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Fear-potentiated startle in posttraumatic stress disorder.

Exaggerated startle is reputed to be one of the cardinal symptoms of posttraumatic stress disorder (PTSD); however, objective studies have given conflicting results as to whether or not startle is increased in PTSD. The present study investigated startle in PTSD during the threat of shock (fear-potentiated startle). The eyeblink component of the startle reflex was measured at various times preceding and following the anticipation of unpleasant electric shocks in 9 PTSD subjects and 10 age-matched, healthy controls. Startle amplitude was significantly greater during baseline and during shock anticipation in the PTSD subjects, compared to the controls. Habituation of the startle reflex was normal. Because other studies in the literature, as well as in our own laboratory, have failed to find exaggerated startle at baseline (i.e., absence of stress) in PTSD patients, it is unlikely that the present results reflect a chronic elevation of startle in this group. Instead, the higher levels of startle in the PTSD group probably resulted from a greater conditioned emotional response in this group, triggered by anticipation of electric shocks that generalized to the unfamiliar experimental context in which testing occurred. Hence, emotionally charged test procedures may be especially informative in distinguishing PTSD patients from other psychiatric diagnostic groups.

Adult↗

The effects of smoking high nicotine cigarettes on prepulse inhibition, startle latency, and subjective responses.

RATIONALE: Several previous investigations with animals and humans have suggested that nicotine enhances prepulse inhibition of the startle reflex (PPI). However, the administration of nicotine activates mesolimbic dopamine, and activation of mesolimbic dopamine is known to attenuate prepulse inhibition of the startle reflex (PPI), which might suggest that nicotine would decrease PPI. OBJECTIVE: The primary aim of this study was to test rigorously the effects of smoking high nicotine cigarettes on PPI and other measures (e.g., heart rate, craving, and mood) when the concentration of nicotine peaks in the brain (i.e., immediately after smoking). METHODS: Thirty smokers participated in two experimental sessions 1 week apart. Two high nicotine cigarettes were smoked in one session, and two control cigarettes were smoked in the other session after overnight deprivation. RESULTS: The results indicated that smoking the high nicotine cigarettes decreased PPI and that PPI increased across trials in both conditions. The interaction between nicotine dose and trial was not significant, although it appeared that high nicotine may have reversed an increase in PPI across trials in the control condition. High nicotine cigarettes also significantly increased heart rate, decreased the latency to peak startle response on control trials, but did not alter the magnitude of the startle response. DISCUSSION: The findings suggest that either high nicotine cigarettes reduced PPI, or possibly, that high nicotine cigarettes may have reversed an increase in PPI across trials as evident in the control condition.

Adult↗

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↗

Emotion in criminal offenders with psychopathy and borderline personality disorder.

BACKGROUND: Criminal offenders with a diagnosis of psychopathy or borderline personality disorder (BPD) share an impulsive nature but tend to differ in their style of emotional response. This study aims to use multiple psychophysiologic measures to compare emotional responses to unpleasant and pleasant stimuli. METHODS: Twenty-five psychopaths as defined by the Hare Psychopathy Checklist and 18 subjects with BPD from 2 high-security forensic treatment facilities were included in the study along with 24 control subjects. Electrodermal response was used as an indicator of emotional arousal, modulation of the startle reflex as a measure of valence, and electromyographic activity of the corrugator muscle as an index of emotional expression. RESULTS: Compared with controls, psychopaths were characterized by decreased electrodermal responsiveness, less facial expression, and the absence of affective startle modulation. A higher percentage of psychopaths showed no startle reflex. Subjects with BPD showed a response pattern very similar to that of controls, ie, they showed comparable autonomic arousal, and their startle responses were strongest to unpleasant slides and weakest to pleasant slides. However, corrugator electromyographic activity in subjects with BPD demonstrated little facial modulation when they viewed either pleasant or unpleasant slides. CONCLUSIONS: The results support the theory that psychopaths are characterized by a pronounced lack of fear in response to aversive events. Furthermore, the results suggest a general deficit in processing affective information, regardless of whether stimuli are negative or positive. Emotional hyporesponsiveness was specific to psychopaths, since results for offenders with BPD indicate a widely adequate processing of emotional stimuli.

Adult↗

[The sensorimotor reactivity of rats with an initially high anxiety-phobia level].

