Prepulse Inhibition Levels Research Articles

T36. THE ANTIPSYCHOTIC-LIKE PROPERTIES OF EVENAMIDE (NW-3509) REFLECT THE MODULATION OF GLUTAMATERGIC DYSREGULATION

BackgroundThe lack of adequate benefit with current 5HT2 / D2 antipsychotics in large proportions of schizophrenic patients suggests it is essential to modulate other mechanisms for improving symptoms of schizophrenia (SCZ). Increasing evidence implicates NMDAr hypofunction, and hippocampal hyperactivity, in the dysregulation not only of mesolimbic DA neurons but also of Glu neurons, leading to increasing synaptic activity of Glu in the PFC. Injection of NMDAr antagonists (PCP, ketamine) at doses that produce psychotomimetic effects lead to a downstream increase of Glu neurotransmission at non-NMDAr. The excessive firing and the hyper-glutamatergic tone represent alternative targets of treatment for SCZ ultimately affecting positive, negative, cognitive symptoms. The addition of Glu release inhibitors may augment the benefits of the antipsychotics in patients showing inadequate response.Evenamide uniquely does not interact with monoaminergic (DA, 5-HT, NA, H) pathways affected by current antipsychotics, or with more than 130 different targets that are involved in CNS activity, except sodium channels. Preclinical data suggests that by the modulation of the firing abnormalities, evenamide normalizes the aberrant spread of Glu excitatory transmission that occurs in the brains of patients with SCZ. Evenamide showed efficacy in animal models relevant to SCZ (sensory motor gating, mania, psychosis, depression, impulse control, cognition, social interaction), in monotherapy and as an add on to first or second generation antipsychotics irrespective of whether impairment was either spontaneous, induced by amphetamine or NMDAr antagonists or stress. Evenamide, has also shown significant benefit in a p.c phase 2 trial as an add-on to risperidone and aripiprazole in patients worsening on dopaminergic/serotoninergic antagonist medication, suggesting it acts through other mechanisms. New animal data further confirm evenamide’s activity in reducing SCZ symptoms provoked by Glu alteration.MethodsEffects of evenamide (EVE 1.25, 5, 15 mg/kg PO) to restore the impaired information processing (a deficit observed in SCZ), were evaluated in the rat model of the Pre-Pulse Inhibition (PPI) deficit induced by injection of the NMDAr antagonist ketamine (KET 6 mg/kg, SC). Clozapine (CLO 7.5 mg/kg, IP) was used as a positive control.ResultsPPI analysis showed significant main effects for KET to lower PPI levels [F(1,264)=139.67, P<0.0001], for EVE [F(3,264)=3.14, P<0.05] and CLO to enhance PPI levels [F(1,98)=30.89, P<0.001]. Notably, significant EVE x KET [F(3,264)=2.79, P<0.05] and CLO x KET interactions [F(1,98)=5.45, P<0.05] were found.Post-hoc analyses (Tukey’s) revealed that KET significantly lowered PPI (P<0.0001) for each group; both EVE (5 mg/kg) and CLO significantly increased PPI in KET-treated rats (P=0.02; p<0.001).DiscussionEvenamide as monotherapy has similar effect to clozapine in reversing ketamine- induced worsening of PPI. Together with previously demonstrated effects to reverse PCP-induced PPI and social interaction deficits, this further supports its potential to affect both positive and negative symptoms of SCZ by targeting altered Glu transmission.Efficacy of evenamide as an add-on to antipsychotics would revolutionize development of novel antipsychotics that would target aberrant firing and Glu transmission in SCZ. Two clinical trials have been planned to support the hypothesis that the addition of evenamide should add a non-dopaminergic mechanism for augmenting antipsychotic efficacy in patients who are not responding adequately to current antipsychotic, and in patients with treatment resistant SCZ who are not responding/worsening on clozapine.

