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5-HT1B receptor knockout, but not 5-HT1A receptor knockout mice, show reduced startle reactivity and footshock-induced sensitization, as measured with the acoustic startle response.

To investigate whether the hyperreactivity to mild environmental and novel stimuli in 5-HT1B receptor knockout (1BKO) mice, as suggested by measures of exploratory, aggressive, and impulsive behaviors, can be extended to phasic stimuli, 1BKO and wildtype mice were tested in acoustic startle reactivity and plasticity paradigms, including habituation, prepulse inhibition, and footshock-induced sensitization of the startle response. Furthermore, we compared 5-HT1A receptor knockout (1AKO) and 1BKO mice to further test the suggested opposite behavioral profiles in these two genotypes. Results show that startle reactivity and footshock-induced sensitization was reduced in 1BKO mice, with no changes in habituation or PPI. In contrast, 1AKO mice did not differ from WT mice in any of the measures. These results indicate that an absence of 5-HT1B receptors, but not of 5-HT1A receptors, affects the modulation of startle reactivity and footshock-induced sensitization, without influencing startle plasticity. Moreover, this study suggests that 1AKO mice display a distinct, but not opposite behavioral profile from 1BKO mice. Furthermore, it is concluded that the hyperreactivity in 1BKO mice cannot be generalized to all stimuli, including the startling stimuli used in this study, but is probably restricted to mild environmental stimuli only.

Acoustic Stimulation↗

[Use of the acoustic startle response in the mouse to evaluate the pharmacodynamic action of ethanol].

A method of the pharmacological screening of psychotropic drugs that is based on the estimation of the peak amplitude and latency of the acoustic startle response (ASR) is suggested. A linear relationship between the changes of the ASR parameters induced by acute i.p. 14C-ethanol administration and its contents in brain is demonstrated. It is proposed that changes of the ASR parameters are strictly dependent upon the concentration of a modulatory drug in the biophase of action (brain, serum) and therefore can be utilised for the effector analysis of pharmacokinetics and preliminary screening of psychotropic drugs.

Acoustic Stimulation↗

Acquisition of acoustic startle response in relation to growth and thyroid function in rats.

Thiourea was administered by gavage to pregnant and lactating rats from gestational day 18 until postnatal day 10, at doses of 100 or 250 mg per day (approximately 350 or 900 mg/kg/day). From the day after birth until postnatal day 14 the neonates were weighed, and beginning on postnatal day 10 acquisition of acoustic startle reflex was assessed. Serum thyroxine and thyrotropin were measured on postnatal day 14. High dose thiourea severely inhibited thyroid function in pups, significantly depressed body growth, and retarded development of the acoustic startle response. At the low dose there was a significant reduction in growth, but no effect on acquisition of acoustic startle reflex. Low dose pups appeared to be functionally euthyroid (free T4 and thyrotropin were not significantly different from control). In conjunction with other studies, these results strongly suggest that, while development of acoustic startle is dependent upon thyroid hormone, it is not readily affected by retarded body growth.

Animals↗

Effects of bromocriptine and haloperidol on prepulse inhibition of the acoustic startle response in man.

Experiments with animals have shown that D2 dopamine (DA) receptors are involved in prepulse inhibition of the acoustic startle reflex (suppression of the reflex response evoked by a loud sound by prior presentation of a low-intensity stimulus). The present experiment attempted to extend this observation to man. Twelve healthy males (18-30 years), screened for normal hearing thresholds, participated in four sessions in which they received oral doses of placebo, bromocriptine 1.25 mg (a D2 receptor agonist), haloperidol 3 mg (a D2 receptor antagonist) and combined treatment with bromocriptine 1.25 mg+haloperidol 3 mg, according to a balanced double-blind protocol. Thirty-minute electromyographic recordings from the orbicularis oculi muscle of the right eye were carried out 120 min after ingestion of haloperidol and/or 90 min after ingestion of bromocriptine. Subjects received 36 40-msec sound pulses (115 dB), separated by variable intervals (mean 25 sec); in 24 of the trials the pulse was preceded by a 40-msec prepulse (75 dB in 12 trials and 85 dB in 12 trials; prepulse-pulse interval, 120 msec). The amplitude of the startle response was not significantly altered by any of the active treatments. Under the placebo condition, both 75- and 85-dB prepulses inhibited the startle response. Bromocriptine significantly attenuated this prepulse inhibition; haloperidol also produced a small but statistically significant attenuation of prepulse inhibition. Haloperidol significantly antagonized the attenuation of prepulse inhibition produced by bromocriptine. Neither drug altered self-rated alertness, physiological finger tremor, systolic or diastolic blood pressure or salivation. Bromocriptine significantly suppressed and haloperidol significantly elevated serum prolactin levels, these changes being absent when the two drugs were given in combination. The results provide evidence for the involvement of D2 DA receptors in prepulse inhibition of the startle reflex in man.

