking attentional deficits in schizophrenics. Here we examined therapeutic efficacy of a newly developed atypical antipsychotic compound (YKP1447;YKP) on PPI impairment induced by various doses of APO and PCP. METHODS: This study was composed of 3 experiments. YKP (0.5-15 mg/kg) or vehicle (VEH) was administered 15 min before the injection of APO (0.5 mg/kg, Exp1) or PCP (2.0 mg/kg, Exp2:1.5 mg/kg, Exp3). They were then tested for PPI in which a mix of startle stimulus and prepulse was presented. RESULTS: APO or PCP treatment effectively impaired PPI in tested animals (VEH/APO or VEH/PCP). Impaired PPI in APO group was reversed in animals that were pretreated with YKP (5-10 mg/kg) (Exp1). However YKP treatment was not effective in PCP group (Exp2-3). CONCLUSION: High concentration of YKP pretreatment had antipsychotic effect on APO-induced impairment in attentional function suggesting that the compound could potentially be used to treat cognitive impairment due to increased dopaminergic receptorbinding.