Effect of d-amphetamine on prepulse inhibition of the startle reflex in humans

Rationale: Prepulse inhibition of the startle reflex (PPI) is attenuated in animals after administration of d-amphetamine and other drugs that stimulate mesolimbic dopamine activity. Objective: The aim of the present study was to evaluate the effects of d-amphetamine (20 mg) on a variety of psychophysiological and subjective measures, including PPI, in humans. Method: Thirty-six participants (18 women) participated in a double-blind, placebo controlled, repeated measures study. In one session, participants received d-amphetamine (20 mg) orally, and in the other session, participants received an identical appearing placebo. Participants were assessed at 60, 90, and 120 min after ingestion with a 5-min block of startle trials (six control trials and six prepulse trials) followed by subjective measures of stimulation and mood. Results: d-Amphetamine increased subjective measures of stimulation and euphoria, attenuated PPI, and increased heart rate, relative to placebo treatment. Conclusions: The effect of d-amphetamine on the subjective measures was substantial and consistent over time, while the effect on PPI was only observed at 90 min after ingestion, and the effect on heart rate was limited to 90 and 120 min after ingestion. Received: 22 June 1998/Final version: 23 November 1998     

Variables affecting prepulse inhibition of the startle reflex and the response to antipsychotics in DBA/2NCrl mice

Rationale DBA/2 mice demonstrate poor prepulse inhibition (PPI) as is also observed in schizophrenic patients, and their PPI is improved by antipsychotics. Thus, the DBA/2 mouse is increasingly used for testing of novel antipsychotics in PPI; however, the strain has not been fully characterized for relevant variables affecting compound testing. Objectives The objectives of this study were to compare four DBA/2 substrains, evaluate light- and dark-phase testing on startle, PPI, and drug-induced improvement in PPI in DBA/2NCrl mice, test chamber lighting on startle and PPI in DBA/2NCrl mice and to evaluate vehicles on baseline PPI in DBA/2NCrl mice. Results DBA/2NCrl and DBA/2J mice were acceptable for PPI testing, while DBA/2NHsd mice had diminished startle reflexes. Startle responses to the prepulses alone were observed in 46% of the DBA/2NTac mice. PPI and startle did not show diurnal variations or variations due to chamber lighting. Olanzapine and aripiprazole showed better drug-induced improvements in PPI during the light phase. The vehicle 25% (2-hydroxypropyl)-β-cyclodextrin variably improved PPI, an effect not observed with other vehicles. Conclusions DBA/2NHsd and DBA/2NTac mice were unacceptable for PPI experiments. The finding of responses to the prepulses alone by DBA/2NTac mice further indicates the advisability of routinely monitoring responses to prepulses alone. Unlike rats, DBA/2NCrl mice did not have greater startle amplitudes during the dark phase. Compound efficacy was better during the light phase because of poorer PPI in the vehicle group. Some vehicles may have unacceptable effects on PPI in DBA/2NCrl mice and may not be appropriate for studies evaluating novel compounds.     

Apomorphine,d-amphetamine,strychnine and yohimbine do not alter prepulse inhibition of the acoustic startle reflex

Rats were presented with noise bursts alone or noise bursts 60 ms after presentation of either a 60 dB or an 80 dB prepulse after injection of the dopamine agonists apomorphine (3 mg/kg) or d-amphetamine (4 mg/kg), the glycine antagonist strychnine (1.5 mg/kg) or the ₂ antagonist yohimbine (5 mg/kg). Presentation of prepulses inhibited startle, with greater inhibition following an 80 dB versus 60 dB prepulse. Apomorphine, d-amphetamine and strychnine increased overall startle levels but did not attenuate prepulse inhibition, since the absolute change in startle following prepulse presentation was significantly greater after administration of these drugs. A lower dose of apomorphine also increased startle but had no effect on prepulse inhibition using test intervals of 10, 60, 100, 200 or 1000 ms. While these drugs did decrease per cent prepulse inhibition, this seemed wholly attributable to their increasing overall startle levels, rather than a real attenuation of prepulse inhibition. Yohimbine did not alter either startle baseline or prepulse inhibition. The results do not support the conclusion that overactivity of dopamine systems attenuates prepulse inhibition and, in addition, suggest that prepulse inhibition does not result from activation of either glycine or norepinephrine projecting to ₂ adrenergic receptors.     