Acoustic Stimulation↗

Acoustic startle response in young and aging C57BL/6J and CBA/J mice.

C57BL/6J (C57) mice demonstrate progressive age-related hearing loss during the first year of life, whereas CBA/J (CBA) mice lose little sensitivity through 18 months of age. The acoustic startle response (ASR) was measured in these strains to determine behavioral correlates of aging with and without presbycusis. The stimuli were tone pips (10-ms duration, 1-ms rise-fall) with frequencies of 4, 8, 12, 16, or 24 kHz at intensities of 70, 80, 90, or 100 dB SPL. ASR "thresholds" (the minimum SPL required to elicit ASRs more than 50% of the time) increased with age, and startle amplitudes became smaller in both strains. However, the changes in these startle parameters were much more pronounced in C57 mice, with middle to high frequencies (12-24 kHz) severely affected. The startle latencies at and above ASR "threshold" increased with age in C57 mice, but did not change in CBA mice. The CBA data indicate that aging, per se, has little effect on ASR parameters; the C57 data show that hearing loss is a cogent factor. However, ASR parameters of C57 mice are altered to a greater extent than expected, on the basis of the elevations of absolute sensory thresholds, particularly for middle frequencies (12-16 kHz). Both peripheral and central mechanisms are proposed to account for the discrepancy.

Aging↗

Attenuation of acoustic and tactile startle responses of vitamin B-6 deficient rats.

Vitamin B-6 deficient rats exhibit changes in behavior, sensory function, and other nervous system abnormalities such as convulsive seizures and motor disturbances. Sensorimotor reactivity was evaluated quantitatively by measuring auditory and tactile startle responses in 12 week old female Long-Evans rats fed a diet devoid of added vitamin B-6 (DEF) or a control diet, either ad lib (AL-CON) or pair-fed to deficient rats (PF-CON). Deficiency was confirmed with a tryptophan-load test administered to a separate group of rats fed simultaneously according to the same protocol. At week 18, body weight and feed efficiency were different among groups (p less than 0.001), and were lowest in DEF. Amplitude of response to both acoustic and tactile stimuli was depressed in DEF compared to both control groups, which generally did not differ in response. This effect was seen most dramatically in responses to the acoustic stimulus (p = 0.034), and especially to the first presentation (p = 0.017). Latency to maximum response was not affected by diet. Possible mechanisms for this nervous system abnormality, not previously reported in vitamin B-6 deficiency, are discussed.

Animals↗

Fear-potentiated startle responses in temperamentally different human infants.

Previous research has indicated that 4-month-old human infants who exhibit high degrees of motor activity and negative affect in response to the presentation of unfamiliar auditory and visual stimuli are likely to display behavioral inhibition as toddlers, while 4-month-old infants who display high degrees of motor activity and positive affect in response to the same stimuli are likely to be behaviorally exuberant toddlers. The present study examined baseline and fear-potentiated startle eyeblink responses during a stranger-approach paradigm at age 9 months in a group of infants, some of whom displayed high motor activity and negative affect and some of whom displayed high motor activity and positive affect at 4 months. The analyses revealed that the high motor/high negative group of infants exhibited a significantly greater increase in fear-potentiated startle amplitude at 9 months compared with the high motor/high positive group. There were no differences among groups of infants on baseline startle responses. These findings suggest that the origins of behavioral inhibition in early childhood may be linked to a low threshold for arousal in forebrain limbic areas.