Pdxdc1 modulates prepulse inhibition of acoustic startle in the mouse

Current antipsychotic medications used to treat schizophrenia all target the dopamine D2 receptor. Although these drugs have serious side effects and limited efficacy, no novel molecular targets for schizophrenia treatment have been successfully translated into new medications. To identify novel potential treatment targets for schizophrenia, we searched for previously unknown molecular modulators of acoustic prepulse inhibition (PPI), a schizophrenia endophenotype, in the mouse. We examined six inbred mouse strains that have a range of PPI, and used microarrays to determine which mRNA levels correlated with PPI across these mouse strains. We examined several brain regions involved in PPI and schizophrenia: hippocampus, striatum, and brainstem, found a number of transcripts that showed good correlation with PPI level, and confirmed this with real-time quantitative PCR. We then selected one candidate gene for further study, Pdxdc1 (pyridoxal-dependent decarboxylase domain containing 1), because it is a putative enzyme that could metabolize catecholamine neurotransmitters, and thus might be a feasible target for new medications. We determined that Pdxdc1 mRNA and protein are both strongly expressed in the hippocampus and levels of Pdxdc1 are inversely correlated with PPI across the six mouse strains. Using shRNA packaged in a lentiviral vector, we suppressed Pdxdc1 protein levels in the hippocampus and increased PPI by 70%. Our results suggest that Pdxdc1 may regulate PPI and could be a good target for further investigation as a potential treatment for schizophrenia.

The effects of multiphasic prepulses on automatic and attention-modulated prepulse inhibition.

Prepulse inhibition (PPI) is widely viewed as an operational measure of sensorimotor gating. Previous research has shown that sensorimotor gating can occur automatically and also can be influenced by selective attention. The present research investigated the relationship of the transient detection response (TDR) with automatic and attention-modulated PPI using a novel "multiphasic" prepulse stimulus. Experiment 1 compared discrete versus multiphasic prepulse types in a no-task PPI protocol to validate multiphasic prepulses as effective elicitors of automatic sensorimotor gating. Results revealed that the two prepulse types elicited equivalent levels of PPI. Experiment 2 compared the effectiveness of continuous monophasic versus continuous multiphasic prepulses within a task-based PPI protocol using a lead interval of 120ms. Results revealed a significant attention effect for monophasic prepulses only. However, robust PPI was produced by the multiphasic prepulses independent of attention as well as over time. These results suggest that multiple influences on PPI can be assessed concurrently depending on prepulse parameters designed to activate the TDR when used in a PPI protocol capable of assessing the effects of selective attention on prepulse processing [corrected]

129. Lower Prepulse Inhibition in Clinical High-Risk Group but not in Familial Risk Group for Psychosis Compared to Healthy Controls

Abstract Although lower level of prepulse inhibition (PPI) of startle response is well known in schizophrenia, it is not clear when this begins. The aim of this study is to investigate acoustic PPI in clinical and familial risk of psychosis We studied PPI in a sample of individuals with Ultra High Risk (UHR) for psychosis, a group of familial risk for psychosis and healthy controls (HC). UHR was defined based on CAARMS (n = 25), FR group consist of siblings of patients with schizophrenia (n = 24). We collected clinical data by using BPRS-E, SANS, SAPS, PAS when individuals with UHR were antipsychotic-naive. A cognitive battery containing RVLT, WCST, Stroop, digit-symbol and TMT was applied to all participants. Interval between S1 (20 ms, 86 dB) and S2 (40 ms, 115 dB) was 120 ms, and there was a 70-dB background white noise during the experiment. There was a significant difference in PPI among the 3 groups. Post hoc analysis showed that PPI was lower in UHR group than both FR (z = 2.27, = .02) and HC groups (z = 2.53, = .01), and there was no difference between FR and HC groups. Mean S1 was higher in FR group than UHR group (z = 2.23, = .02). PPI and S1 amplitude were not found correlated with BPRS-E, SANS, SAPS scores, and cognitive test scores. Our findings show that PPI deficits begins before the onset of psychosis, and it is more prominent in those with clinical risk rather than familial risk for psychosis

