Seroquel restores sensorimotor gating in phencyclidine-treated rats

Phencylidine (PCP) is a psychotomimetic noncompetitive glutamate antagonist that has been used in studies of the neural substrates of psychosis. Both schizophrenic patients and PCP-treated rats exhibit reduced amounts of prepulse inhibition (PPI) of the startle reflex, which is the normal inhibition of startle that occurs when the starting noise is preceded 30 to 500 msec by a weak prepulse. The present study assessed the effects of seroquel (ICI 204,636), a mixed D2/5-hydroxytryptamine2 antagonist with a preclinical profile suggestive of potential antipsychotic efficacy, on the PCP-induced disruption of PPI. Clozapine, risperidone and haloperidol were also studied as comparison compounds. PCP (1.25 mg/kg) significantly reduced PPI, with prepulses that were 1 to 12 dB above background. Seroquel and clozapine significantly restored PPI in PCP-treated rats, whereas haloperidol and risperidone did not. Similar findings were obtained in studies using separate animals, a slightly lower dose of PCP (1.0 mg/kg) and a high dose of each of these antipsychotics. Separate studies verified that risperidone and haloperidol restored PPI in apomorphine-treated rats. In the present studies, seroquel exhibited a profile consistent with those exhibited by other "atypical" antipsychotics.     

Individual differences in prepulse inhibition of startle as a measure of individual dopamine function.

This study investigated whether individual differences in prepulse inhibition (PPI) of the acoustic startle reflex reflect meaningful trait differences in the function of dopaminergic substrates that regulate it. Baseline PPI of individual rats showed strong test-retest reliability across 3 consecutive test days, and there was a significant negative correlation between individual baseline PPI and both disruption of PPI produced by apomorphine and facilitation of PPI by haloperidol. The test-retest reliability and the inverse association between baseline PPI and drug-induced effects were stronger with 8–10 dB prepulses compared with less intense prepulses. These results demonstrate that individual differences in baseline PPI predict individual differences in sensitivity of PPI to drugs that affect the dopamine system and that PPI produced by more intense prepulses may be more representative of these individual differences. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Prepulse inhibition of acoustic startle in rats after lesions of the pedunculopontine tegmental nucleus.

Prepulse inhibition (PPI) of startle is impaired in schizophrenics, which suggests they have disturbances in circuitry that controls PPI. How activity in forebrain circuitry is communicated to the primary startle circuit to modulate PPI was explored. Subpallidal cells innervate the pedunculopontine tegmental nucleus (PPTg). Infusion of the γ-aminobutyric acid antagonist picrotoxin into the subpallidum impaired PPI. In other rats, electrolytic PPTg lesions decreased or eliminated PPI, potentiated startle amplitude, and did not alter habituation. The disruption of PPI correlated significantly with the extent of PPTg damage. PPTg lesions reduced PPI when startle stimuli were weak or intense (104 or 140 db) and when prepulse stimuli ranged from 2 to 17 db above background but were most profound with prepulses 5–8 db above background. The PPTg modulates sensorimotor gating and may process and transmit information from forebrain structures to the primary startle curcuit. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Stimulus quality affects expression of the acoustic startle response and prepulse inhibition in mice.

The relationship between stimulus intensity and startle response magnitude (SIRM) can assess the startle reflex and prepulse inhibition (PPI) with advantages over more commonly used methods. The current study used the SIRM relationships in mice to determine differences between white noise and pure tone (5 kHz) stimuli. Similarly to rats, the SIRM relationship showed a sigmoid pattern. The SIRM-derived reflex capacity (RMAX) and response efficacy (slope) of the white noise and pure tone stimuli in the absence of prepulses were equivalent. However, the pure tone startle response threshold (DMIN) was increased whereas the stimulus potency (1/ES??) was decreased when compared to white noise. Prepulses of both stimulus types inhibited RMAX and increased DMIN, but the white noise prepulses were more effective. Both stimulus intensity gating and motor capacity gating processes are shown to occur, dependent on prepulse intensity and stimulus onset asynchrony. Prepulse intensities greater than 10 dB below the startle threshold appear to produce PPI via stimulus intensity gating, whereas a motor capacity gating component appears at prepulse intensities near to the startle threshold. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of isolation rearing on startle reactivity, habituation, and prepulse inhibition in male Lewis, Sprague-Dawley, and Fischer F344 rats

This study compared the interaction of strain with isolation rearing on startle reactivity, habituation, and prepulse inhibition (PPI) in male Lewis, Sprague-Dawley, and Fischer F344 rats tested as adults. Lewis and Fischer rats exhibited lower startle reactivity than Sprague-Dawley rats. Lewis rats displayed more rapid habituation than the other strains. Most important, isolation rearing produced deficits in PPI in both Sprague-Dawley and Fischer rats but had no effect in Lewis rats. By contrast, isolation rearing had no effect on startle reactivity or habituation. In a separate study, 0.5 mg/kg apomorphine disrupted PPI in Fischer but not in Lewis rats. Thus, PPI in Lewis rats is relatively unaffected by either a pharmacological or a developmental manipulation, both of which disrupt PPI in Sprague-Dawley and Fischer F344 rats.     