Affect↗

The cardiovascular startle response: anxiety and the benzodiazepine receptor complex.

Benzodiazepine receptor (BZR) agonists are prototypic anxiolytic agents, whereas BZR inverse agonists exert anxiogenic effects. The effects of these compounds offer a potentially important pharmacological model system to examine the central mechanisms of anxiety. In accord with its putative anxiogenic properties, we previously found that the BZR partial inverse agonist, FG 7142, enhances the cardiovascular defensive response to a nonsignal acoustic stimulus in rats. In contrast, we found in the present study that this agent attenuates both the somatic and cardiovascular components of the acoustic startle response. BZR agonists and inverse agonists are known to modulate the basal forebrain cortical cholinergic system, and we consider the potential involvement of this system in the disparate psychophysiological actions of FG 7142 and in anxiety states in general.

Animals↗

Increased sensitization of acoustic startle response in spasmodic mice with a mutation of the glycine receptor alpha1-subunit gene.

The spontaneous mutant mouse spasmodic (spd) carries a missense mutation affecting the glycine receptor alpha1-subunit gene. This results in a decreased binding affinity to glycine. Spd mutants show exaggerated acoustic startle responses (ASR). The present study sought to elucidate whether this increased ASR is due to a changed auditory processing or to stronger motor output resulting from a disinhibited motor system or, alternatively, to changes in modulatory influences on the startle pathway, namely in the mechanisms underlying habituation and sensitization. We found that in homozygous spd/spd mutants the startle threshold was lower, and the recorded slope of input/output (i/o) function, which reflects the relation between sensory input and motor output, was steeper. During repetitive presentation of high sound pressure level (SPL) startle stimuli (25 dB above startle threshold), ASR amplitudes did not decrease in spd/spd mutants as they do in the wildtype. In contrast, ASR amplitudes decreased when low SPL startle stimuli were presented. Footshocks presented after high SPL startle stimuli did not cause a further increase in ASR amplitudes of spd/spd mutants as in the wildtype. In heterozygous spd/+ mutants all these parameters were between those of spd/spd mutants and wildtype mice but closer to those of the wildtype. The steeper slope of i/o function in spd/spd mutants may be caused by both an increased sensory input and an increased motor output. The altered course of ASR amplitudes during repetitive stimulation and the deficit in additional footshock sensitization, however, can only be explained by an increased sensitization level in the spd/spd mutants. In accordance with the "dual process theory" strong sensitization evoked by high SPL startle stimuli supposedly counteracts habituation, leading to a constant high ASR amplitude. Furthermore, additional footshock sensitization is prevented. The increased sensitization level may be due to a change in auditory processing leading to a stronger sensitizing effect of the startle stimuli with high SPL. Alternatively, glycinergic tonic inhibition of sensitizing structures (e.g. the amygdala) in the wildtype may be diminished in spd/spd mutants, thus leading to a high sensitization level.

Acoustic Stimulation↗

Drop episodes in Coffin-Lowry syndrome: an unusual type of startle response.

We present a patient with a complete Coffin-Lowry syndrome, associated with drop episodes precipitated by sudden auditory stimuli, which provoked in turn, a definite loss of muscle tone in both legs. Electrophysiological studies showed that these episodes are an unusual type of startle response and that they may be associated with Coffin-Lowry syndrome.

Acoustic Stimulation↗

Neural cell adhesion molecule (NCAM-/-) null mice show impaired sensitization of the startle response.

The neural cell adhesion molecule (NCAM) plays important roles in development of the nervous system and in synaptic plasticity and memory formation in the adult. The present study sought to further investigate the role of NCAM in learning by testing habituation and footshock sensitization learning of the startle response (SR) in NCAM null mutant (NCAM-/-) and wildtype littermate (NCAM+/+) mice. Whereas habituation is a form of non-associative learning, footshock sensitization is induced by rapid contextual fear conditioning. Habituation was tested by repetitive presentation of acoustic and tactile startle stimuli. Although NCAM-/- mice showed differences in sensitivity in both stimulus modalities, habituation learning was intact in NCAM-/- mice, suggesting that NCAM does not play a role in the mechanisms underlying synaptic plasticity in the startle pathway. Footshock sensitization was elicited by presentation of electric footshocks between two series of acoustic stimuli. In contrast to habituation, footshock sensitization learning was attenuated in NCAM-/- mice: the acoustic SR increase after the footshocks was lower in the mutant than in wildtype mice, indicating that NCAM plays an important role in the relevant brain areas, such as amygdala and/or the hippocampus.