Update of studies about prepulse inhibition in psychiatric disorders

Prepulse inhibition (PPI) is the suppression of the startle reflex when the startling stimulus 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 schizophrenic 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 obsessive compulsive disorder had lower levels of PPI. PPI deficits in bipolar disorder patients were gender-dependent. Studying PPI and the top-down modulation of PPI could provide a basis to study the interaction of sensory processing and attention, and facilitate the researches of neural mechanism underlying the deficits of sensory gating. To establish advanced paradigms of PPI, new cognitive components could be introduced, such as attention, emotion, motor control, compulsivity and so on, thus improving the specificity of PPI test and promoting the PPI test as new biomarker and endophenotype in various psychiatric disorders. Key words: Prepulse inhibition; Schizophrenia; Tourette’s syndrome; Obsessive compulsive disorder; Bipolar disorder

Efecto de la cocaína sobre la inhibición por prepulso de la respuesta de sobresalto

Prepulse inhibition (PPI) of the startle response is an index used to evaluate how the pre-attention system works. PPI is altered in patients with a mental disorder such as schizophrenia and in subjects who are vulnerable to it. Likewise, cocaine users also frequently exhibit psychiatric disorders as schizophrenia. To know the alterations that cocaine produces on PPI. A comprehensive review is carried out, covering both clinical and preclinical studies with animal models that have evaluated the effects of cocaine exposure on the PPI paradigm. Underlying neural bases and mechanisms of action are suggested to explain these findings. Cocaine alters PPI through its action on the dopaminergic system. Acute exposure of cocaine decreases PPI by increasing dopamine, while with chronic use, depending on withdrawal time, PPI can be restored. However, the effects of cocaine on PPI appear to depend on the baseline levels of PPI shown by the individual. Thus, since a deficit in PPI has been associated with a greater vulnerability to developing mental pathologies such as schizophrenia, PPI level in subjects could be considered as a biomarker of psychiatric vulnerability. Therefore, a better understanding of the effect of drugs such as cocaine on PPI may help to understand the development of dual pathology.

Sensory Gating Deficits in First-Episode Psychosis: Evidence From Neurophysiology, Psychophysiology, and Neuropsychology.

Sensory gating deficits are commonly found in patients with schizophrenia. However, there is still scarce research on this issue. Thirty-eight patients with first-episode psychosis (FEP) were compared to thirty-eight controls. A condition-test paradigm of event-related potentials (ERP), prepulse inhibition (PPI), and some specific tasks of the MATRICS Consensus Cognitive Battery (MCCB) were used (i.e., TMT, BACS-SC, and Fluency for processing speed and CPT-IP for attention and vigilance). The ERP components measured were P50, N1, and P2. The PPI intervals examined were 30, 60, and 120 msec. Regarding the MCCB, processing speed and attention/vigilance cognitive domains were selected. FEP patients showed significant deficits in N1 and P2 components, at 30 and 60 PPI levels and in all the MCCB subtests selected. We obtained significant relationships in N1 with PPI-60, and with one MCCB subtest for processing speed. In addition, this same subtest showed significant association with P2. Therefore, sensory gating functioning is widely impaired since the very early stages of schizophrenia.

Investigation of the role of alpha-2 adrenergic receptors on prepulse inhibition of acoustic startle reflex in rats.

