The effects of prepulse-blink reflex trial repetition and prepulse change on blink reflex modification at short and long lead intervals

Prepulse inhibition and facilitation of the blink reflex are said to reflect different responses elicited by the lead stimulus, transient detection and orienting response respectively. Two experiments investigated the effects of trial repetition and lead stimulus change on blink modification. It was hypothesized that these manipulations will affect orienting and thus blink facilitation to a greater extent than they will affect transient detection and thus blink inhibition. In Experiment 1 (N = 64), subjects were trained with a sequence of 12 lead stimulus and 12 blink stimulus alone presentations, and 24 lead stimulus-blink stimulus pairings. Lead interval was 120 ms for 12 of the trials and 2000 ms for the other 12. For half the subjects this sequence was followed by a change in pitch of the lead stimulus. In Experiment 2 (N = 64), subjects were trained with a sequence of 36 blink alone stimuli and 36 lead stimulus-blink stimulus pairings. The lead interval was 120 ms for half the subjects and 2000 ms for the other half. The pitch of the lead stimulus on prestimulus trials 31-33 was changed for half the subjects in each group. In both experiments, the amount of blink inhibition decreased during training whereas the amount of blink facilitation remained unchanged. Lead stimulus change had no effect on blink modification in either experiment although it resulted in enhanced skin conductance responses and greater heart rate deceleration in Experiment 2. The present results are not consistent with the notion that blink facilitation is linked to orienting whereas blink inhibition reflects a transient detection mechanism. (C) 1998 Elsevier Science B.V.

The effect of repeated prepulse and reflex stimulus presentations on startle prepulse inhibition

The magnitude of a startle reflex is inhibited if the reflex-eliciting stimuli is preceded by a prepulse stimulus at a short lead interval. Previous research in humans has shown that the extent of prepulse inhibition decreases over repeated presentations of reflex stimuli and prepulse-reflex stimulus pairings. The present study (N=70) investigated the effect of repeated presentations of prepulse stimuli, reflex stimuli, or prepulse-reflex stimulus pairings on prepulse inhibition. Five groups of subjects were presented during habituation training with either (a) reflex stimuli, (b) prepulse-reflex stimulus pairings, (c) a random sequence of prepulse and reflex stimuli, (d) prepulse stimuli, or (e) experimentally irrelevant light stimuli. Prepulse inhibition was reduced if startle stimuli were presented during habituation ((a), (b), (c)), but not after repeated presentation of the prepulse or the light stimulus ((d), (e)). The reduction in prepulse inhibition was abolished after dishabituation of the startle reflex. The present results indicate that habituation of the startle reflex can result in a reduction of prepulse inhibition. (C) 1998 Elsevier Science B.V.

The relationship between prepulse inhibition and perceived intensity of the blink-eliciting stimulus: Stimulus intensity and lead interval effects

The hypothesis that prepulse inhibition of the blink reflex reflects a transient process that protects preattentive processing of the prepulse was investigated. Participants were presented with pairs of blink-eliciting noises, with some noises preceded by a prepulse, and were asked to rate the intensity of the second noise relative to the first. Inhibition of blink amplitude was greater for a 110 dB(A) noise than for a 95 dB(A) noise with a 120 ms lead interval, whereas there was no difference with a 30 ms lead interval. The reduction in perceived intensity was greater for the 110 dB(A) noise than for the 95 dB(A) noise with the 120 ms lead interval, but not with the 30 ms lead interval. The parallel results support an association between prepulse inhibition and perceived intensity. However, the prepulse did not reduce intensity ratings relative to control trials in some conditions, suggesting that prepulse inhibition is not always associated with an attenuation of the impact of the blink-eliciting stimulus.

Nitric oxide synthase inhibitors improve prepulse inhibition responses of Wistar rats