Caffeine and prepulse inhibition of the acoustic startle reflex

Rationale: A stimulus presented immediately prior to a startle reflex-eliciting stimulus inhibits the startle reflex. This is termed prepulse inhibition (PPI) and is postulated to index automatic and controlled attentional processing of the prepulse. Objective: Two experiments investigated the effect of 0, 2, and 4 mg/kg oral caffeine on PPI of the acoustic startle eyeblink reflex across stimulus onset asynchronies (SOAs) ranging from 30 to 420 ms. In experiment 1, acoustic prepulses were used and automatic attention was investigated, whereas in experiment 2, acoustic and tactile prepulses were used and automatic and controlled attention was investigated. Controlled attention was investigated by instructing the subjects to attend to one stimulus (attended stimulus) and not to another stimulus (non-attended stimulus). Methods: Caffeine was administrated to human subjects in within-subjects designs (n=24 and n=18). Startle reflexes to 100 dB noise were recorded by electromyography. A mood scale and readings of blood pressure indexed arousal. Results: Caffeine increased the indexes of arousal. There were, however, no significant main effects of caffeine on startle, nor did caffeine significantly interact with any other variable. Attended acoustic prepulses increased PPI at the 120 ms and longer SOAs. Caffeine 4 mg/kg abolished this difference between attended and non-attended stimuli. Attended tactile prepulses facilitated startle at short SOAs, and caffeine reduced facilitation of startle by tactile prepulses. Conclusions: Caffeine did not facilitate automatic attention. Caffeine 4 mg/kg abolished the effect of controlled attention on PPI. Facilitation of startle by attended acoustic prepulses is best explained by facilitation of motoneurons in the facial nucleus. Received: 11 May 1999 / Final version: 1 July 1999     

Mood stabilizers increase prepulse inhibition in DBA/2NCrl mice

Rationale  Lithium and several antiepileptic drugs have mood-stabilizing effects in bipolar disorder and schizophrenia. Both disorders are characterized by deficits in prepulse inhibition (PPI) of the acoustic startle response. Objectives  Using the DBA/2 model of naturally low PPI, which is reliably increased by antipsychotics, five mood stabilizers in clinical use were tested to determine whether they would also increase PPI in this model. All drugs were administered intraperitoneally (i.p.) 30 min before testing. Results  Lithium chloride (30 mg/kg), topiramate (100 and 300 mg/kg), carbamazepine (30, 60, and 100 mg/kg), valproic acid (178 and 316 mg/kg), and lamotrigine (3, 10, and 30 mg/kg) increased percent PPI. The antiepileptic drugs carbamazepine, valproic acid, and lamotrigine at high doses also decreased no-stimulus amplitudes and increased startle amplitudes. At high doses of carbamazepine, valproic acid, and lamotrigine, increases in percent PPI were independent of the increases in startle amplitude. Conclusions  The demonstrated efficacy of five mood stabilizers in the DBA/2 model of naturally low PPI points to the translational value of this model in predicting therapeutic activity in schizophrenia and bipolar disorder of compounds with diverse mechanisms of action.     

Noise benefit in prepulse inhibition of the acoustic startle reflex

Rationale  

Under some conditions, external sensory noise enhances cognitive functions, a phenomenon possibly involving stochastic resonance and/or enhanced central dopamine transmission. Prepulse inhibition (PPI) of the startle reflex is a robust measure of sensorimotor gating and can be modulated by activity in the cortex and basal ganglia, including the central dopamine pathways.     

Brain stem circuits mediating prepulse inhibition of the startle reflex

RATIONALE: Prepulse inhibition (PPI) of the startle reflex occurs when brief, non-startling tactile, acoustic or visual stimuli are presented 20-500 ms before the startling stimulus. OBJECTIVE: To review information about PPI-mediating brain stem circuits and transmitters, and their functions. RESULTS: Midbrain systems are most critical for the fast relay of these PPI stimuli. Acoustic prepulses for PPI are relayed through the inferior colliculus (IC). The superior colliculus (SC) is important for acoustic PPI, and may be important for the mediation of tactile and visual prepulses. This collicular activation for PPI is quickly relayed through the pedunculopontine tegmental nucleus (PPTg), with lesser contributions to PPI from the laterodorsal tegmental nucleus (LDTg) and substantia nigra, pars reticulata (SNR). The transient activation of midbrain nuclei by PPI stimuli is converted into long-lasting inhibition of the giant neurons of the caudal pontine reticular nucleus (PnC). We propose that muscarinic and GABA(B) inhibitory receptors (both metabotropic receptors) on PnC giant neurons combine to produce the long-lasting inhibition of startle. Activation of mesopontine cholinergic neurons leads to cortical arousal, turning and exploratory approach responses. CONCLUSION: PPI is mediated by a circuit involving the IC, SC, PPTg, LDTg, SNR and PnC. By reducing startle, PPI allows the execution of approach responses and perceptual processing following salient stimuli.     