Alpha-2 adrenergic receptors target several behavioral functions. These receptors may connect with the brain pathways mediating sensorimotor gating system that associate with psychoses, and the literature that investigate the relationship between alpha-2 receptors and sensorimotor gating system is very limited and some results are controversial. Thus, we aimed to investigate the role of alpha-2 receptors on prepulse inhibition (PPI) of acoustic startle reflex which is a measure of sensorimotor gating. Adult male Wistar rats were subjects. PPI was measured as the per cent inhibition of the startle reflex produced by a startling pulse stimulus. The average PPI levels were used in the further analyses. Clonidine (0.03-1 mg/kg), an agonist of alpha-2 receptors, idazoxan (10 mg/kg), an antagonist alpha-2 receptors, and saline were injected to rats intraperitoneally. PPI was evaluated at two different startle intensity levels (78 and 86 dB, respectively). Treatments produced some significant changes on PPI of startle reflex at all two levels of startle intensity. While clonidine (0.06, 0.25, 0.5, and 1 mg/kg) disrupted significantly PPI, idazoxan (10 mg/kg) did not produce any significant effect on PPI. However, pretreatment with idazoxan reversed significantly clonidine-induced disruption of PPI. Neither idazoxan (10 mg/kg) nor clonidine (1 mg/kg) produces any significant change on locomotor activity in naive rats. Because idazoxan and clonidine also act through imidazoline receptors, our results suggest that alpha-2 and/or imidazoline receptors are associated with PPI of acoustic startle reflex in rats. Stimulation of these receptors may cause sensorimotor gating disturbances.

CHRNA4 was associated with prepulse inhibition of schizophrenia in Chinese: a pilot study

ABSTRACTIntroduction: Prepulse inhibition (PPI) of the auditory startle reflex, as an operational measurement used to evaluate the function of brain sensorimotor gating, appears to be a sensitive potential endophenotype for schizophrenia. CHRNA4 is highly expressed in the central nervous system and has been demonstrated to be significantly associated with schizophrenia by previous studies. The purpose of the current study was to evaluate the effect of CHRNA4 on PPI and acoustic startle parameters in schizophrenia.Methods: 77 patients with schizophrenia and 62 controls were administered the test PPI, and 3 single nucleotide polymorphisms (SNPs) (rs3746372, rs1044396, and rs3787140) of CHRNA4 were genotyped in these subjects.Results: Patients with schizophrenia showed significantly lower levels of PPI at the 120 ms prepulse intervals and longer peak latency than controls, and the GG genotype of rs3746372 and the TT genotype of rs1044396 were associated with decreased PPI levels in schizophrenia but not in controls.Conclusion: PPI may be influenced by the polymorphisms of the CHRNA4 in schizophrenia and it may be a potential endophenotype of schizophrenia. An independent replication would greatly increase the value of this study.

The neurosteroidogenic enzyme 5α-reductase modulates the role of D1 dopamine receptors in rat sensorimotor gating

Neurosteroids exert diverse modulatory actions on dopamine neurotransmission and signaling. We previously documented that the enzyme 5α-reductase, which catalyzes the main rate-limiting step in neurosteroid synthesis, is required for the behavioral responses of Sprague–Dawley rats to non-selective dopaminergic agonists, such as the D1–D2 receptor agonist apomorphine. Specifically, systemic and intra-accumbal administrations of the 5α-reductase inhibitor finasteride countered apomorphine-induced deficits of sensorimotor gating, as measured by the prepulse inhibition (PPI) of the startle reflex; the classes of dopamine receptors involved in these effects, however, remain unknown. Prior rodent studies have revealed that the contributions of dopamine receptors to PPI regulation vary depending on the genetic background; thus, we analyzed the effect of finasteride on the PPI deficits induced by selective dopamine receptor agonists in Long–Evans (a strain exhibiting PPI deficits in response to both D1 and D2 receptor agonists) and Sprague–Dawley rats (which display PPI reductions following treatment with D2, and D3, but not D1 receptor agonists). In Long–Evans rats, finasteride opposed the PPI deficits induced by activation of D1, but not D2 receptors; conversely, in Sprague–Dawley rats, finasteride prevented the reductions in %PPI and accumbal dopamine extracellular levels caused by selective stimulation of D3, but not D2 receptors; however, the effects on %PPI were not confirmed by analyses on absolute PPI values. Our findings suggest that 5α-reductase modulates the effects of D1, but not D2 receptor agonists on sensorimotor gating. These data may help elucidate the role of neurosteroids in neuropsychiatric disorders featuring PPI deficits, including schizophrenia and Tourette syndrome.