Introduction: Cognitive and attentional deficits in schizophrenia include impairment of the sensorimotor filter as measured by prepulse inhibition (PPI). In this way, the study of animals that naturally present low PPI responses could be a useful approach for screening new antipsychotic drugs. Several pieces of evidence suggest that dopamine and nitric oxide (NO) can modulate PPI but their role in those animals is unknown. Objectives: The aim of this study was to investigate the role of dopamine and NO in Wistar rats with naturally low PPI response. Methods: Male Wistar rats with low PPI responses received an i.p. injection of the antipsychotics haloperidol (0.1, 0.3 or 1 mg/kg) or clozapine (0.5, 1.5 or 5 mg/kg), the anxiolytic diazepam (1 or 3 mg/kg) or the NO synthase (NOS) inhibitors, N(G)- nitro-L-arginine (L-NOARG; 40 mg/kg, acutely or sub-chronically) or 7-Nitroindazole (7-NI; 3, 10 or 30 mg/kg). All animals were submitted to the PPI test 1 h after injection. Striatal and cortical dopamine, DOPAC, and noradrenaline levels of rats with low PPI responses were compared to rats with normal PPI responses. Results: We found increased levels of catecholamines on the striatum and prefrontal cortex of Wistar rats with low PPI. In these animals, both antipsychotics, typical and atypical, and NOS inhibitors significantly increased PPI. Conclusion: Taken together, our findings suggest that the low PPI phenotype may be driven by an over-active catecholamine system. Additionally, our results corroborate the hypothesis of dopamine and NO interaction on PPI modulation and suggest that Wistar rats with low PPI may represent an interesting non-pharmacological model to evaluate new potential antipsychotics. (C) 2010 Elsevier B.V. All rights reserved.

Nitric oxide modulation of methylphenidate-induced disruption of prepulse inhibition in Swiss mice

Drugs that facilitate dopaminergic neurotransmission induce cognitive and attentional deficits which include inability to filter sensory input measured by prepulse inhibition (PPI) Methylphenidate, an amphetamine analog is used in the treatment of attention deficit hyperactivity disorder Given that nitric oxide (NO) modulates dopamine effect our aim is to analyze the nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC) inhibitors effect on PPI disruption induced by methylphenidate The inhibitors effects were compared to those produced by haloperidol and clozapine Male Swiss mice received a first I p. Injection (one hour before testing), of either saline, or N(G) nitro L-arginine (10, 40 or 90 mg/kg) or 7-Nitroindazole (3, 10, 30 or 60 mg/kg). or oxadiazolo-quinoxalin (5 or 10 mg/kg). or haloperidol (1 mg/kg), or clozapine (5 mg/kg) Thirty min later mice received the second injection of either saline or methylphenidate (20 or 30 mg/kg) or amphetamine (5 or 10 mg/kg). One group of mice received intracerebroventricular 7-Nitroindazole (50 or 100 nM) followed by systemic administration of saline or methylphenidate (30 mg/kg) The results revealed a methylphenidate dose-dependent disruption of PPI comparable to amphetamine. The effect was prevented by either nitric oxide synthase or guanilate cyclase inhibitors or clozapine or haloperidol In conclusion, methylphenidate induced a dose-dependent PPI disruption in Swiss mice modulated by dopamine and NO/sGC. The results corroborate the hypothesis of dopamine and NO interacting to modulate sensorimotor gating through central nervous system. It may be useful to understand methylphenidate and other psychostimulants effects (C) 2009 Elsevier B.V All rights reserved

Routine post-weaning handling of rats prevents isolation rearing-induced deficit in prepulse inhibition

Rats reared under isolation conditions from weaning present a number of behavioral changes compared to animals reared under social conditions (group housing). These changes include deficits in prepulse inhibition (PPI) of the startle reflex to a loud sound. PPI refers to the reduction of the magnitude of the startle reflex when a relatively weak stimulus (the prepulse) precedes by an appropriate time interval the intense startle-elicing stimulus (the pulse). PPI is useful for studying sensorimotor integration. The present study evaluated the effect of handling on the impairment of PPI induced by isolation-rearing. Male Wistar rats (N = 11-15/group) were housed in groups (5 per cage and handled three times a week) or isolated (housed individually) since weaning (21 days) for 10 weeks when they reach approximately 150 g. The isolated rats were divided into "minimally handled" animals (handled once a week for cleaning purposes only) or "handled" animals (handled three times a week). This handling consisted of grasping the rat by the tail and moving it to a clean cage (approximately 5 s). A statistically significant reduction (52%) in the PPI test was found only in the isolated group with minimal handling while no difference was seen between grouped animals and isolated handled animals. These results indicate that isolation rearing causes disruption in the PPI at adult age, which serves as an index of attention deficit. This change in the sensory processing of information induced by post-weaning isolation can be prevented by handling during the development of the animal.