Differential effects of apomorphine on prepulse inhibition of acoustic startle reflex in two rat strains

Apomorphine disruption of prepulse inhibition (PPI) has been proposed as an animal model of sensorimotor gating deficits exhibited by schizophrenics. The effects of apomorphine on PPI of the acoustic startle reflex in male rats of Wistar and CD (Sprague-Dawley derived) strains were compared under identical test conditions. In Wistar rats, subcutaneous administration of 0.25–1.0 mg/kg apomorphine blocked PPI without affecting startle amplitude. In CD rats, apomorphine (0.3–3.0 mg/kg, SC) had no effect on PPI, but increased startle amplitude. Therefore, choice of rat strain is an important factor in the design of experiments studying apomorphine effects on PPI.     

Smoking withdrawal, nicotine dependence and prepulse inhibition of the acoustic startle reflex

The present study examined the relationship between nicotine dependence as measured by the Fagerstrom Tolerance Questionnaire (FTQ) and prepulse inhibition (PPI) of the acoustic startle reflex measured after overnight smoking withdrawal in a non-clinical population of male smokers with no history of psychiatric disorders or drug/alcohol abuse. It was found that smokers who scored high (>median) on the FTQ showed significantly less PPI as compared to those scoring low (<median) on this scale. This finding further supports a role for nicotine in modulation of PPI, as has previously been found in rats and also in human beings. Received: 26 November 1997/Final version: 8 June 1998     

Antipsychotics improve Delta9-tetrahydrocannabinol-induced impairment of the prepulse inhibition of the startle reflex in mice

Recently, cannabinoid receptor agonists have been reported to impair prepulse inhibition (PPI) of the startle reflex. In the current study, we examined the effect of Delta9-tetrahydrocannabinol (THC), the principal psychoactive component of cannabis, on the PPI, and found that THC (10 mg/kg, i.p.) impaired the PPI concomitant with a decrease in the startle response. Antipsychotics such as haloperidol (0.3 mg/kg, i.p.) and risperidone (0.1 mg/kg, i.p.), which are potent dopamine D2 receptor antagonists, and SR141716 (10 mg/kg, i.p.), a CB1 cannabinoid receptor antagonist, reversed these THC-induced PPI deficits. Moreover, THC (10 mg/kg) increased dopamine (DA) release in the nucleus accumbens but not medial prefrontal cortex over a 50-100-min period (time of PPI test) after treatment, and SR141716 (10 mg/kg) reversed this increase in DA release induced by THC. These results suggest that dopaminergic hyperfunction in the nucleus accumbens may be involved in THC-induced PPI deficits.     

Effects of physostigmine and human butyrylcholinesterase on acoustic startle reflex and prepulse inhibition in C57BL/6J mice

The use of exogenously administered cholinesterases as bioscavengers of highly toxic organophosphorus nerve agents is a viable prophylactic against this threat. To use this strategy, cholinesterases must provide protection without disrupting behavior when administered alone. To assess behavioral safety, the acoustic startle reflex and prepulse inhibition (PPI) of C57BL/6J mice were investigated following administration of human plasma-derived butyrylcholinesterase (HuBChE). Two hours before testing, four groups of mice (n=10 per group) were pretreated with saline or HuBChE (2000 U, ip). Fifteen minutes before testing, subjects received either saline or the carbamate physostigmine (0.4 mg/kg, sc). Mice exposed to physostigmine exhibited a significant attenuation of the startle reflex, an increased time to peak startle amplitude, and significantly increased PPI. This effect was partially mitigated in mice pretreated with HuBChE. HuBChE alone did not change startle behavior or PPI significantly compared to saline controls. The circulatory time-course of butyrylcholinesterase was assessed in a separate group of mice and revealed levels approximately 600 times the physiological norm 2-4 h post administration. Thus, HuBChE does not appear to significantly alter startle or PPI behavior at a dose 30-fold higher than that estimated to be necessary for protection against 2LD50 of soman in humans.     

Does sensitization occur to prepulse inhibition of the startle reflex effects of repeated apomorphine treatments in rats?