Disruptions of sensorimotor gating, cytokines, glycemia, monoamines, and genes in both sexes of rats reared in social isolation can be ameliorated by oral chronic quetiapine administration

The pathogenesis of schizophrenia in patients with metabolic abnormalities remains unclear. Our previous study demonstrated that isolation rearing (IR) induced longitudinal concomitant changes of pro-inflammatory cytokine (pro-CK) levels and metabolic abnormalities with a developmental origin. However, the general consensus, believes that these abnormalities are caused by antipsychotic treatment in schizophrenic patients. The IR paradigm presents with face, construct, and predictive validity for schizophrenia. Therefore, we employed IR rats of both sexes to examine whether chronic quetiapine (QTP, a second-generation antipsychotic medication) treatment induces disruptions of metabolism (body weight, blood pressure, and the glycemic and lipid profiles) or cytokines [interleukin (IL)-1 beta, IL-6, IL-10, interferon-gamma, and tumor necrosis factor (TNF)-alpha], and further, whether it reverses deficits of behaviors [locomotor activity and prepulse inhibition (PPI)] and the expression of monoamines (dopamine and serotonin) and related genes (Htr1a, Htr2a, Htr3a, Drd1a, and Gabbr2). IR induced higher levels of pro-CK, dysglycemia, blood pressure, locomotor activity, and impaired PPI, simultaneously destabilizing cortico-striatal monoamines and relevant genes in both sexes, while QTP demonstrated dose-dependent reversal of these changes, suggesting that QTP might reduce the pro-CKs to regulate these abnormalities. Our data implied that antipsychotics may not be the solitary factor causing metabolic problems in schizophrenia and suggested that inflammatory changes may play a vital role in the developmental pathophysiology of schizophrenia and related metabolic abnormalities.

Effects of selective estrogen receptor alpha and beta modulators on prepulse inhibition in male mice

Multiple lines of evidence suggest that the sex steroid hormone 17-β estradiol (E2) plays a protective role in schizophrenia. Systemic E2 enhances prepulse inhibition (PPI) of the acoustic startle reflex, an operational measure of sensorimotor gating known to be impaired in schizophrenia and related disorders. However, the relative contribution of different estrogen-receptor (ER) isoforms in these associations still awaits examination. The present study explored the effects of ER-α and ER-β stimulation or blockade on PPI and their functional relevance in an amphetamine-induced PPI deficiency model in male mice. Prior to the assessment of PPI, C57BL/6N male mice were injected with the ER-α agonist 4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT), the ER-α antagonist 1,3-bis (4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy) phenol]-1N-pyrozole dihydrochloride (MPP), the ER-β agonist 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN), or the ER-β antagonist 4-[2-phenyl-5,7-bis (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-3-yl] phenol (PHTPP), with or without concomitant amphetamine treatment. Acute pharmacological stimulation and blockade of ER-α, respectively, led to a dose-dependent increase and decrease in basal PPI. In contrast, acute treatment with preferential ER-β modulators spared PPI under basal conditions. Pretreatment with either ER-α or ER-β agonist was, however, effective in blocking amphetamine-induced PPI disruption. Our study demonstrates that activation of either ER isoform is capable of modulating dopamine-dependent PPI levels. At the same time, our results suggest that endogenous ER-α signaling may be more relevant than ER-β in the regulation of sensorimotor gating under basal conditions.