Sensorimotor response was measured by acoustic startle reflex in Wistar male rats with innate high and low levels of anxiety. The levels of anxiety were determined using a complex multiparameter method for evaluating anxiety-phobic states in rats by a ranged scale. Amplitude and prepulse inhibition of the acoustic startle response were increased, but latency of the startle reflex was decreased in rats with innate high level of anxiety as compared with those with innate low level. In rats with innate high level of anxiety injection of subconvulsive doses of pentylenetetrazol (10 and 15 mg/kg i.p.) resulted in an increase of the amplitude of the acoustic startle response and, additionally (under the dose 10 mg/kg) in a decrease of its latency. Facilitation of acoustic startle in rats with innate high level of anxiety is suggested to reflect either a deficit of inhibitory, or intensification of excitatory modulating influences on signal transmission in nerve circuit of acoustic startle. Studies of the sensorimotor response by acoustic startle in rats with innate high level of anxiety are believed to be useful for elucidating basic mechanisms of anxiety and phobia.

Acoustic Stimulation↗

Tricyclic antidepressants vary in decreasing alpha 2-adrenoceptor sensitivity with chronic treatment: assessment with clonidine inhibition of acoustic startle.

1 Clonidine inhibition of the acoustic startle reflex in the rat was used as a behavioural measure of alpha 2-adrenoceptor sensitivity following acute or chronic administration of tricyclic antidepressants. 2 Chronic (14 day) administration of desipramine (10 mg/kg, i.p.) attenuated the depressant effect of clonidine (20 or 40 microgram/kg) on the startle reflex. 3 No change in response to clonidine was obtained after chronic treatment with two other tricyclic antidepressants, amitriptyline (10 mg/kg) or iprindole (5 mg/kg). 4 Acute administration of these tricyclics (1 h) did not modify the effect of clonidine on startle. 5 It is suggested that the development of alpha 2-adrenoceptor subsensitivity produced by chronic tricyclics may be unique to those compounds, such as desipramine, which are active in blocking the uptake of noradrenaline.

Animals↗

Anatomically discrete functional effects of adenoviral clostridial light chain gene-based synaptic inhibition in the midbrain.

The gene for the Light Chain fragment of Tetanus Toxin (LC) induces synaptic inhibition by preventing the release of synaptic vesicles. The present experiment applied this approach within the rat midbrain in order to demonstrate that LC gene expression can achieve functionally and anatomically discrete effects within a sensitive brain structure. The deep layers of the superior colliculus/deep mesencephalic nucleus (dSC/DpMe) that are located in the rostral midbrain has been implicated in fear-induced increase of the acoustic startle reflex (fear potentiated startle) but exists in close proximity to neural structures important for a variety of critical functions. The dSC/DpMe of adult rats was injected bilaterally with adenoviral vectors for LC, green fluorescent protein, or vehicle. Synaptobrevin was depleted in brain regions of adenoviral LC expression. LC gene expression in the dSC/DpMe inhibited the increase in startle amplitude seen with the control viral infection, and blocked context-dependent potentiation of startle induced by fear conditioning. Although LC gene expression reduced the absolute amount of cue-specific fear potentiated startle, it did not decrease percent potentiated startle to a cue, nor did it reduce fear-induced contextual freezing, nonspecific locomotor activity, or general health, indicating that its effects were functionally and anatomically specific. Thus, vector-driven LC expression inhibits the function of deep brain nuclei without altering the function of surrounding structures supporting its application to therapeutic neuromodulation.

Adenoviridae↗

Discrimination of auditory from nonauditory toxicity by reflex modulation audiometry: effects of triethyltin.

The evaluation of toxicity in sensory systems presents particular problems because of the need to distinguish specific sensory loss from other toxic effects. It has recently been shown that modulation of reflex behavior by low-intensity test stimuli can be used to provide a rapid assessment of sensory acuity and of ototoxic hearing loss. In this report the ability of the method to distinguish the known neuromuscular consequences of triethyltin (TET) from hearing loss is demonstrated. Rats treated with TET bromide (30 mg/liter) in their drinking water for 3 weeks showed a profound decrease in acoustic startle reflex amplitudes which was apparent prior to overt neuromuscular weakness and subsequent hindlimb paralysis. Following cessation of treatment, startle levels recovered to preexposure values. Despite these large changes in startle reflex amplitudes, TET treatment did not alter the ability of pure tone stimuli to modulate reflex behavior. These results indicate that TET as administered in these studies disrupted neuromuscular function but did not affect hearing.

Analysis of Variance↗

Effects of alcohol on baseline startle and prepulse inhibition in young men at risk for alcoholism and/or anxiety disorders.