Effects of nicotine and stress on startle amplitude and sensory gating depend on rat strain and sex

We recently reported that 14 days of nicotine administration (12 mg/kg/day) reduced acoustic startle reflex amplitude and impaired prepulse inhibition (PPI) of startle in male and female Long-Evans rats. These findings contrasted with reports of nicotine-induced enhancement of startle and PPI in Sprague-Dawley (a different strain) male rats. The present experiment administered 0, 6, or 12 mg/kg/day nicotine via osmotic minipump for 14 days to 120 Sprague-Dawley rats (male and female) and to 120 Long-Evans rats (male and female) and examined ASR and PPI. Half of the subjects also were stressed by immobilization once each day to examine nicotine-stress interactions. Nicotine enhanced ASR and PPI responses of Sprague-Dawley rats but impaired these responses in Long-Evans rats, regardless of sex. Effects of stress were complex and depended on strain, sex, and drug dose. These findings indicate that effects of nicotine on measures of reactivity (ASR) and sensory gating (PPI) depend on genotype and that nicotine stress interactions depend on genotype, sex, and nicotine dosage.     

Habituation of prepulse inhibition of the startle reflex using an auditory prepulse close to background noise.

This study examined whether prepulse inhibition habituates with repeated presentation of the prepulse alone. Prepulse inhibition was determined by measuring the decrement in the startle response when the acoustic startle-eliciting stimulus was preceded by an auditory prepulse. Rats received repetitive exposures of the same auditory prepulse alone (experimental condition) and of a visual prepulse alone (control condition). To reduce habituation of startle itself and the possible dishabituating influence the startle stimulus might have on habituation of prepulse inhibition, startle stimulus presentations were infrequently interspersed among a much larger number of prepulse-alone presentations. Stimulus-specific habituation of prepulse inhibition occurred using an auditory prepulse 2.5 dB, but not 13 dB, above background noise. Implications are discussed for the role of prepulse inhibition in sensory gating. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Activation of a distinct arousal state immediately after spontaneous awakening from sleep

In contrast to the many neural studies into the mechanisms of sleep onset and maintenance, few studies have focused specifically on awakening from sleep. However, the abrupt electrographic changes and large brief cardio-respiratory activation at awakening suggest that a distinct, transiently aroused, awake state may exist compared to later wakefulness. To test this hypothesis we utilized the acoustic startle reflex, a standard un-conditioned reflex elicited by a sudden loud noise. This reflex is modulated under specific conditions, one being a diminution of startle when a quieter pre-stimulus is presented immediately before the loud stimulus. This pre-pulse inhibition (PPI) is used as a measure of sensorimotor gating, with smaller PPI indicating less filtering of sensory inputs and increased responsiveness to external stimuli. Eight rats with electrodes for recording sleep-wake state were studied. An accelerometer measured startle responses. The startle reflex was elicited by 115 dB, 40 ms tones. PPI was produced by 74 dB, 20 ms tones preceding the 115 dB tone by 100 ms. Responses within 100 ms were measured. Stimuli were applied either 3-10 s after spontaneous awakenings, or in established wakefulness (> 30 s). Responses to the startle stimuli alone were similar in the different awake states (P = 0.821). However, PPI was smaller at awakening from non-REM sleep compared to established wakefulness (45.4 +/- 7.5% vs. 74.3 +/- 6.1%, P = 0.0002). PPI after awakening from REM sleep (52.8 +/- 17.9%) was not significantly different than established wakefulness (P = 0.297). Reduced PPI of the startle reflex at awakening from non-REM sleep supports the hypothesis that wakefulness immediately after spontaneous sleep episodes is neurophysiologically distinct from later wakefulness and associated with reduced gating of motor responses to sensory inputs. Spontaneous activation of this distinct, transiently aroused, state upon awakening may serve a protective function, preparing an animal to respond immediately to potentially threatening stimuli.     