Social interaction of rats is related with baseline prepulse inhibition level

The symptoms of schizophrenia are evaluated in three general categories: positive, negative and cognitive symptoms. Disruption of prepulse inhibition (PPI) of the acoustic startle reflex is commonly used to model positive and cognitive symptoms in experimental animals. On the other hand, deficient social interaction (SI) is a common model of negative symptoms. Here we tested whether PPI provides information about negative symptoms by using a SI test. Baseline PPI and its relation with anxiety-like behavior were also examined with elevated plus maze (EPM) test. In the first experiment, baseline PPI levels of 30 Wistar rats were measured and animals with the highest 1/3 and the lowest 1/3 of PPI scores were respectively assigned in high-inhibitory (HI) and low-inhibitory (LI) groups. Subsequently, rats in the HI and LI groups were paired with animals from the same group and tested for SI. In the second experiment, another batch of animals was assigned to HI and LI groups and they were investigated in the EPM test. The results demonstrate a significant difference between the PPI values of HI and LI groups. Both the SI time and the moving distance of LI rats were significantly lower, and the average distance between rat pairs was significantly longer than HI rats. In the EPM test LI and HI rats showed similar levels of anxiety-like behaviors, however our results imply that performance of the rats in the SI test is related to baseline PPI levels. Thus PPI test can provide predictive information about the outcome of animal models for negative symptoms in rats.

Characterizing cannabis-induced psychosis: A study with prepulse inhibition of the startle reflex

Cannabis-induced psychotic disorder (CIPD) refers to psychotic symptoms that arise in the context of cannabis intoxication. Prepulse inhibition (PPI) deficits have been extensively identified in schizophrenia and in cannabis abusers. We aimed to characterize PPI in CIPD patients. We used a sample of 48 CIPD patients, 54 schizophrenia patients and cannabis abuse (SCHZ), 44 cannabis dependents (CD), and 44 controls. CIPD, SCHZ and CD were abstinent of cannabis consumption for 9 months. Participants were assessed with PPI at 30, 60, and 120ms. At 30ms, CIPD showed lower PPI levels than controls, and SCHZ obtained worse functioning than controls and CD. At 60ms, only SCHZ exhibited worse PPI percentages (of object) than controls. Finally, at 120ms, CIPD showed higher PPI levels than SCHZ, and SCHZ obtained lower percentages than controls. We found that CIPD and SCHZ patients showed deficits at the most pre-attentional levels, whereas CIPD patients performed better than SCHZ at higher attentional levels. These results suggest that CIPD constitutes a different group of patients than that of SCHZ. Deficits in PPI functioning at 30ms could be a useful psychophysiological measure to detect CIPD patients, who are frequently confused with cannabis abusers whose symptoms may mimic that of schizophrenia.

CDP-choline attenuates scopolamine induced disruption of prepulse inhibition in rats: Involvement of central nicotinic mechanism

It has been shown that cholinergic system plays an important role in schizophrenia-associated cognitive deficits, therefore cholinergic drugs are novel targets for the treatment of cognitive deficits seen in schizophrenia. We aimed to test the effects of CDP-choline on sensorimotor gating functioning, which is an important function for the integration of sensory and cognitive information processing and the execution of appropriate motor responses. In this study, prepulse inhibition (PPI) of the acoustic startle reflex was used to test the sensorimotor gating functioning, and the effects of CDP-choline on scopolamine induced PPI disruption were evaluated in rats. Furthermore, the contribution of the cholinergic mechanism in these effects was determined. CDP-choline (75, 250, 500mg/kg) by itself had no effect on the PPI in naïve animals. Scopolamine (0.4mg/kg; s.c.) significantly decreased the PPI levels and intraperitoneal administration of CDP-choline (250mg/kg) attenuated the effects of scopolamine. A non-specific nicotinic receptor antagonist, mecamylamine and an alpha 7 nicotinic receptor (α7-nAChR) antagonist, methyllycaconitine were used to investigate the mechanism underlying the effects of CDP-choline. Mecamylamine (3mg/kg; s.c.), and methyllycaconitine (10μg; i.c.v.) completely blocked the reversal effects of CDP-choline on scopolamine induced disruption of PPI. These results demonstrate that exogenous administration of CDP-choline attenuates scopolamine induced PPI disruption and show that the activation of central α7-nAChR may play a critical role in this effect.

