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     

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.     

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     

Noradrenergic influence on the prepulse inhibition of acoustic startle

Oral administration of p,p'-1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT), a chemical believed to increase neuronal membrane excitability increased the acoustic startle responsiveness of rats. Inhibition of the acoustic startle response with a brief, prepulse white-noise stimulus was evident at 12.5 to 25 mg/kg of p,p'-DDT, but not at 50 mg/kg. Pretreatment of rats with phenoxybenzamine, an adrenergic receptor antagonist, attenuated the effects of 12.5 mg/kg of p,p'-DDT on the acoustic startle reflex, and decreased the maximum magnitude reduction produced by the prepulse stimulus in DDT-exposed rats. These data extend previous work showing that p,p'-DDT augments startle reactivity in rats and is in accord with the existence of an excitatory norepinephrine(NE)-containing pathway modulating motor outflow in the acoustic startle reflex arc.     

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.     

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     

Changes in the acoustic startle response and prepulse inhibition of acoustic startle in rats after local injection of pertussis toxin into the ventral tegmental area

The effect of local injection of pertussis toxin (PTX) into the ventral tegmental area (VTA) on acoustic startle in rats was investigated. The PTX treatment caused only minor effects of its own on the acoustic startle response (ASR) or prepulse inhibition (PPI) of acoustic startle. However, systemic treatment with the indirect DA receptor agonist, amphetamine (2 mg/kg, SC) caused a significant increase in ASR magnitude and a significant disruption of PPI in PTX-treated rats while no such effects were observed in sham-treated rats. Treatment with the direct DA receptor agonist, apomorphine (2 mg/kg, SC), caused a significant disruption of PPI, an effect that was observed in both PTX-and sham-treated rats. Treatment with the 5-HT_1A receptor agonist, 8-OH-DPAT (0.5 mg/kg, SC), did not affect PPI in either group but caused a marked increase in ASR magnitude in sham-treated rats. Interestingly, this effect was blocked in PTX-treated rats. The present results suggest that local injection of PTX into the VTA causes an increased sensitivity to the behavioural effects of psychostimulants on acoustic startle and may also suggest that intact midbrain 5-HT_1A receptors are essential for the effect of 5-HT_1A agonists on acoustic startle.     

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.     

Estrogen increases prepulse inhibition of acoustic startle in rats.

Epidemiological studies have shown gender differences in the age of onset and symptoms of schizophrenia. Because sensorimotor gating mechanisms are deficient in schizophrenia, we studied the effect of administration of estrogen on prepulse inhibition of startle in rats, an animal model of sensorimotor gating. Rats were tested in an automated startle apparatus for their responses to random combinations of 115-dB sound pulses and prepulses of various intensity. Startle responses were reduced by increasing intensities of prepulses, indicating prepulse inhibition. Repeated administration of startle pulses caused gradual habituation of startle responses. Ovariectomy did not induce significant changes in either habituation of the startle response or prepulse inhibition of startle. Treatment with 17beta-estradiol caused an increase in percentage prepulse inhibition at all prepulse intensities at 18 h, but only at higher prepulse intensities at 30 min after injection. Habituation of startle responses was not affected. The enhancing effect of estradiol on prepulse inhibition was mimicked by testosterone, but not by dihydrotestosterone. Estradiol treatment increased prepulse inhibition similarly in controls or after disruption of prepulse inhibition induced by treatment with apomorphine or dizocilpine (MK-801). Our results may help to explain gender differences in schizophrenia and some of the beneficial clinical effects of estrogen treatment in this disease.     

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     

Provisional mapping of quantitative trait loci modulating the acoustic startle response and prepulse inhibition of acoustic startle.