Acoustic Stimulation↗

Cysteamine impairs the development of the acoustic startle response in rats: possible role of somatostatin.

Somatostatin is transiently expressed in many regions of the developing brain, among others in auditory brainstem nuclei of neonatal rats. To explore the functional significance of somatostatin during the ontogeny of acoustically elicited behavior, the acoustic startle response (ASR) was measured in developing rats after chronic application of cysteamine, which, when applied in low doses, most selectively depletes somatostatin. Cysteamine treatment drastically reduced somatostatin immunoreactivity in the cochlear nuclear complex and the caudal pontine reticular nucleus, i.e. in structures mediating the ASR. It did not affect the ASR amplitude of postnatal day (P) 13 animals, yet it resulted in a significant reduction of the ASR amplitude at P18. Our results therefore suggest that somatostatin can influence the maturation of sensorimotor information processing.

Acoustic Stimulation↗

Effects of acute ethanol or amphetamine administration on the acoustic startle response and prepulse inhibition in adolescent and adult rats.

RATIONALE: Adolescents differ from adults in their sensitivity to a variety of psychoactive drugs. For example, adolescent rats are less sensitive to locomotor stimulant and stereotypic effects of amphetamine as well as to motor-impairing and hypnotic effects of ethanol while more sensitive to ethanol-induced disruption of brain plasticity. OBJECTIVE: The current study further explored age differences in psychopharmacological sensitivity by examining the effects of d-amphetamine (1.0 and 4.0 mg/kg) or ethanol (0.5, 1.0 and 1.5 g/kg) given interperitoneally on the acoustic startle response (ASR) and prepulse inhibition (PPI) in male adolescent and adult Sprague-Dawley rats. MATERIALS AND METHODS: The animals were given five startle trials (120 dB for 40 ms) before semi-randomized presentation of 12 startle trials interspersed with ten trials at each prepulse intensity (40 ms pulse of 5, 10, or 20 dB above background; 100 ms before the startle stimulus). RESULTS: Adolescent controls showed significantly less PPI than adults, replicating previous ontogenetic findings. The higher dose of amphetamine disrupted PPI in adult but not in adolescent animals, extending previous reports of an adolescent insensitivity to amphetamine to include this measure of sensorimotor gating. Ethanol exposure failed to alter PPI at either age, although both the 1.0 and 1.5 g/kg doses of ethanol significantly suppressed the magnitude of the ASR at both ages, potentially reflecting sedative or anxiolytic effects. CONCLUSION: These data provide further evidence of the relative insensitivity of adolescent animals to amphetamine, although no age effects were found in terms of ethanol sensitivity using these measures of startle and sensorimotor gating.

Age Factors↗

The long-term effects of diazepam and pentylenetetrazol on the potentiated startle response.

Stress desensitization is observed as a decrease in the disruptive effects of a stressor on behavior when the organism is repeatedly exposed to the stressor. For instrumental behavior, stress desensitization was also reported for rats preexposed to anxiogenic drugs; stress sensitization was reported for rats preexposed to an anxiolytic compound. The present study investigated whether similar effects are found in a noninstrumental task situation. First, rats received 12 daily injections of pentylenetetrazol (PTZ, 20 mg/kg, IP), diazepam (DZP, 5 mg/kg, IP) or saline. After each injection the effect of the drugs on the acoustic startle reflex was measured. No drugs were given during the remainder of the experiment. Eight days later rats were given 5 days of Pavlovian fear conditioning to establish a light as a shock signal. During the next 3 days, potentiation of the startle response by the light was measured. None of the drug treatments had an effect on startle potentiation, indicating that stress sensitivity is not affected by previous administration of PTZ and DZP in a noninstrumental task. An explanation for the different effects found for instrumental and noninstrumental tasks is suggested.