Varenicline disrupts prepulse inhibition only in high-inhibitory rats

Varenicline, a widely used smoking cessation drug, has partial agonistic activity at α4β2 nicotinic receptors, and full agonistic activity at α7 nicotinic receptors. Thus it may interact with cognitive processes and may alleviate some of the cognitive disturbances observed in psychotic illnesses such as schizophrenia. We aimed to test the effects of varenicline on sensorimotor gating functioning, which is crucial for normal cognitive processes, especially for the integration of sensory and cognitive information processing and the execution of appropriate motor responses. Prepulse inhibition (PPI) of the acoustic startle reflex was used to test the sensorimotor gating functioning. First, the effects of varenicline and nicotine on rats having high or low baseline PPI levels were evaluated; then, varenicline was applied prior to apomorphine (0.5 mg/kg), and MK-801 (0.15 mg/kg), which are used as comparative models of PPI disruption. Varenicline (0.5-3 mg/kg) did not change PPI when given alone in naïve animals. When rats were selected according to their baseline PPI values, varenicline (1 mg/kg) significantly decreased PPI in high-inhibitory (HI) but not in low-inhibitory (LI) rats. Nicotine (1 mg/kg; tartrate salt) produced a similar activity in LI and HI groups. In combination experiments, varenicline did not reverse either apomorphine or the MK-801-induced disruption of PPI. These results demonstrate that the effects of both varenicline and nicotine on sensorimotor gating are influenced by the baseline PPI levels. Moreover, varenicline has no effect on apomorphine or the MK-801-induced disruption of PPI.

EPA-0460 – Effects of comt val158/met polymorphism on sensory-motor gating and blood monoamines level in russian schizophrenia patients and healthy persons

Catechol-O-methyltransferase (COMT) is candidate gene for schizophrenia, as it encodes enzyme involved in dopamine and noradrenaline methabolism. However, data concerning association of COMT polymorphism with schizophrenia onset in different ethnic groups are controversial. Impaired acoustic startle prepulse inhibition (PPI) is potential hallmark of vulnerability to schizophrenia, but a few investigations of COMT polymorphism effects on PPI revealed controversial results (Liu et al., 2013). To estimate effects of COMT polymorphism on PPI and blood monoamines level in Russian populations of schizophrenia patients and healthy persons. (males 22–55 years old): 39 schizophrenia patients and 32 healthy persons. PPI was estimated according to standard protocol (Calkins et al., 2007). Blood monoamnes estimated using HPLC with electrochemical detection. COMT polymorphism was detected by real-time PCR. There were significantly (p<0,05) lower heterozygotes frequency, impaired PPI, increased baseline startle latency, decreased plasma DOPAC in patients relatively to controls. Group x Genotype interaction was revealed for PPI and startle latency. In controls VAL/VAL carriers displayed the lowest PPI. In patients the lowest PPI showed VAL/ME T and the longest startle latency - MET/MET carriers. In controls PPI positively correlated with dopamine turnover ratio whereas in patients - with plasma adrenaline level. In Russian population effects of COMT VAL158/MET polymorphism on PPI significantly differ at healthy and schizophrenia persons. One can propose that PPI level in healthy subjects more strictly depends on dopamine turnover than in schizophrenia patients. Further investigations are needed to clear this problem. Supported by RHF grant 12-06-00809a

Prepulse Inhibition is Associated with Attention, Processing Speed, and 123I-FP-CIT SPECT in Parkinson's Disease

