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     

Sleep deprivation disrupts prepulse inhibition of the startle reflex: reversal by antipsychotic drugs

Sleep deprivation (SD) is known to induce perceptual impairments, ranging from perceptual distortion to hallucinatory states. Although this phenomenon has been extensively described in the literature, its neurobiological underpinnings remain elusive. In rodents, SD induces a series of behavioural patterns that might be reflective of psychosis and mania, such as hyperlocomotion and sensitization to psychotogenic drugs. Notably, such changes are accompanied by transitory alterations of dopaminergic signalling. Based on the hypothesis that both psychotic and manic disorders reflect gating impairments, the present study was aimed at the assessment of the impact of SD on the behavioural model of prepulse inhibition (PPI) of the startle reflex, a reliable paradigm for the study of informational filtering. Rats subjected to SD (24 h, 48 h, 72 h) exhibited a time-dependent increase in startle reflex and a dramatic deficit in PPI. Both alterations were reversed 24 h after termination of the SD period. Interestingly, PPI disruption was efficiently prevented by haloperidol (0.1 mg/kg i.p.) clozapine (5 mg/kg i.p.) and risperidone (1 mg/kg i.p.). Conversely, neither the anxiolytic diazepam (5 mg/kg i.p.) nor the antidepressant citalopram (5 mg/kg i.p) affected the PPI disruption mediated by SD, although diazepam reversed the enhancement in startle reflex magnitude induced by this manipulation. Our data suggest that SD induces gating deficits that might be relevant to the hallucinatory phenomena observed in humans, and provide a novel reliable animal model where such relationship can be studied.     

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.     

Intracortical 5,7-dihydroxytryptamine depletes brain serotonin concentrations without affecting spontaneous activity

Microinjections of either 2 or 4 micrograms of the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) were made into either the right or left frontal cortex of male rats pretreated with desmethylimipramine. Although both the 2 and 4 micrograms doses produced significant depletions of serotonin concentrations in the cortex and median raphe, neither dose produced a significant increase in spontaneous activity. This is in contrast to our findings with the noradrenergic neurotoxins, 6-hydroxydopamine and DSP-4, which produced hyperactivity following right but not left hemisphere injections. These findings do not rule out the involvement of 5-HT in the asymmetrically elicited hyperactivity but they do suggest some transmitter and neural pathway specificity to the lateralized response to cortical injury.     

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.     

Effects of topiramate on the prepulse inhibition of the acoustic startle in rats.

The anticonvulsant topiramate (TPM) has been recently proposed as a novel adjuvant therapy for bipolar disorder and schizophrenia, yet its efficacy remains controversial. As both disorders are characterized by gating deficits, we tested the effects of TPM on the behavioral paradigm of prepulse inhibition (PPI) of the acoustic startle response, a validated animal model of sensorimotor gating. TPM (10, 18, 32, 58, 100 mg/kg, intraperitoneal, i.p.) enhanced PPI in rats in a dose-dependent fashion, prevented the PPI reduction mediated by the dopaminergic agonist apomorphine (0.25 mg/kg, subcutaneous, s.c.) and potentiated the effects of the antipsychotic drugs haloperidol (0.05, 0.1 mg/kg, i.p.) and clozapine (2.5, 5 mg/kg, i.p.). Conversely, TPM elicited no significant effect on the PPI disruption mediated by the NMDA receptor antagonist dizocilpine (0.05, 0.1 mg/kg, s.c.) and surprisingly antagonized the attenuation of dizocilpine-induced PPI disruption mediated by clozapine (5 mg/kg, i.p.). Our results suggest that TPM may exert diverse actions on the neural substrates of sensorimotor gating. While the pharmacological mechanisms of such effects are still elusive, our findings might contribute to shed light on some controversies on the therapeutic action of TPM, and point to this drug as a putative novel adjuvant therapy for some clusters of gating disturbances.     

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.     

Increased tilt-cage activity after serotonin depletion by 5,7-dihydroxytryptamine.

