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)     

Sexual orientation-related differences in prepulse inhibition of the human startle response.

Prepulse inhibition (PPI) refers to a reduction in the startle response to a strong sensory stimulus when this stimulus is preceded by a weaker stimulus--the prepulse. PPI reflects a nonlearned sensorimotor gating mechanism and also shows a robust gender difference, with women exhibiting lower PPI than men. The present study examined the eyeblink startle responses to acoustic stimuli of 59 healthy heterosexual and homosexual men and women. Homosexual women showed significantly masculinized PPI compared with heterosexual women, whereas no difference was observed in PPI between homosexual and heterosexual men. These data provide the first evidence for within-gender differences in basic sensorimotor gating mechanisms and implicate the known neural substrates of PPI in human sexual orientation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Experience increases the prepulse inhibition of the acoustic startle response in mice.

The authors have previously shown that inhibition of the acoustic startle response by a prepulse increases when it is repetitively elicited over days. The present experiments show in C3H and C57 mice that this change is caused by an increase in prepulse inhibition (PPI) and not by a decrease in prepulse facilitation. This PPI increase is only evoked if prepulses and startle stimuli are repeatedly given in a temporally paired ("contingent") order, proposing an associative learning process. (Only in C57 mice, PPI was additionally increased by adaptation in the same, but not in a different, context). As an underlying mechanism for this PPI increase by experience, the authors hypothesize Hebbian plasticity of an inhibitory synapse. (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)     

Smoking cues decrease prepulse inhibition of the startle response and increase subjective craving in humans.

The present study investigated whether exposure to smoking cues would attenuate prepulse inhibition (PPI) of the startle reflex and increase craving among smokers across 2 experimental sessions. It was hypothesized that exposure to smoking cues would result in a decrease in PPI. Twenty-six smokers were exposed to smoking cues and control cues in 2 experimental sessions 1 week apart. Results indicate that smoking cues reliably attenuated PPI in both the 1st and 2nd sessions as compared with control cues. Findings also suggest that smoking cues reliably increased craving, increased negative affect, and reduced positive affect relative to baseline measures in both sessions. Results are consistent with the premise that exposure to smoking cues precipitates increases in dopamine activation or changes in information processing that cause a disruption of PPI. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The septohippocampal system is involved in prepulse inhibition of the acoustic startle response in rats.

Prepulse inhibition (PPI) of the acoustic startle response (ASR) can be used as an operational measure for brain mechanisms that prevent disruption of ongoing stimulus processing routines by other stimuli and that thereby avoid behavioral interference. Deficient PPI has been observed in schizophrenics; therefore, much interest has been devoted to the understanding of the neural basis of PPI. This study investigated the role of the septohippocampal system in the modulation of PPI in rats. Stimulation of the medial septum by injection of the glutamate agonist kainate led to a profound disturbance of PPI and reduced the ASR amplitude. The PPI deficit induced by intraseptal kainate was attenuated by systemic or intrahippocampal administration of the acetylcholine antagonist scopolamine. Lesions of the medial septum, made by the neurotoxin AMPA, did not affect PPI. The present data indicate that activation of the septohippocampal system reduces PPI of the ASR, suggesting its role in sensorimotor gating. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Strain differences in the isolation-induced effects on prepulse inhibition of the acoustic startle response and on locomotor activity.

The authors investigated the effects of isolation rearing on acoustic startle response, prepulse inhibition (PPI), its modification by apomorphine, and locomotor activity in 3 rat strains: Wistar (WS), Sprague-Dawley (SD), and Lister hooded (ListH). SD and ListH, but not WS, showed isolation-induced PPI deficits. In 2 consecutive PPI tests, only SD isolates showed significant PPI deficits. An isolation rearing effect in ListH was significant only in the 1st PPI test. Apomorphine dose-dependently (0.0–0.5 mg/kg) disrupted PPI, but sensitivity to the drug differed, with WS and SD rats being more sensitive to lower doses (0.01–0.05 mg/kg) than ListH rats (0.5 mg/kg). Isolates, irrespective of strain, did not differ from grouped rats in their response to the apomorphine challenge. Only WS and ListH isolates demonstrated significantly increased locomotor activity. Strain differences in the different parameters measured did not predict isolation-induced effects on PPI. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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)     

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)     

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.     

Cholinergic mechanisms in startle and prepulse inhibition: Effects of the false cholinergic precursor N-aminodeanol.