Maternal separation followed by isolation-housing differentially affects prepulse inhibition of the acoustic startle response in C57BL/6 mice

Exposure to chronic stress is associated with an increased incidence of neuropsychiatric dysfunction. The current study evaluated two competing hypotheses, the cumulative stress and the match/mismatch hypothesis of neuropsychiatric dysfunction, using two paradigms relating to exposure to “stress”: pre-weaning maternal separation and post-weaning isolation-housing. C57BL/6 offspring were reared under four conditions: typical animal facility rearing (AFR, control), early handling (EH, daily 15 min separation from dam), maternal separation (MS, daily 4 hr separation from dam), and maternal and peer separation (MPS, daily 4 hr separation from dam and from littermates). After weaning, mice were either housed socially (2–3/cage) or in isolation (1/cage) and then tested for prepulse inhibition in adulthood. Isolation-housed MPS subjects displayed greater deficits in prepulse inhibition relative to socially-housed MPS subjects while socially-housed AFR subjects displayed greater deficits in prepulse inhibition relative to isolation-housed AFR subjects. The results indicate that these treatment conditions represent a potentially valuable model for evaluating the match/mismatch hypothesis in regards to neuropsychiatric dysfunction.

Combined prenatal and chronic postnatal vitamin D deficiency in rats impairs prepulse inhibition of acoustic startle

There is growing evidence that 1,25-dihydroxyvitamin D-3 is involved in normal brain development. The aim of this study was to examine the impact of prenatal and postnatal hypovitaminosis D on prepulse inhibition (PPI) of acoustic startle in adult rats. We compared six groups of rats: control rats with normal vitamin D throughout life and normal litter size (Litter); control rats with normal vitamin D but with a reduced litter size of two (Control); offspring from reduced litters of vitamin D deplete mothers who were repleted at birth (Birth), repleted at weaning (Weaning) or remained on a deplete diet until 10 weeks of age (Life); or control rats that were placed on a vitamin D-deficient diet from 5 to 10 weeks of age (Adult). All rats were tested in acoustic startle chambers at 5 and 10 weeks of age for acoustic startle responses and for PPI. There were no significant group differences at 5 weeks of age on the acoustic startle response or on PPI. At 10 weeks of age, rats in the Life group only had impaired PPI despite having normal acoustic startle responses. We conclude that combined prenatal and chronic postnatal hypovitaminosis D, but not early life hypovitaminosis D, alters PPI. (C) 2004 Elsevier Inc. All rights reserved.

Effects of reflex stimulus intensity and stimulus onset asynchrony on prepulse inhibition and perceived intensity of the blink-eliciting stimulus

Prepulse inhibition of the blink reflex is widely applied to investigate information processing deficits in schizophrenia and other psychiatric patient groups. The present experiment investigated the hypothesis that prepulse inhibition reflects a transient process that protects preattentive processing of the prepulse. Participants were presented with pairs of blinkeliciting noises, some preceded by a prepulse at a variable stimulus onset asynchrony (SOA), and were asked to rate the intensity of the second noise relative to the first. Inhibition of blink amplitude was greater for a 110-dB (A) noise than for a 95-dB(A) noise with a 120-ms SOA, whereas there was no difference with a 30-ms SOA. The perceived intensity was also lower for the 110-dB(A) noise than for the 95-dB(A) noise with the 120-ms SOA, but not with the 30-ms SOA. The parallel results support a relationship between prepulse inhibition of response amplitude and perceived intensity. However, the prepulse did not reduce intensity ratings relative to control trials in some conditions, suggesting that prepulse inhibition is not always associated with an attenuation of the perceived impact of the blink-eliciting stimulus.

Dopamina, óxido nítrico e suas interações em modelos para o estudo da esquizofrenia

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.

Investigation of threat-related attentional bias in anxious children using the startle eyeblink modification paradigm

We used the startle eyeblink modification paradigm to investigate whether clinically anxious children, like high trait-anxious adults, display a bias in favour of threat words compared to neutral words. The present study included 16 clinically anxious children whose diagnostic status was determined using the parent version of a semistructured diagnostic interview as part of a larger childhood anxiety study. The children were presented with threat and neutral words fur 6 s each. A startle-eliciting auditory stimulus - a 100 dBA burst of white noise of 50 ms duration - was presented during the words at lead intervals of 60, 120, 240, or 3500 ms and during intertrial intervals. The overall pattern of startle eyeblink modification indicated inhibition at the 120 and 240 ms lead intervals and facilitation at the 3500 ms lead interval. startle-latency shortening during threat words at the :60 ms lead interval was larger than at other intervals, whereas there was no difference during neutral words. This result reflects an anxiety-related bias in favour of threat words occurring at a very early - and possibly preattentive stage - of information processing.