There are conflicting reports as to whether or not the effects of dopamine agonist effects at reducing prepulse inhibition of the acoustic startle reflex develop sensitization with repeated treatments. In this experiment, rats (12 per each dose group) were treated for 10 days prior to startle-testing on each day with 0 (vehicle), 50, 200 or 800 microg/kg of apomorphine. Startle testing was conducted with each rat receiving no stimulus trials (null trials), startle pulse only trials (40 ms 105 dB white noise), prepulse only trials (20 ms 72 dB 5 kHz tone) and prepulse+pulse trials with a 100 ms stimulus onset asynchrony (SOA, i.e. the lead time from onset of prepulse to onset of pulse). The rats were then challenged after 5-7 days of withdrawal from the treatment regimen with a vehicle and apomorphine (200 microg/kg) injection with the order of injection counterbalanced. A range of SOAs and two different prepulse intensities (68 and 70 dB) were presented to every rat on the challenge tests. Sensitization developed during treatment to the increase in motor activity produced by the two higher doses, and to the increase in an orienting response produced by the prepulse stimulus in the highest dose group, but not to the prepulse inhibition effect of the drugs. The 50 microg/kg inhibitory autoreceptor selective dose decreased responses on the first of three blocks of both null trials and prepulse only trials. The two higher doses dose-dependently increased startle reflex amplitudes on the prepulse+pulse trials (reduced prepulse inhibition), but this effect did not exhibit sensitization during treatment. The lowest dose significantly increased prepulse inhibition relative to the vehicle-treated group on the first block of trials over days. After apomorphine challenge, sensitization to the effects of apomorphine on reducing prepulse inhibition was apparent for some dose groups at some SOAs. Sensitization to the effects of apomorphine on prepulse inhibition can be demonstrated upon a subsequent drug challenge if pretreatments are associated exclusively with the startle testing environment.     

Prenatal alcohol exposure: effects on acoustic startle and prepulse inhibition

The present study evaluated the effects of prenatal exposure to alcohol on the acoustic startle reflex and prepulse inhibition in rats. Pregnant rats consumed an average of 12.36 g/kg/day of ethanol in a saccharin solution which served as their sole fluid source throughout gestation. Their offspring were found to be developmentally delayed on tests of physical maturation, but were not consistently impaired on tests of neuroreflexive development when compared to pair-fed and ad lib control groups. With development, subjects in the ethanol exposed group exhibited enhanced reactivity to an acoustic startle stimulus, which was evident at 35 but not at 21 days of age. In contrast, general activity levels were similar for all groups at 35 days of age, and there was no apparent disruption of the inhibitory effects of a prepulse stimulus. These results provide evidence that in utero exposure to alcohol may result in age dependent hyperreactivity, with no obvious disruption of normal prepulse inhibition or general activity levels.     

Midazolam effects on prepulse inhibition of the acoustic blink reflex

AIMS: The eye-blink response following sudden acoustic noise bursts is part of the startle reflex. The magnitude of the startle response can be attenuated by presentation of a weak stimulus before the 'startle-eliciting' stimulus (prepulse inhibition, PPI). PPI is a stable finding in awake humans but may be altered by anaesthetic drugs. We investigated whether the application of benzodiazepines altered the magnitude of PPI in healthy male volunteers. METHODS: In an open-label noncontrolled investigation, the effect of the benzodiazepine agonist midazolam on PPI was assessed in the absence and presence of the antagonist flumazenil. After an initial control period of 60 min three consecutive periods, each of 60 min, with progressively increasing concentrations of midazolam were studied (0. 02, 0.06, 0.14 mg kg-1 h-1 ). A final 60 min period during the administration of flumazenil (0.004 mg kg-1 h-1 ) and while the agonist was still present was also studied. Drug was administered intravenuously as a combination of bolus, 50% of total dose and continuous infusion over the 60 min period. Electromyographic (EMG) response of the right orbicularis oculi muscle was used to assess the startle response to noise bursts of 50 ms duration (95 dB(A)). Noise bursts were randomly preceded by nonstartling prepulses (800 Hz sinus, 50 ms duration, 65 dB(A), prepulse to noise interval 120 ms). The magnitude of PPI was calculated by dividing the EMG response to nonprepulsed stimuli by the response to prepulsed stimuli for each individual and period. Eleven subjects participated in the study, two of them were excluded from the statistical analysis because startle responses could not be reliably elicited (final sample size n=9). RESULTS: The magnitude of PPI was inversely related to the concentration of midazolam. This relationship was described by a sigmoidal Emax model, giving an Emax of 0.65+/-0.13, an ED50 of 33.9+/-10.9 ng ml-1 and gamma of 3.5+/-1.0. During infusion of flumazenil and in the presence of midazolam, the magnitude of PPI increased by 0.11 (95% CI, 0-0.22, P相似文献   

Lesions of the laterodorsal tegmental nucleus disrupt prepulse inhibition of the acoustic startle reflex

