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)     

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.     

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)     

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.     

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.     

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)     

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)     

Inbred mouse strains differ in the regulation of startle and prepulse inhibition of the startle response.

The startle response and adaptability of the startle response (prepulse inhibition and habituation) have been observed in animals. The studies reported here screened 8 inbred mouse strains to determine whether genetic factors influence these behaviors. Strain differences were found in both the sensitivity to acoustic startle and the magnitude of both the auditory and tactile startle as well as the magnitude of prepulse inhibition (PPI) of both tactile and acoustic startle. Neither the 2 startle responses nor the 2 forms of PPI were significantly correlated with one another, suggesting that different genes regulate these 2 forms of startle and PPI. Acoustic-acoustic PPI was significantly correlated, however, with hippocampal auditory gating (TC ratio) suggesting an overlap in the genes that regulate these 2 forms of sensory gating. (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)     

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)     

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

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

The 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.     

Effects of single oral administrations of haloperidol and d-amphetamine on prepulse inhibition of the acoustic startle reflex in healthy male volunteers

The effects of acute administration of an indirect dopamine-agonist, d-amphetamine, and a non-selective dopamine receptor antagonist, haloperidol, were investigated in normal male volunteers on habituation and prepulse inhibition (PPI) of the acoustic startle reflex in two experiments. In Experiment 1, 40 male non-smoker volunteers were tested for habituation and PPI (defined as percentage reduction of the pulse-alone amplitude; prepulses 9 dB above background) before and after double-blind administration of either 2 mg haloperidol or placebo. No influence of haloperidol was observed on either habituation or PPI of the startle reflex in this experiment. In Experiment 2, 60 male volunteers underwent startle testing before and after double-blind administration of a single oral dose of 5 mg haloperidol, 5 mg d-amphetamine or placebo. Habituation and PPI (prepulses 15 dB above background) for the placebo group did not differ significantly from that observed for the d-amphetamine or for the haloperidol group. However, in a subgroup of smoking subjects, both d-amphetamine and haloperidol reduced PPI as compared to that observed prior to drug administration. The implications of these findings in relation to animal pharmacological studies and observed sensorimotor gating deficits in schizophrenia are discussed.     

Potentiation of the acoustic startle response by a conditioned stimulus paired with acoustic startle stimulus in rats.

The hypothesis that the standard acoustic startle habituation paradigm contains the elements of Pavlovian fear conditioning was tested. In a potentiated startle response paradigm, a startle stimulus and a light conditioned stimulus (CS) were paired. A startle stimulus then was tested alone or following the CS. Freezing behavior was measured to index conditioned fear. The startle response was potentiated on CS trials, and rats froze more in CS than in non-CS periods. In Experiment 1, response to a previously habituated, weak startle stimulus was potentiated. In Experiment 2, response to the same stimulus used as the unconditioned stimulus (US) in training was potentiated. This CS-potentiated response retarded the course of response decrements over training sessions as compared with an explicitly unpaired control group. Conditioned fear is a standard feature of this habituation paradigm, serves to potentiate the startle response, and provides an associative dimension lacking in the habituation process per se. (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)     

Activated immune system in patients with Huntington''s disease

Abnormalities of immune system compartments were determined in 12 patients with Huntington's disease (eight males, four females; age 42.4+/-11.7 years) and 11 controls (7 males, 4 females; age 47.0+/-12.0). All patients were free from infectious diseases. Serum concentrations of a panel of serum soluble markers of immune activation were investigated, namely neopterin, 55-kDa-type soluble tumor necrosis factor receptor (sTNF-R), interleukin-2-receptor (sIL-2R), kynurenine, tryptophan, immunoglobulins (Ig) A, M and G as well as routine laboratory tests. Compared to controls, we found significantly higher serum levels of IgA (p<0.01), sTNF-R, sIL-2R, neopterin, and complement component C3 (all p<0.05), and serum tryptophan was decreased (p<0.001). Higher concentrations of circulating immune complexes, cardiolipin antibodies, IgM, neopterin and lower tryptophan were associated with loss of cognitive function as assessed by the mini-mental-test. Five patients died within 1 year after measurements were performed. In these patients IgM, circulating immune complexes and neopterin concentrations were higher compared to survivors and serum tryptophan was lower. The data indicate an activation of various immune system compartments in Huntington's disease and that systemic immunological alterations might be important in the course of the disease.     

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.     

Towards a cross-species pharmacology of sensorimotor gating: effects of amantadine, bromocriptine, pergolide and ropinirole on prepulse inhibition of acoustic startle in rats

Animal models in behavioral pharmacology can be evaluated based on their face, predictive and construct validity. A further level of validity may be achieved if a model is reproduced precisely across species--from laboratory animal to human--using identical conditions and manipulations to elicit identical behavioral changes. Under circumstances in which a model achieves 'homologous' validity, it should be possible to demonstrate that the same pharmacological agents produce parallel changes in the same behavior (as distinct from the clinical condition that the animal behaviors are hypothesized to model), when studied in laboratory animals and in humans. Studies have demonstrated that the disruption of sensorimotor gating of the startle reflex, measured by prepulse inhibition (PPI), in rats by dopamine agonists exhibits face, predictive and construct validity for the relative loss of PPI in schizophrenia patients. To assess the homologous validity of this model, and to expand its utility in understanding the pathophysiology of sensorimotor gating deficits and in developing novel antipsychotic agents to reverse these deficits, it will be important to study PPI across species, comparing response profiles to identical pharmacological manipulations. In the present studies, we report that PPI in rats is reduced in a dose-dependent manner by four dopamine agonists that can be administered with relative ease to humans. We also report that the PPI-disruptive effects of the clinically useful dopamine agonist pergolide are reversed by both typical and atypical antipsychotics. These studies establish a foundation for pursuing human pharmacological studies of PPI, and for extrapolating the substantial neurochemical and neurophysiological information from animal studies of PPI, towards understanding the neural basis for deficient sensorimotor gating in specific neuropsychiatric disorders.     

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)