Administration of 5,7-dihydroxytryptamine (5,7-DHT, 8 μg) into the medial forebrain bundle produced a 78% decrease in forebrain serotonin (5-HT) and a 2-fold increase in 24 hr tilt-cage activity. Intraventricular administration of 5.7-DHT (200 μg) resulted in a 4-fold increase in 24 hr activity and 5-HT depletions of 83%, 58% and 71% in forebrain, brainstem and spinal cord, respectively. The diurnal index of activity was identical for 5,7-DHT and control groups, suggesting preservation of the normal light-dark activity rhythm which contrasts with the disruption of this rhythm reported in p-chlorophenylalanine (p-CPA)-induced hyperactivity. Furthermore, unlike rats with median raphe lesions, 5,7-DHT-treated-rats were hypoactive when tested in the open-field. Administration of p-CPA produced a dose-dependent increase in tilt-cage activity in normal rats, but had relatively little effect on activity in 5,7-DHT-treated-rats. It is concluded that different methods of 5-HT depletion can result in different effects on various behavioral measures, but that this does not appear to be the case for tilt-cage hyperactivity. That is, this effect occurs following electrolytic raphe lesions, p-CPA or 5,7-DHT. It is, therefore, suggested that this effect is not the result of non-specific damage but rather is due to subnormal 5-HT synaptic activity in the central nervous system.     

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.     

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     

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.     

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.     

Effects of single and repeated exposure to apomorphine on the acoustic startle reflex and its inhibition by a visual prepulse

The acoustic startle reflex (ASR) is inhibited by startle-irrelevant stimuli that briefly precede reflex elicitation. This effect, prepulse inhibition (PPI), is reduced in strength for animals that have received dopamine agonists, such as apomorphine (APO). Reduction in PPI is most evident for weak masked noise prepulses, thus suggesting that APO disrupts the reception of stimuli to the extent that they present a low signal-to-noise ratio. Here we examine the effect of APO on PPI produced by non-masked visual prepulses. Light flashes were given at two intensities, 40, 70, 110, or 220 ms before ASR elicitation. In phase 1 (5 weeks in duration) half of the animals received one weekly injection of APO (0.5 mg/kg, IP) and one of vehicle (VEH), while the other half received two injections of VEH. Within these groups, half were tested 30 min after the injections, the other half kept test naive (four groups total). In phase 2, following a 4-week rest, all groups were tested after a low dose of APO (0.1 mg/kg) and VEH, 1 week apart. APO eliminated PPI for a dim flash and reduced PPI for a brighter flash to a level normally obtained with the dim flash, while increasing both ASR control values and activity. The bright light was maximally effective at a lead time of 70 ms and APO did not alter this value. Because in general the time of maximal inhibition varies with prepulse intensity for visual stimuli, the finding that the time of the peak remained constant reveals that APO has its effect on inhibition rather than on effective stimulus intensity. In phase 2, APO reduced PPI with no sign of sensitization from past drug exposure. However, APO increased the ASR only in groups previously exposed to APO, indicating behavioral sensitization. The differential effects of repeated exposure on these response measures suggest that neural substrates for the several behavioral effects of APO function at least in part independently.This research was supported by USPHS Research Grants MH00859 and AG09524, and a Center Support Grant to the Center for Visual Science at the University of Rochester, EY01319. A preliminary report of these data was presented at the Meeting of the Society for Neuroscience, Washington DC, November 1993     

Intracerebral administration of metabotropic glutamate receptor agonists disrupts prepulse inhibition of acoustic startle in Sprague-Dawley rats

 The functional role of striatal metabotropic glutamate receptors (mGluRs) was examined by measuring prepulse inhibition (PPI) of an acoustic startle response following the intracerebral administration of selective agonists in male Sprague-Dawley rats prepared with bilateral cannulae aimed at either the nucleus accumbens or dorsal striatum. mGluR subtypes (1–8) are classed in three groups based on sequence homology, signal transduction mechanism and pharmacology. Intra-accumbens 1S,3R-ACPD, an agonist at group 1 and 2 mGluRs (0.5–1.0 μmol/2 μl), caused a dose-dependent loss of PPI. The effect of 1S,3R-ACPD was diminished when injected into dorsal striatum. Intra-accumbens infusion of the group 1 selective agonist 3,5-DHPG (1 μmol) and the group 2 selective agonist l-CCG-I (100 nmol) also led to statistically significant disruptions of PPI, while the group 3 selective agonist l-AP4 (0.4–1.0 μmol) had no significant effect. Although the group 1/2 mGluR antagonist (+) MCPG (0.5 μmol) had no significant effect of its own on PPI, co-administration with 1S,3R-ACPD (1 μmol) blocked ACPD-induced loss of PPI. In addition, pretreatment (30 min) with haloperidol (0.3 mg/kg IP) attenuated the PPI disruption induced by 1 μmol 1S,3R-ACPD, suggesting dopamine may play a role in mGluR agonist induced loss of PPI. These results support a role for group 1 and group 2 mGluRs in the nucleus accumbens in the regulation of PPI, a measure of sensory gating. As PPI is abnormal in some patient populations, such as Huntington’s and schizophrenia, mGluRs may have potential as novel therapeutic targets for these diseases. Received: 15 April 1998 / Final version: 23 July 1998     

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