Prepulse inhibition is a measure of sensorimotor gating, which reflects the ability to filter or 'gate' irrelevant information. Prepulse inhibition is dramatically altered in basal ganglia disorders associated with dysfunction in the midbrain dopaminergic system, and corresponding cognitive information processing deficits such as slowed processing speed. Parkinson's disease is characterised by the degeneration of the midbrain dopaminergic system and is associated with cognitive dysfunction, including slowed information processing. Although sensorimotor processes in Parkinson's disease have been extensively studied in relation to motor function, less is known about the potential role of sensorimotor processes in cognitive function. We investigated the relationship between prepulse inhibition, cognition and nigrostriatal dysfunction, as measured with 123I-FP-CIT-SPECT scanning, in patients with Parkinson's disease. 38 Parkinson patients were assessed with prepulse inhibition, neuropsychological tests, and neurological investigation. A subset of these patients underwent 123I-FP-CIT-SPECT scanning. Patients with a higher level of prepulse inhibition performed better on cognitive measures tapping attention and processing speed than patients with a lower level of prepulse inhibition. Furthermore, there were significant correlations between prepulse inhibition and 123I-FP-CIT uptake in the striatum. Our results suggest that the level of prepulse inhibition is related to the efficiency of information processing in Parkinson's disease, and to the density of dopamine transporters in the striatum.

Meclizine Enhancement of Sensorimotor Gating in Healthy Male Subjects with High Startle Responses and Low Prepulse Inhibition

Histamine H1 receptor systems have been shown in animal studies to have important roles in the reversal of sensorimotor gating deficits, as measured by prepulse inhibition (PPI). H1-antagonist treatment attenuates the PPI impairments caused by either blockade of NMDA glutamate receptors or facilitation of dopamine transmission. The current experiment brought the investigation of H1 effects on sensorimotor gating to human studies. The effects of the histamine H1 antagonist meclizine on the startle response and PPI were investigated in healthy male subjects with high baseline startle responses and low PPI levels. Meclizine was administered to participants (n=24) using a within-subjects design with each participant receiving 0, 12.5, and 25 mg of meclizine in a counterbalanced order. Startle response, PPI, heart rate response, galvanic skin response, and changes in self-report ratings of alertness levels and affective states (arousal and valence) were assessed. When compared with the control (placebo) condition, the two doses of meclizine analyzed (12.5 and 25 mg) produced significant increases in PPI without affecting the magnitude of the startle response or other physiological variables. Meclizine also caused a significant increase in overall self-reported arousal levels, which was not correlated with the observed increase in PPI. These results are in agreement with previous reports in the animal literature and suggest that H1 antagonists may have beneficial effects in the treatment of subjects with compromised sensorimotor gating and enhanced motor responses to sensory stimuli.

Effects of smoking on the acoustic startle response and prepulse inhibition in smokers with and without posttraumatic stress disorder

Cigarette smokers smoke in part because nicotine helps regulate attention. Prepulse inhibition (PPI) of the startle reflex is a measure of early attentional gating that is reduced in abstinent smokers and in groups with attention regulation difficulties. Attention difficulties are found in people with posttraumatic stress disorder (PTSD). The aim of this study is to assess whether smoking and abstinence differentially affect the startle response and PPI in smokers with and without PTSD. Startle response and PPI (prepulses at 60, 120, or 240ms) were measured in smokers with (N = 39) and without (N = 61) PTSD, while smoking and again while abstinent. Participants with PTSD produced both larger magnitude and faster latency startle responses than controls. Across groups, PPI was greater when smoking than when abstinent. The PTSD and control group exhibited different patterns of PPI across prepulse intervals when smoking and when abstinent. Older age was associated with reduced PPI, but only when abstinent from smoking. The effects of PTSD on startle magnitude and of smoking on PPI replicate earlier studies. The different pattern of PPI exhibited in PTSD and control groups across prepulse intervals, while smoking and abstinent suggests that previous research on smoking and PPI has been limited by not including longer prepulse intervals, and that nicotine may affect the time course as well as increasing the level of PPI. The reduced PPI among older participants during abstinence suggests that nicotine may play a role in maintaining attention in older smokers, which may motivate continued smoking in older individuals.