Sensitivity of the mouse to changes in azimuthal sound location: Angular separation, spectral composition, and sound level.

Auditory spatial acuity was measured in mice using prepulse inhibition (PPI) of the acoustic startle reflex as the indicator response for stimulus detection. The prepulse was a “speaker swap” (SSwap), shifting a noise between two speakers located along the azimuth. Their angular separation, and the spectral composition and sound level of the noise were varied, as was the interstimulus interval (ISI) between SSwap and acoustic startle reflex elicitation. In Experiment 1 a 180° SSwap of wide band noise (WBN) was compared with WBN Onset and Offset. SSwap and WBN Onset had near equal effects, but less than Offset. In Experiment 2 WBN SSwap was measured with speaker separations of 15, 22.5, 45, and 90°. Asymptotic level and the growth rate of PPI increased with increased separation from 15 to 90°, but even the 15° SSwap provided significant PPI for the mean performance of the group. SSwap in Experiment 3 used octave band noise (2–4, 4–8, 8–16, or 16–32 kHz) and separations of 7.5 to 180°. SSwap was most effective for the highest frequencies, with no significant PPI for SSwap below 8–16 kHz, or for separations of 7.5°. In Experiment 4 SSwap had WBN sound levels from 40 to 78 dB SPL, and separations of 22.5, 45, 90, and 180°: PPI increased with level, this effect varying with ISI and angular separation. These experiments extend the prior findings on sound localization in mice, and the dependence of PPI on ISI adds a reaction time-like dimension to this behavioral analysis. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Facilitation and inhibition of the acoustic startle reflex in the rat after a momentary increase in background noise level

Small increments in background noise were shown to increase the amplitude of a subsequently elicited acoustic startle reflex (ASR) in rats by as much as 100% under optimal conditions. Increment lead time (5-160 ms) and level (1.5-15 dB), initial noise level (30-70 dB), startle level (95-125 dB), number of test days (1-5), and drug condition (diazepam or saline ip) were varied in 6 experiments. Prepulse facilitation (PPF), measured by difference scores, was greatest for intermediate increments (3 dB) and lead times (20-40 ms) and was replaced by prepulse inhibition (PPI) for higher values, especially in the later test days. Diazepam reduced baseline ASR and diminished PPI, but it did not affect PPF. These data argue against hypotheses that attribute PPF of this sort to either temporal integration within the ASR pathways or to the elicitation of a nonspecific arousal reaction by the prepulse.     

Memory facilitation following the administration of the benzodiazepine triazolam.

The benzodiazepine, triazolam, facilitates the retrieval from memory of information presented just before the administration of this drug at doses that impair explicit recall of information presented and remembered after drug administration. This effect was apparent for recall of unrelated words (Experiment 1) as well as highly related stimuli (category exemplars, Experiment 2). Normal volunteers were administered placebo and 4.6 and 6.0 μg/kg of triazolam (Experiment 1) and placebo, 0.258, 0.375, and 0.500 mg of triazolam (Experiment 2) using double-blind crossover designs. The observed effect is interpreted as due to changes in how information is retrieved from memory rather than as a result of either blockage of interference effects or alterations in processes involved in memory consolidation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Clozapine and PD149163 elevate prepulse inhibition in Brown Norway rats.

Unmedicated schizophrenia patients exhibit deficits in prepulse inhibition (PPI) of the acoustic startle response. Similar deficits can be induced in rodents via a variety of manipulations and these deficits can be reversed by antipsychotics. Brown Norway (BN) rats exhibit natural PPI deficits under certain parametric conditions. We treated BN rats with haloperidol or clozapine to determine if the BN rat is a useful animal model with predictive validity for the effects of antipsychotics. In addition, we also tested PD149163, a neurotensin-1 receptor agonist, which has been shown to exhibit antipsychotic-like effects in several other animal models. BN rats received subcutaneous injections of either saline or one of two doses of haloperidol (0.5 mg/kg, 1.0 mg/kg), clozapine (7.5 mg/kg, 10 mg/kg) or PD149163 (1.0 mg/kg, 2.0 mg/kg). PPI was measured in startle chambers 30 min after injection. Systemic clozapine and PD149163 but not haloperidol facilitated PPI in BN rats (p     

Effects of a Typical and an Atypical Antipsychotic on the Disruption of Prepulse Inhibition Caused by Corticotropin-Releasing Factor and by Rat Strain.