Prepulse inhibition (PPI) of the acoustic startle response (ASR) is a form of sensorimotor gating, defined as an inhibition of the startle response when a low intensity stimulus, the prepulse, precedes the startling stimulus. Deficits in PPI have been reported in schizophrenia and other psychiatric/neurological disorders, and correlate with symptom severity in schizophrenia, suggesting that deficient PPI per se or abnormalities in neural circuits regulating PPI may cause some symptoms of schizophrenia. If so, then genes conferring reduced PPI may contribute toward genetic vulnerability to schizophrenia. Studies with selectively bred rodent strains indicate that PPI is under genetic control; however, the identity of the relevant genes is unknown. The current study used recombinant congenic mouse strains derived from C57BL/6J and A/J parents to assess genetic variability in PPI and in ASR and to identify provisional quantitative trait loci (QTLs) modulating these phenotypes. Significant between-strain differences in ASR and in PPI at each of several prepulse intensities (75, 80, 85, 90, 95 dB) were found. Correlations between PPI at the various prepulse intensities were highly significant, suggesting appreciable overlap in genetic regulation of PPI across prepulse intensities. Five QTLs (chromosomes 3, 5, 7, 16) associated with PPI across all prepulse intensities, but not with ASR, were identified. Two additional QTLs (chromosomes 2, 11) associated with both PPI and ASR were found. Fifteen QTLs were associated with ASR alone. Data on genotypes of informative congenic strains were used to support probable involvement of loci modulating PPI and to narrow the probable chromosomal location of QTLs. If confirmed, these QTLs may suggest candidate genes directing novel mechanisms for regulation of PPI     

Dopamine antagonists in the orbital prefrontal cortex reduce prepulse inhibition of the acoustic startle reflex in the rat.

Schizophrenia is characterized by, among other things, (a) information processing deficits that have been indexed by a number of measures, including deficits in prepulse inhibition (PPI) of the acoustic startle reflex; and (b) pathophysiology of the frontal lobe. Recent studies have implicated the prefrontal cortex (PFC) in the modulation of PPI in rats. These studies suggest that dopamine (DA) ablation of the PFC (using 6-OHDA) leads to disruption of PPI. To better understand the role of DA type 1 (D1) and type 2 (D2) receptors in the modulation of PPI, we investigated the effects of two pharmacologically distinct DA antagonists on the modulation of PPI. Microinjection of SCH23390 (a D1 antagonist) into the orbital PFC markedly decreased PPI (at 0.1, 0.5, and 1.5 microg), whereas raclopride (a D2 antagonist) decreased PPI at some doses (0.1 and 0.5 mg/ml) but not at others (5.0 microg). We conclude that both D1 and D2 receptors mediate the cortical modulation of PPI.     

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   

Involvement of the medial geniculate body in prepulse inhibition of acoustic startle

Prepulse inhibition of acoustic startle is the normal reduction in startle response to an intense auditory stimulus when this stimulus is immediately preceded by a weaker prestimulus. Previous studies have shown that several neuroanatomical structures and pathways in the brain are involved in the modulation of prepulse inhibition. In the present study, the functional importance of the medial geniculate body (MG) in the modulation of prepulse inhibition was investigated. To this end, in vivo brain microdialysis probes were used to infuse drugs locally into the MG of awake, freely moving rats simultaneously with startle response and prepulse inhibition measurements in the same animals. Intrageniculate infusion of the sodium channel blocker, tetrodotoxin, significantly reduced prepulse inhibition without affecting baseline startle amplitude. A similar effect was obtained after intrageniculate infusion of the GABA_B receptor agonist, baclofen. In addition, intrageniculate infusion of muscimol, an agonist at the GABA_A receptor complex, reduced prepulse inhibition, although this effect was obtained at a higher concentration of the drug compared to that of baclofen. These studies suggest that the MG is involved in the modulation of prepulse inhibition and that auditory signals relayed via the MG may be subjected to inhibitory control at this level, involving GABA neurotransmission. Received: 31 March 1998/Final version: 15 June 1998     

Hippocampal modulation of acoustic startle and prepulse inhibition in the rat.