OBJECTIVE: This study examined the hypothesis that a decreased reaction to alcohol and a deficit in prepulse inhibition (PPI) of the startle reflex are characteristics of male offspring of alcoholics without comorbid anxiety disorder. METHOD: Male offspring (N = 51) with a parental history of (1) alcoholism only, (2) anxiety disorder only, (3) alcoholism and anxiety disorder, and (4) no psychiatric disorder participated in an experiment examining the effects of alcohol on the acoustic startle reflex and on PPI. The experiment was carried out in two sessions in which subjects received an alcoholic beverage and placebo beverage on alternate days. RESULTS: The magnitude of startle was reduced by alcohol in each group. However, the degree of reduction was less in the offspring of alcoholics only compared to the other groups. In addition, PPI was reduced in the offspring of alcoholics only compared to the offspring of parents with no psychiatric disorder. CONCLUSIONS: A reduced reactivity to the effect of alcohol and a deficit in PPI might constitute vulnerability markers for alcoholism, but only in offspring of alcoholics without comorbid anxiety disorder.

Adult↗

Airpuff startle probes: an efficacious and less aversive alternative to white-noise.

Fear-potentiated startle (FPS) is an increasingly popular psychophysiological method for the objective assessment of fear and anxiety. Studies applying this method often elicit the startle reflex with loud white-noise stimuli. Such intense stimuli may, however, alter psychological processes of interest by creating unintended emotional or attentional artifacts. Additionally, loud acoustic probes may be unsuitable for use with infants, children, the elderly, and those with hearing damage. Past studies have noted robust and reliable startle reflexes elicited by low intensity airpuffs. The current study compares the aversiveness of white-noise (102 dB) and airpuff (3 psi) probes and examines the sensitivity of each probe for the assessment of fear-potentiated startle. Results point to less physiological arousal and self-reported reactivity to airpuff versus white-noise probes. Additionally, both probes elicited equal startle magnitudes, response probabilities, and levels of fear-potentiated startle. Such results support the use of low intensity airpuffs as efficacious and relatively non-aversive startle probes.

Acoustics↗

Long-lasting behavioral changes induced by pre- or neonatal exposure to diazepam in rats.

Prenatal treatment with small doses of diazepam may counteract the effect of physical stress in rats, normalizing the time course of neonatal reflexes and the behavioral responses in adulthood. However, prenatal administration of diazepam in greater doses may induce desensitization of gamma-aminobutyric acid A (GABA(A)) receptors and induce hypersensitivity to convulsants. This study was designed to examine in rats the influence of prenatal or neonatal diazepam treatment on development of neonatal reflexes, as index of brain maturation, and susceptibility to pentylenetetrazol-induced convulsions in adulthood. Pregnant Wistar rats were injected with diazepam 2.5 mg/kg/day, intraperitoneally (i.p.) on days 14-21 of pregnancy. Offspring showed a delay in the appearing of neonatal reflexes (cliff aversion, forelimb placing, forelimb grasping and bar holding) except for righting and startle reflexes. At 50 days of age, male rats showed a greater sensitivity to pentylenetetrazol compared to controls. In contrast, females showed a decreased susceptibility to convulsions. The appearance of reflexes in pups exposed to diazepam during neonatal life appeared to be similar to that of controls. Only the appearance of cliff aversion and startle reflexes appeared to be delayed in animals exposed neonatally to diazepam as compared to controls. In adulthood, female rats exposed in early neonatal life to diazepam again showed a resistance to pentylenetetrazol-induced convulsions as compared to male animals. These data suggest that prenatal exposure to diazepam induces long-lasting behavioral changes, which may be influenced by sex-dependent factors.

Animals↗

Information-processing deficits and cognitive dysfunction in panic disorder.

OBJECTIVE: The plasticity of the startle reflex, including prepulse inhibition (PPI) and habituation, provides operational measures of information processing that are abnormal in several neuropsychiatric disorders characterized by deficits in suppression or inhibition of intrusive or irrelevant stimuli. Clinically, patients with panic disorder (PD) have been described as having difficulties in the inhibition of their response to sensory and cognitive events. Because such difficulties may be the result of failures in early stages of information processing, we hypothesized that startle reactivity, PPI and habituation are deficient in unmedicated patients with PD. Moreover, we tested whether there was a relation between startle reflex measures and dysfunctional cognition. METHODS: Fourteen unmedicated patients with PD (7 men, 7 women) and 28 healthy comparison subjects (14 men, 14 women) were recruited. Acoustic startle reactivity, habituation and PPI (30-ms, 60-ms, 120-ms, 240-ms and 2000-ms interstimulus intervals) were assessed in the patients with PD and the age-matched and sex-matched healthy controls. These data for unmedicated patients with PD were compared with those for 24 medicated patients with PD. Moreover, dysfunctional cognition in patients with PD was measured using the Body Sensations Questionnaire. RESULTS: Unmedicated patients with PD exhibited increased startle reactivity, reduced habituation and significantly reduced PPI in the 30-ms, 60-ms, 120-ms and 240-ms prepulse conditions. Furthermore, in unmedicated patients with PD, increased startle response and decreased habituation were correlated significantly with higher cognitive dysfunction scores, but this was not the case for PPI. CONCLUSIONS: These data indicate that the early stages of sensory information processing are abnormal in patients with PD in the absence of medication. The observed deficits in PPI and habituation could reflect a more generalized difficulty in suppressing or gating information in PD. The correlation between cognitive symptoms and higher startle response and deficient habituation supports the hypothesis that subjects with PD have abnormalities in the early stages of information processing that lead to a cascade of downstream effects on cognition.