Male Wistar-Kyoto (WKY) and Brown Norway (BN) rats (11-12 weeks, n = 184) received an injection of saline, haloperidol, or clozapine, followed by an intracerebroventricular infusion of saline or corticotropin-releasing factor (CRF). Rats were tested for prepulse inhibition (PPI) of the acoustic startle response. BN rats showed less PPI than WKY rats, and neither antipsychotic alone enhanced PPI. In WKY rats, both haloperidol and clozapine attenuated the CRF-induced decrease in PPI. In CRF-treated BN rats, clozapine-enhanced PPI. A clozapine-induced decrease in startle amplitude was seen in CRF-treated BN rats but not in CRF-treated WKY rats. Although the disruption of PPI caused by exogenous CRF administration can be reversed by acute antipsychotic treatment, baseline PPI is not altered. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Plasticity of the acoustic startle response in the acutely decerebrate rat.

In 4 experiments, plasticity of the acoustic startle reflex was measured in male albino Sprague-Dawley rats in which a complete transection between the forebrain and midbrain was made. During a period from 60 to 100 min after surgery, startle amplitude in the transected Ss was relatively stable and comparable with that of controls (anesthetized with halothane and placed in a stereotaxic instrument). During this period the transection did not alter the temporal recovery process (with intervals of 2, 4, 8, or 16 sec) or auditory prepulse inhibition (with intervals of 25, 50, 100, 500, or 1,000 msec) or the normal reduction in startle caused by high levels of background noise. The transection did prevent the normal increase in startle caused by moderate levels of background noise and eliminated within-session habituation. The effect on habituation was particularly noticeable since the curves of the transected and nontransected Ss actually crossed. Results are dicussed in terms of how the transection procedure can be used to evaluate various hypotheses about underlying mechanisms of startle plasticity. (50 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Prepulse inhibition in the rat is regulated by ventral and caudodorsal striato-pallidal circuitry.

It has been shown that the acoustic startle reflex is inhibited by weak auditory prepulses presented 30–500 ms prior to the startling stimulus and that this prepulse inhibition (PPI) is modulated by ventral striato-pallidal circuitry. However, dorsal striatal modulation of PPI has not been examined. Cell-specific lesions and intracerebral drug infusions were used to elucidate striatal modulation of PPI. Quinolinic acid lesions of the ventral and caudodorsal striatum significantly decreased PPI, whereas lesions of the rostrodorsal and middorsal striatum did not significantly alter PPI. Infusion of the GABA-A antagonist picrotoxin into the ventral and caudal dorsal pallidum also significantly reduced PPI, whereas rostral pallidal picrotoxin infusion had no significant effect. Thus, PPI in the rat seems to be modulated by both ventral and caudodorsal striato-pallidal circuitry, but not by rostrodorsal or middorsal striato-pallidal projections. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Orbital decompression in exophthalmos due to thyroid disease. Report of 69 cases]

Preclinical studies suggest that acoustic startle amplitude is increased during ethanol withdrawal. The current study evaluated the effects of intravenous infusion of the alpha 2-adrenergic antagonist, yohimbine (0.4 mg/kg), the serotonin partial agonist m-chlorophenylpiperazine (mCPP, 0.1 mg/kg), and placebo administered to 22 male patients meeting DSM-III-R criteria for alcohol dependence and 13 male healthy subjects. Patients and healthy subjects completed 3 test days under double-blind conditions in a randomized order. Patients were sober for 12-26 days prior to testing. On each test day, participants completed startle testing 80 min following drug infusion. Stimuli with varying intensities (90, 96, 102, 108, 114 dB) were presented in a randomized order balanced across four blocks. Stimuli consisted of 40-ms bursts of white noise administered every 45-60 s for 15-20 min through headphones. Analyses indicated that patients exhibited elevated acoustic startle magnitudes on the placebo day relative to healthy subjects. In patients, the magnitude of startle amplitudes elicited at 90 dB, but not 114 dB, correlated significantly with the number of previous alcohol detoxifications. Yohimbine increased startle magnitudes and reduced startle latencies relative to placebo and mCPP in both patients and healthy subjects. mCPP did not alter startle magnitude in either group. Yohimbine also increased the probability that a 90-dB stimulus produced a startle response in healthy subjects, but not in patients. Blunting of yohimbine effects on startle probability may reflect the baseline elevations in startle probability levels in patients, but may also be consistent with other evidence of reduced postsynaptic, but not presynaptic, noradrenergic function in these same patients. These data replicate and extend previous reports indicating that yohimbine facilitates the acoustic startle response in humans. They also further implicate the number of episodes of ethanol withdrawal as a factor influencing subsequent neurobiological responsivity in chronic alcoholic patients. Based on the current data, future research should explore whether measurement of the acoustic startle response provides an objective quantitative severity measure of ethanol withdrawal.     