Examined the effects of cholinergic deficiency on prepulse inhibition (PPI) of the acoustic startle. Rats treated with a choline-free diet that contained the false cholinergic precursor N-aminodeanol showed great deficit in PPI. This deficit does not appear to be secondary to an increase of stereotyped behaviors. Startle threshold was also greatly reduced, as these rats startled to the 70-dB prepulse, and the baseline startle amplitude was increased by 60% over the control rats. Arecoline (4 mg/kg) partially reversed the deficit in PPI. This improvement persisted beyond the period of drug treatment. On the other hand, scopolamine (1 mg/kg) reduced PPI in the control rats. Results suggest that cholinergic systems play a major role in both the elicitation and prepulse inhibition of startle. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Ventral pallidal GABA-A receptors regulate prepulse inhibition of acoustic startle

Prepulse inhibition (PPI) of the acoustic startle reflex occurs when a weak auditory stimulus is presented 30-500 ms before the startling stimulus. Previous studies have shown that PPI is modulated by GABAergic projections from the ventral striatum to the ventral pallidum (VP). To evaluate the anatomical and pharmacological substrates of pallidal modulation of PPI, we measured PPI after intrapallidal infusion of GABA-B and GABA-A antagonists. Intrapallidal infusion of the GABA-B antagonist, 2-OH-saclofen (0.025-0.10 microgram), did not significantly alter PPI, startle amplitude or peak startle latency. Infusion of the GABA-A antagonist, picrotoxin (0.02-0.08 microgram), into the medial or central VP significantly reduced PPI; this effect appeared somewhat weaker after picrotoxin infusion into the lateral VP and was absent after infusion into the adjacent fundus striatum (FS). There was no significant effect of picrotoxin infusion into any of the VP sites or FS on startle amplitude or peak startle latency. Thus, ventral striato-pallidal GABAergic modulation of PPI appears to be mediated solely by GABA-A receptors and this modulatory substrate is predominantly distributed across the medial and central portions of the VP.     

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)     

Dopamine autoreceptors in rat nucleus accumbens modulate prepulse inhibition of acoustic startle

Dopamine and 3,4-dihydroxy phenylacetic acid (DOPAC) levels in discrete regions and apomorphine- or (-)-sulpiride-induced changes in electrically evoked dopamine release from nucleus accumbens slices were assessed after testing prepulse inhibition of acoustic startle (PPI) in rats. Dopamine and DOPAC levels in the nucleus accumbens, but not in the striatum, correlated well with PPI (r = -0.64 for dopamine, r = -0.48 for DOPAC). Evoked dopamine release from the nucleus accumbens did not differ between the high-PPI (more than 60%) and the low-PPI (less than 40%) group. When slices were superfused with 1 microM apomorphine, the S2/S1 ratio in rats showing high PPI was 0.77 +/- 0.02 (mean +/- SEM, 66% of control), significantly smaller than in the low-PPI group (S2/S1 ratio = 0.97 +/- 0.08, 94% of control, p < 0.05). Moreover, (-)-sulpiride-induced increase in evoked dopamine release from the nucleus accumbens in the high-PPI group was inclined to be greater than in the low-PPI group. The results suggest that PPI differences between individuals may reflect the sensitivity of release-modulating dopamine autoreceptors in the nucleus accumbens.     

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)     

Modification of the acoustic startle response in hearing-impaired C57BL/6J mice: Prepulse augmentation and prolongation of prepulse inhibition.

Modification of acoustic startle amplitude by a 10-ms tone prepulse (S1) was evaluated as a function of the interstimulus interval (ISI) between the onset of S1 and the onset of the startle-evoking stimulus (S2). Subjects were normal-hearing 1-month-old C57BL/6J (C57) mice and CBA/CaJ mice and 5-month-old C57 mice with high-frequency hearing loss. With a 2-ms ISI, 5-month-old C57 mice (but not the normal-hearing mice) exhibited pronounced prepulse augmentation (PPA) of startle: Amplitudes were much larger when S1 was present. Prepulse inhibition (PPI) occurred with ISls of 10–100 ms in all subject groups. With long ISls of 200 and 500 ms, however, PPI was strong only in 5-month-old C57 mice and only with S1 frequencies of 8, 12, and 16 kHz. Physiological studies of neural plasticity have shown that frequencies of 8–16 kHz become "over-represented" (more neurons responding) in the central auditory system of C57 mice, suggesting a link with prolonged PPI observed here. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Novel antipsychotic-like effects on prepulse inhibition of startle produced by a neurotensin agonist

Agonists of the neuropeptide neurotensin have been proposed as potential novel antipsychotics based on their ability to modulate neurotransmission in brain regions associated with schizophrenia. To test this hypothesis, we examined the effects of a neurotensin mimetic with improved metabolic stability in an animal model with strong predictive validity for antipsychotic activity. Subcutaneous injections of PD149163, a reduced amide neurotensin(8-13) mimetic, significantly antagonized the reduction of prepulse inhibition (PPI) of the rat startle reflex produced by amphetamine and by the phencyclidine analog dizocilpine. PD149163 had no significant effect on baseline PPI or on baseline startle amplitude and did not antagonize the reduction of PPI produced by the direct dopamine agonist apomorphine. These findings suggest that PD149163 has novel antipsychotic-like properties that are distinct from known members of both the "typical" and "atypical" families of antipsychotics.     