Prepulse inhibition (PPI) is the normal reduction in a startle response that occurs when the startling stimulus is preceded by a weak lead stimulus ("prepulse"). Schizophrenic patients exhibit abnormally low levels of PPI; therefore, animal models of deficient PPI may provide information regarding neural dysfunctions underlying schizophrenia. We recently reported that infusion of the cholinergic agonist carbachol into the dentate gyrus (DG) disrupts PPI in the rat. We now report the effects of carbachol microinjected into CA1, the DG, or the ventral subiculum (VS) on acoustic startle and PPI. Carbachol infusion into CA1 or the DG depressed startle. Carbachol infusion decreased PPI with a regional rank-order potency CA1 > DG > VS. CA1 infusions more potently depressed the startle reflex. By contrast, DG infusions preferentially decreased PPI, while VS infusions decreased PPI without altering startle amplitude. Coinfusion with the muscarinic cholinergic antagonist atropine opposed the effects of carbachol. These results demonstrate the regional heterogeneity and pharmacological specificity of the hippocampal cholinergic modulation of acoustic startle and PPI and suggest that abnormalities within various regions of the hippocampal formation may contribute to deficient sensorimotor gating in schizophrenic patients.     

Effects of smoking on acoustic startle and prepulse inhibition in humans

RATIONALE: Prepulse inhibition of the acoustic startle response (PPI) is a paradigm in which a startle response to an auditory stimulus is reduced when that stimulus is preceded by a lower intensity, non-startling stimulus (prepulse). PPI is used as an operational measure of sensorimotor gating in both humans and other mammals. Acute administration of nicotine enhances PPI in rats, an effect that has been recently demonstrated in humans. OBJECTIVES: We compared PPI in 12 male smokers and 14 male non-smokers tested in four repeat startle sessions across 2 test days in order to examine further the effects of smoking and smoking withdrawal on acoustic startle and PPI. METHODS: In a crossover design, the smokers smoked ad lib or abstained from smoking overnight prior to 9 a.m. testing. These 2 test days were in randomized order. On both days, smokers were immediately retested after smoking three cigarettes. Non-smokers were tested twice on each of 2 separate days. RESULTS: Across sessions, the smokers had reduced startle to pulse alone stimuli in the first block of each session when compared to the non-smokers. The non-smokers had no change in gating across their four test sessions. For the smokers, the abstinence condition produced a non-significant reduction in PPI compared to that of the ad lib smoking day. During the smoking abstinence session, smokers had comparable gating to non-smokers. Smoking immediately after washout produced a significant improvement in PPI such that gating in the smokers exceeded that of the non-smokers. CONCLUSION: Smoking after overnight washout from cigarettes enhanced sensorimotor gating compared to pre-smoking values and compared to gating in non-smokers.     

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.     

Reduced brain serotonin activity disrupts prepulse inhibition of the acoustic startle reflex. Effects of 5,7-dihydroxytryptamine and p-chlorophenylalanine.

These experiments examined the impact of extensive depletions of forebrain 5-hydroxytryptamine (5-HT; serotonin) levels on prepulse inhibition (PPI) of the acoustic startle reflex in rats. In Experiment 1, injection of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into the dorsal and median raphe nuclei disrupted PPI. This deficit was observed beginning 2 days after lesioning and was still apparent 8 weeks later. Basal startle reactivity was not altered. The 5-HT(1A) receptor agonist 8-OH-DPAT (0.1 mg/kg) and the dopamine receptor agonist apomorphine (1mg/kg) also disrupted PPI; the effect of 8-OH-DPAT, but not apomorphine, was potentiated in 5-HT-depleted rats. Basal startle reactivity was enhanced by 8-OH-DPAT in sham-lesioned rats but not in 5,7-DHT-lesioned rats. In Experiment 2, a second method for depleting 5-HT was used. The tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA) also disrupted PPI without altering basal startle reactivity. Again, 8-OH-DPAT disrupted PPI in control animals; this effect was not altered in PCPA-treated rats but the increase in basal startle reactivity induced by 8-OH-DPAT was not observed in PCPA-treated rats. Taken together with the results of previous experiments involving drugs that enhance 5-HT neurotransmission it appears that both increases and decreases in 5-HT activity disrupt PPI.