The purpose of the present studies was to determine the effects of bilateral lesions of the laterodorsal tegmental nucleus (LDTg) on prepulse inhibition (PPI) of the acoustic startle reflex under conditions of varying prepulse intensity and interstimulus interval (ISI) durations. Rats with bilateral ibotenic acid lesions of the LDTg were evaluated for changes in PPI and startle amplitude in comparison with an unoperated group, sham-LDTg lesioned group and a group with bilateral ibotenic acid lesions of the subcoeruleus nucleus, a brainstem nucleus approximately 1 mm ventrolateral to the LDTg. Bilateral lesions of the LDTg produced a robust decrease in PPI with no effect on startle amplitude as compared with the three control groups. In contrast, bilateral lesions of the subcoeruleus produced no effect on either PPI or startle amplitude. The effects of bilateral lesions of the LDTg on PPI were observed across prepulse intensities of 5, 10 and 15 dB above background and ISI durations of 30, 100, 300 and 1000 ms without significantly decreasing startle amplitude in either test paradigm as compared with the sham-LDTg lesioned group. Our data provide evidence for a role of the LDTg in modulating PPI.     

Effect of cigarette smoking on prepulse inhibition of the acoustic startle reflex in healthy male smokers

The present study investigated the effects of cigarette smoking on prepulse inhibition (PPI) of the acoustic startle reflex in healthy men. Cigarette smoking in a group of overnight smoking-deprived smokers increased PPI as compared to the smoking-deprived condition. This finding is consistent with previous animal studies showing that nicotine increases PPI of the acoustic startle reflex. In addition, cigarette smoking also reduced startle amplitude during the first 6–7 min of the post-smoking session. Received: 4 March 1996 / Final version: 17 June 1996     

The effects of smoking high nicotine cigarettes on prepulse inhibition, startle latency, and subjective responses

RATIONALE: Several previous investigations with animals and humans have suggested that nicotine enhances prepulse inhibition of the startle reflex (PPI). However, the administration of nicotine activates mesolimbic dopamine, and activation of mesolimbic dopamine is known to attenuate prepulse inhibition of the startle reflex (PPI), which might suggest that nicotine would decrease PPI. OBJECTIVE: The primary aim of this study was to test rigorously the effects of smoking high nicotine cigarettes on PPI and other measures (e.g., heart rate, craving, and mood) when the concentration of nicotine peaks in the brain (i.e., immediately after smoking). METHODS: Thirty smokers participated in two experimental sessions 1 week apart. Two high nicotine cigarettes were smoked in one session, and two control cigarettes were smoked in the other session after overnight deprivation. RESULTS: The results indicated that smoking the high nicotine cigarettes decreased PPI and that PPI increased across trials in both conditions. The interaction between nicotine dose and trial was not significant, although it appeared that high nicotine may have reversed an increase in PPI across trials in the control condition. High nicotine cigarettes also significantly increased heart rate, decreased the latency to peak startle response on control trials, but did not alter the magnitude of the startle response. DISCUSSION: The findings suggest that either high nicotine cigarettes reduced PPI, or possibly, that high nicotine cigarettes may have reversed an increase in PPI across trials as evident in the control condition.     

A comparison of the effects of amphetamine, strychnine and caffeine on prepulse inhibition and latent inhibition

Sensorimotor gating deficits characterize several neuropsychiatric disorders, including schizophrenia. Prepulse inhibition (PPI) and latent inhibition (LI) are measures that are used to assess sensorimotor gating and have been found to be reduced in schizophrenia patients. In PPI, a weak stimulus presented immediately prior to a startling stimulus attenuates the startle response. In LI, pre-exposure to a stimulus retards the subsequent association of that stimulus with a consequence (e.g. footshock). In rats, indirect dopamine (DA) agonists such as amphetamine disrupt both PPI and LI. Amphetamine has also been reported to increase exploratory locomotion at doses that decrease PPI and LI. Such behavioral activation might complicate the interpretation of amphetamine-induced changes in measures of sensorimotor gating. The present study was conducted in order to compare the effects of three behaviorally activating drugs on PPI, LI and locomotor activity. Separate groups of rats were treated with either vehicle, the DA releaser amphetamine (1.5mg/kg), the glycine antagonist strychnine (0.75mg/kg), or the adenosine receptor antagonist caffeine (10mg/kg) and then tested in either startle chambers (for PPI) or an active avoidance chamber (for LI). Locomotion was measured by inter-trial crossing in the avoidance chamber. Amphetamine stimulated locomotion and disrupted both PPI and LI, but did not elevate startle amplitude. In contrast, caffeine increased locomotion, but had no effect on PPI or LI. Strychnine did not increase locomotion significantly, but did increase startle amplitude and disrupt PPI and LI. Hence, neither increased startle amplitude nor locomotor activation are necessary or sufficient conditions for disruption of sensorimotor gating as measured by PPI and LI.