Acoustic Stimulation↗

[Evoked responses and impulse activity of the neocortex during the startle response following stimulation of the midbrain reticular formation].

The stimulation of the mid-brain reticular formation (RF) by single electrical stimuli caused a reticulo-cortical response (RCR) with 2.5--3 msec latency, composed of early (negative-positive complex) and late components. An interconnection is shown between the neuronal response and the formation of different phases of the surface RCR. The neurones of the upper cortical level took part in the response mainly during the development of the negative RCR phases. The appearance of the early positive potential was accompanied by an increase in the frequency of the background activity in the cells of the lower cortical layers. The neurones with initial inhibitory response to the RF stimulation changed their activity in the period of the early RCR components: a considerable part of neurones in the lower layers reduced their spike activity during the development of the short-latency negative oscillation.

Animals↗

Normal prepulse inhibition and habituation of acoustic startle response in suicidal depressive patients without psychotic symptoms.

BACKGROUND: Until now, there is a lack of useful biological markers to predict suicidal behavior in depressive patients. However, it is consistently found that suicidality is associated with a central serotonin deficit. Animal data suggest that prepulse inhibition (PPI) as well as habituation of the acoustic startle response (ASR), which are established as operational measures for sensorimotor gating, decreases after serotonin depletion. Thus, we investigated PPI and habituation of ASR in suicidal patients with depressive disorders as potential biological markers for suicidal behavior. METHODS: PPI and habituation of ASR was measured in 20 depressive patients who had at least one suicide attempt within the last three month. Eighteen healthy matched controls were examined likewise. RESULTS: Suicidal depressive patients did not differ from healthy controls in PPI, startle reactivity and habituation of ASR. Subgroup analyses showed that factors such as severity of depression, impulsiveness, gender, smoking, lethality of the last suicide attempt, number of suicide attempts, and medication had no influence on the results. CONCLUSIONS: These results suggest that neither PPI nor habituation of ASR could serve as useful markers for suicidality.

Acoustic Stimulation↗

Drop episodes in Coffin-Lowry syndrome: exaggerated startle responses treated with clonazepam.

A 16-year-old girl had fully manifested Coffin-Lowry syndrome and drop episodes. Her drop episodes were precipitated by sudden unexpected tactile or auditory stimuli associated with the electrostatic circumstances in her leg muscles immediately after the stimuli. Studies revealed that her drop episode symptom was an unusual type of startle response and that it may be associated with Coffin-Lowry syndrome.

Abnormalities, Multiple↗

Maternal exposure to bacterial endotoxin during pregnancy enhances amphetamine-induced locomotion and startle responses in adult rat offspring.

An increased incidence of schizophrenia has been associated with several perinatal insults, most notably maternal infection during pregnancy and perinatal hypoxia. This study used a rat model to directly test if maternal exposure to bacterial endotoxin (lipopolysaccharide, LPS) during pregnancy alters behaviors relevant to schizophrenia, in offspring at adulthood. The study also tested if postnatal anoxia interacted with gestational LPS exposure to affect behavior. At adulthood, offspring from dams administered LPS on days 18 and 19 of pregnancy showed significantly increased amphetamine-induced locomotion, compared to offspring from saline-treated dams. A period of anoxia on postnatal day 7 had no effect on amphetamine-induced locomotion and there was no interaction between effects of gestational LPS and postnatal anoxia on this behavior. Offspring from LPS-treated dams also showed enhanced acoustic startle responses as adults, compared to offspring from saline-treated dams. In offspring tested for pre-pulse inhibition (PPI) of acoustic startle and for apomorphine modulation of PPI, no effects of either gestational LPS or of postnatal anoxia and no interactions between LPS and anoxia were observed. It is concluded that maternal LPS exposure during pregnancy in the rat may be a useful model to study mechanisms responsible for effects of maternal infection on behaviors relevant to schizophrenia, in offspring.

Amphetamines↗