Acoustic startle and prepulse inhibition in 40 inbred strains of mice.

A high-throughput phenotype screening protocol was used to measure the acoustic startle response (ASR) and prepulse inhibition (PPI) in mice. ASRs were evoked by noise bursts; prepulses for PPI were 70 dB sound pressure level tones of 4, 12, and 20 kHz. Forty inbred strains of mice were tested (in most cases using 10 males and 10 females of each strain). The data on both the ASR and PPI had high internal and test-retest reliability and showed large differences among inbred strains, indicative of strong genetic influences. Previously obtained measures of hearing sensitivity in the same inbred strains were not significantly correlated with ASR or PPI measures. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The gene defective in anhidrotic ectodermal dysplasia is expressed in the developing epithelium, neuroectoderm, thymus, and bone

In rats, effects of nicotine administration on sensory gating as indexed by prepulse inhibition (PPI) of the acoustic startle reflex (ASR) are unclear. We have found that nicotine administration enhances ASR and PPI in Sprague-Dawley rats, but other investigators, using Long-Evans rats, have reported no effects or enhancement of PPI only. Numerous methodological differences exist among studies in addition to subject strain, however, making it unclear whether inconsistent behavioral responses are the result of different experimental procedures or indicate a true strain difference. To investigate the role of strain in nicotine's effects on ASR and PPI, 192 male and female Long-Evans rats were administered 12 mg/kg/day nicotine via osmotic minipump for 14 days using identical methodologies employed in studies with Sprague-Dawley subjects. Effects of grouped vs. individual housing on these responses also were examined. Nicotine administration impaired ASR and PPI in Long-Evans subjects. These effects occurred in female rats regardless of housing condition, and interacted with housing in male rats. Results indicate that sex and housing are important variables in nicotine's effects. Results suggest that subject strain may be an important variable in nicotine's effects on sensory gating, and that responses of Sprague-Dawley vs. Long-Evans rats may represent a true strain difference.     

Motivated attention and prepulse inhibition of startle in rats: Using conditioned reinforcers as prepulses.

In humans, prepulse inhibition (PPI) of startle is greater during attended prestimuli than it is during ignored prestimuli, whereas in rats, most work has focused on passive PPI, which does not require attention. In the work described in this article, researchers developed a paradigm to assess attentional modification of PPI in rats using motivationally salient prepulses. Water-deprived rats were either conditioned to attend to a conditioned stimulus (CS; 1-s, 7-dB increase in white noise) paired with water (CS+ group), or they received uncorrelated presentations of white noise and water (CSo group). After 10 conditioning sessions, startle probes (50 ms, 115 dB) were introduced, with the CS serving as a continuous prepulse. Three experiments examined PPI across a range of prepulse intensities (4-10 dB) and stimulus onset asynchronies (SOAs; 30-960 ms). PPI was consistently reduced in the CS+ group, particularly with a 10-dB prepulse and a 60-ms SOA. Thus, PPI in rats differed between attended and ignored prestimuli, but the effect was reversed in the results of research with humans. A fourth study eliminated the group difference by reversing the CS-water contingency. Methodological and motivational hypotheses regarding the current findings are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

On the influence of baseline startle reactivity on the indexation of prepulse inhibition.

Prepulse inhibition (PPI) of the startle reflex refers to the reduction of the reflexive startle response to an intense pulse stimulus when its presentation is shortly preceded by a weak prepulse stimulus. PPI is considered as a cross-species translational model of sensorimotor gating, and deficient PPI has been reported in a number of neuropsychiatric disorders. Although a part of the literature is based on the assumption that PPI is independent of the baseline startle reaction, there is accumulating evidence (Csomor et al., 2006; Sandner & Canal, 2007; Yee, Chang, Pietropaolo, & Feldon, 2005) that argues against such an independency. The authors systematically investigated whether PPI indexed as percentage or difference score is dependent on the magnitude of baseline startle reactivity in healthy human volunteers and in C57BL/6 mice. The results revealed that both indexations of PPI were affected by the magnitude of the baseline startle. The authors highlight the pitfalls of different methods to index PPI, especially when startle reactivity differs considerably between groups under comparison, and offer practical recommendations to satisfactorily deal with such baseline differences. (PsycINFO Database Record (c) 2010 APA, all rights reserved)