Adult↗

Anxiolytic effects of buspirone and gepirone in the fear-potentiated startle paradigm.

Fear potentiation of the acoustic startle reflex was produced by eliciting startle responses in the presence of a light that had been previously paired with a shock. Buspirone (0.6-5.0 mg/kg) and gepirone (1.25-10.0 mg/kg), but not their common metabolite, 1-PP (0.5-40 mg/kg), produced a dose-dependent reduction of fear-potentiated startle. These doses of buspirone and gepirone slightly increased baseline startle levels. Reduction of fear-potentiated startle appears to involve supraspinal sites of action, since intraventricular but not intrathecal administration of buspirone (200 micrograms) reduced fear-enhanced startle. Both buspirone and gepirone were highly efficacious in this model compared to other animal tests that are used to study anxiolytic compounds.

Animals↗

Affective reactions to acoustic stimuli.

Emotional reactions to naturally occurring sounds (e.g., screams, erotica, bombs, etc.) were investigated in two studies. In Experiment 1, subjects rated the pleasure and arousal elicited when listening to each of 60 sounds, followed by an incidental free recall task. The shape of the two-dimensional affective space defined by the mean ratings for each sound was similar to that previously obtained for pictures, and, like memory for pictures, free recall was highest for emotionally arousing stimuli. In Experiment 2, autonomic and facial electromyographic (EMG) activity were recorded while a new group of subjects listened to the same set of sounds; the startle reflex was measured using visual probes. Listening to unpleasant sounds resulted in larger startle reflexes, more corrugator EMG activity, and larger heart rate deceleration compared with listening to pleasant sounds. Electrodermal reactions were larger for emotionally arousing than for neutral materials. Taken together, the data suggest that acoustic cues activate the appetitive and defensive motivational circuits underlying emotional expression in ways similar to pictures.

Acoustic Stimulation↗

Presynaptic dopamine-glutamate interactions in the nucleus accumbens regulate sensorimotor gating.

Prepulse inhibition (PPI) is the normal reduction in startle reflex that occurs when a startling stimulus is preceded by a weak prepulse. PPI is reduced in patients with schizophrenia and in rats after central dopamine (DA) activation. The DA agonist-induced disruption of PPI in rats may thus model some features of impaired sensorimotor gating in schizophrenia. Ascending DAergic and descending glutamatergic fibers converge within the nucleus accumbens (NAC), and interactions at this DA-glutamate interface have been implicated in the pathophysiology of schizophrenia. In this study, we examined the role of NAC DA-glutamate interactions in the regulation of PPI in rats. Intra-NAC infusion of the non-NMDA antagonist, CNQX, attenuated the PPI-disruptive effects of d-amphetamine (AMPH), but CNQX did not affect PPI when injected alone, nor did it reverse the PPI-disruptive effects of the direct D2/D3 agonist quinpirole. Intra-NAC infusion of the non-NMDA agonist AMPA significantly reduced PPI. The PPI-disruptive effects of AMPA were blocked by haloperidol and by 6-hydroxydopamine (6OHDA) lesions of the NAC. These data suggest that the PPI-disruptive effects of AMPH are dependent on tonic non-NMDA receptor activation in the NAC, and that non-NMDA receptor activation in the NAC results in a DA-dependent reduction in PPI. The parsimonious interpretation of these data is that non-NMDA glutamate receptors in the NAC facilitate presynaptic DA function, and that this DA-glutamate interaction is a critical regulatory substrate of sensorimotor gating.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

Repeated self-administered cocaine "binges" in rats: effects on cocaine intake and withdrawal.