The ventral pallidum mediates disruption of prepulse inhibition of the acoustic startle response induced by dopamine agonists, but not by NMDA antagonists

Prepulse inhibition (PPI) of the acoustic startle response is observed when the startling noise pulse is preceded by a weak, non-startling stimulus. PPI has been considered as a measure for sensorimotor gating mechanisms. Disruption of PPI can be found in schizophrenic patients as well as after blockade of NMDA receptors or stimulation of dopamine receptors in rats. The neuronal circuitry which regulates PPI consists of cortico-limbic brain structures where the nucleus accumbens (NAC) plays a key role. The NAC exerts its modulating effects on PPI by way of a projection from the ventral pallidum (VP) to the pedunculopontine tegmental nucleus (PPTg). We recently postulated that the reduction of PPI by intra-NAC infusion of glycine-site NMDA antagonists is not mediated by the VP. We tested here this hypothesis in rats with excitotoxic lesions of the VP which were systemically treated with apomorphine or MK-801 or received intraNAC infusions of dopamine or the glycine-site NMDA antagonist 7-chlorokynurenic acid. Lesioned rats showed a marked deficit in PPI after MK-801 and 7-chlorokynurenate treatment but not after apomorphine or dopamine injection, in contrast to sham-lesioned controls showing deficits in PPI under all conditions. These data provide behavioral evidence for the existence of a pathway which does not include the VP for the mediation of sensorimotor gating deficits. We propose that a direct connection between the NAC and PPTg may be responsible for the effects of NMDA/glycine receptor blockade, whereas the VP is an indispensable relay for the disruptive effects on PPI exerted by the NAC dopamine system.     

Phencyclidine-induced deficits in prepulse inhibition of startle are blocked by prazosin, an alpha-1 noradrenergic antagonist

Prepulse inhibition (PPI) is a form of plasticity of the startle response in which presentation of a weak stimulus immediately before an intense startling stimulus reduces the resultant startle response. Deficits in PPI, an operational measure of sensorimotor gating, are observed in schizophrenia patients and can be modeled in rats by the psychotogen phencyclidine (PCP). PCP-induced deficits in PPI in rats are resistant to dopamine and serotonin antagonists but can be antagonized by antipsychotics such as clozapine, olanzapine and Seroquel. These latter antipsychotics have antagonistic actions at several receptors, including alpha-1 and alpha-2 adrenergic, M1 muscarinic and gamma-aminobutyric acid (GABA)-A receptors. Although the direct actions of PCP are thought to be mediated by noncompetitive antagonism of N-methyl-D-aspartate sites, PCP thereby indirectly activates multiple neurotransmitter systems, including those affected by the aforementioned antipsychotics. The present studies examined the possibility that an antagonist action at a particular receptor subtype might be responsible for the interaction between PCP and the clozapine-like antipsychotics by testing whether a selective antagonist at alpha-1, alpha-2, M1 or GABA-A receptors would prevent the PCP-induced deficit in PPI in rats. Animals were pretreated with either the alpha-1 antagonist prazosin (0, 0.5, 1.0 or 2.5 mg/kg), the alpha-2 antagonist RX821002 (0, 0.2 or 0.4 mg/kg), the M1 muscarinic antagonist pirenzepine (0, 10 or 30 mg/kg) or the GABA-A antagonist pitrazepin (0, 1.0 or 3.0 mg/kg) and then treated with either saline or PCP (1.5 mg/kg). Because prazosin was effective in blocking the effects of PCP, an additional experiment tested the possibility that prazosin (0, 1.0 or 2.5 mg/kg) would block the PPI deficits produced by the dopamine agonist apomorphine (0 or 0.5 mg/kg). After drug administration, animals were tested in startle chambers. PCP was found repeatedly to decrease PPI. Prazosin (1.0 and 2.5 mg/kg) blocked this deficit in two separate experiments but did not increase base-line PPI levels. The effects on PPI were dissociable from changes in startle reactivity. Furthermore, prazosin did not antagonize apomorphine-induced disruptions of PPI, which suggests that the antagonism of the PCP effect was not simply due to a generalized improvement of deficient PPI. The antagonists for alpha-2, for M1 and for GABA-A receptors had no effect on base-line PPI or on PCP-induced disruptions in PPI. These findings indicate that the PPI-disruptive effect of PCP may be mediated in part by alpha-1 adrenergic receptors and that antagonism of alpha-1 receptors may play a major role in mediating the blockade of PCP-induced deficits in PPI by certain antipsychotics.