Effects of microinjections of apomorphine and haloperidol into the inferior colliculus on the latent inhibition of the conditioned emotional response

Electrical or chemical stimulation of the inferior colliculus (IC) induces fear-like behaviors. More recently, consistent evidence has shown that electrical stimulation of the central nucleus of the IC supports Pavlovian conditioning and latent inhibition (Li). LI is characterized by retardation in conditioning and also by an impaired ability to ignore irrelevant stimuli, after a non-reinforced pre-exposure to the conditioned stimulus. LI has been proposed as a behavioral model of cognitive abnormalities seen in schizophrenia. The aim of the present study was to determine whether dopaminergic mechanisms in the IC are involved in LI of the conditioned emotional response (CER). To induce LI, a group of rats was pre-exposed (PE) to six tones in two sessions, while rats that were not pre-exposed (NPE) had two sessions without tone presentations. The conditioning consisted of two tone presentations to the animal, followed immediately by a foot shock. PE and NPE rats received IC microinjections of physiological saline, the dopaminergic agonist apomorphine (9.0 mu g/0.5 mu L/side), or the dopaminergic antagonist haloperidol (0.5 mu g/0.5 mu L/side) before both pre-exposure and conditioning. During the test, the PE rats that received saline or haloperidol had a lower suppression of the licking response compared to NPE rats that received vehicle or haloperidol, indicating that latent inhibition was induced. There was no significant difference in the suppression ratio in rats that received apomorphine injections into the IC, indicating reduced latent inhibition. These results suggest that dopamine-mediated mechanisms of the IC are involved in the development of LI. (C) 2008 Elsevier Inc. All rights reserved.

Attentional modulation of blink startle at long, short, and very short lead intervals

The present research investigated attentional blink startle modulation at lead intervals of 60, 240 and 3500 ms. Letters printed in Gothic or standard fonts, which differed in rated interest, but not valence, served as lead stimuli. Experiment I established that identifying letters as vowels/consonants took longer than reading the letters and that performance in both tasks was slower if letters were printed in Gothic font. In Experiment 2, acoustic blink eliciting stimuli were presented 60, 240 and 3500 ms after onset of the letters in Gothic and in standard font and during intertrial intervals. Half the participants (Group Task) were asked to identify the letters as vowels/consonants whereas the others (Group No-Task) did not perform a task. Relative to control responses, blinks during letters were facilitated at 60 and 3500 ms lead intervals and inhibited at the 240 ms lead interval for both conditions in Group Task. Differences in blink modulation across lead intervals were found in Group No-Task only during Gothic letters with blinks at the 3500 ms lead interval facilitated relative to control blinks. The present results confirm previous findings indicating that attentional processes can modulate startle at very short lead intervals. (C) 2001 Elsevier Science B.V. All rights reserved.

Redox dysregulation in the pathophysiology of schizophrenia and bipolar disorder: insights from animal models.

Abstract Significance: Schizophrenia (SZ) and bipolar disorder (BD) are classified as two distinct diseases. However, accumulating evidence shows that both disorders share genetic, pathological, and epidemiological characteristics. Based on genetic and functional findings, redox dysregulation due to an imbalance between pro-oxidants and antioxidant defense mechanisms has been proposed as a risk factor contributing to their pathophysiology. Recent Advances: Altered antioxidant systems and signs of increased oxidative stress are observed in peripheral tissues and brains of SZ and BD patients, including abnormal prefrontal levels of glutathione (GSH), the major cellular redox regulator and antioxidant. Here we review experimental data from rodent models demonstrating that permanent as well as transient GSH deficit results in behavioral, morphological, electrophysiological, and neurochemical alterations analogous to pathologies observed in patients. Mice with GSH deficit display increased stress reactivity, altered social behavior, impaired prepulse inhibition, and exaggerated locomotor responses to psychostimulant injection. These behavioral changes are accompanied by N-methyl-D-aspartate receptor hypofunction, elevated glutamate levels, impairment of parvalbumin GABA interneurons, abnormal neuronal synchronization, altered dopamine neurotransmission, and deficient myelination. Critical Issues: Treatment with the GSH precursor and antioxidant N-acetylcysteine normalizes some of those deficits in mice, but also improves SZ and BD symptoms when given as adjunct to antipsychotic medication. Future Directions: These data demonstrate the usefulness of GSH-deficient rodent models to identify the mechanisms by which a redox imbalance could contribute to the development of SZ and BD pathophysiologies, and to develop novel therapeutic approaches based on antioxidant and redox regulator compounds. Antioxid. Redox Signal. 18, 1428-1443.