RATIONALE: Repeated access to cocaine may engender behavioral sensitization, which emerges as an enhanced response to the effects of cocaine. Repeated exposure to prolonged self-administration sessions has been shown to produce an escalation in cocaine intake. OBJECTIVE: The objective of the present study was to identify the consequence of repeated exposure to prolonged access to self-administered cocaine. METHODS: Pairs of rats that were matched for training, housing, and surgery were treated as a single experimental unit, and these pairs were separated into groups for two separate experiments. In the first experiment, one animal of the pair acquired and maintained a stable rate for i.v. cocaine self-administration (0.5 mg/infusion), while the second rat was yoked such that it passively received saline infusions in the same pattern. After acquisition, the active self-administration rats were given free access to cocaine for 16 h (binge), while the yoked animal continued to receive infusions of saline. Twenty-four hours after the binge, both animals were exposed to tactile startle stimuli, and ultrasonic vocalizations (USVs) and startle reflexes were measured. The animals were exposed to three cocaine binges and 24 h post-binge startle tests with an interval of 10 days between binges, and then a fourth binge, with an interval of 24 h separating binges three and four. In the second experiment, pairs of rats were separated into three groups (A, B, and C). The active cocaine rats acquired self-administration and were allowed access to a 16-h cocaine binge while their yoked controls received saline. Twenty-four hours after the binge, all animals were tested for emission of USVs and startle reflexes with an identical protocol as that in experiment 1. Immediately after exposure to the startle stimuli, the self-administering animals were again allowed to self-administer cocaine for either 16 (group A), 12 (group B), or 8 h (group C). RESULTS: In experiment 1, the total amount of cocaine self-administered was significantly decreased when the cocaine binges were separated by 10 days, but total cocaine intake during the binge significantly increased when the drug-free interval was 24 h. The pattern of self-administration and the withdrawal response remained unchanged over consecutive binges. In experiment 2, rats that self-administered cocaine for either 16 or 12 h emitted significantly less USVs immediately after renewed access than they emitted 24 h after the first access period. CONCLUSION: It appeared that consecutive prolonged self-administration was insufficient to produce sensitization, as measured by cocaine intake and renewed access to self-administered cocaine was sufficient to reduce the large number of USVs that characterize withdrawal from a cocaine binge.

Animals↗

Waiting in readiness: gating in attention and motor preparation.

In this paper the similarities in the structural and functional organization of motor preparation and attention are discussed. A crucial structure in this organization is the thalamus, a complex of sensory and motor nuclei that transmits information from subcortical origins to the cortex. For the most part, the thalamus is overlapped by the nucleus reticularis, which has a local inhibitory influence on the underlying nuclei. This serves as a gating mechanism for the transmission of sensory information to the cortex. Skinner and Yingling (1977) have provided arguments in favor of a frontal control in the gating of sensory information. The present paper extends their suggestions to the motor system: a similar gating mechanism for the transmission of subcortical motor information to the cortex is hypothesized, also under frontal control. Slow potentials recorded during motor preparation and attention for an upcoming stimulus show a different distribution over the scalp. These distributions are interpreted as an indication of which thalamic gates are open to transmit information to the cortex. Probe responses (spinal reflexes, evoked potentials, and the startle reflex) can also be used to investigate which thalamocortical gates are open under certain experimental conditions. It is concluded that the sensory and motor input to the cortex are subjected to a similar control mechanism.

Attention↗

Reflex modification as a test for sensory function.

Reflex modification is a versatile procedure for the assessment of sensory function because it can provide information about the responses of several sensory systems to both weak and intense stimuli. The procedure has two elements: The elicitation of some reflex, such as the acoustic startle reflex, and the modification of that reflex by preliminary stimuli. In these experiments we used reflex modification and reflex elicitation procedures to examine the normal development of auditory function in rats and to evaluate alterations in auditory function produced by physical and toxic insult. Adult rats exposed to octave bands of noise demonstrated frequency-specific deficits on a test of reflex modification, but not reflex elicitation. In the studies of developing rats, reflex elicitation appeared by postnatal day 12 and modification around day 14. Frequency-specific increases in both measures suggested that the phenomena were sensitive to auditory development and, not simply, motor development. Exposure to kanamycin on postnatal days 8 to 16 produced dose-related deficits in the ability to detect stimuli at 32 and 16 kHz, but not 4 and 0.8 kHz. These effects were observed in the absence of changes in reflex elicitation. The results demonstrate that reflex modification procedures provide more sensitive and specific information than that provided by the use of reflex elicitation alone.

Acoustic Stimulation↗