Enhancement Of Startle Research Articles

Mice Lacking Serotonin 2C Receptors Have increased Affective Responses to Aversive Stimuli.

Although central serotonergic systems are known to influence responses to noxious stimuli, mechanisms underlying serotonergic modulation of pain responses are unclear. We proposed that serotonin 2C receptors (5-HT2CRs), which are expressed within brain regions implicated in sensory and affective responses to pain, contribute to the serotonergic modulation of pain responses. In mice constitutively lacking 5-HT2CRs (2CKO mice) we found normal baseline sensory responses to noxious thermal, mechanical and chemical stimuli. In contrast, 2CKO mice exhibited a selective enhancement of affect-related ultrasonic afterdischarge vocalizations in response to footshock. Enhanced affect-related responses to noxious stimuli were also exhibited by 2CKO mice in a fear-sensitized startle assay. The extent to which a brief series of unconditioned footshocks produced enhancement of acoustic startle responses was markedly increased in 2CKO mice. As mesolimbic dopamine pathways influence affective responses to noxious stimuli, and these pathways are disinhibited in 2CKO mice, we examined the sensitivity of footshock-induced enhancement of startle to dopamine receptor blockade. Systemic administration of the dopamine D2/D3 receptor antagonist raclopride selectively reduced footshock-induced enhancement of startle without influencing baseline acoustic startle responses. We propose that 5-HT2CRs regulate affective behavioral responses to unconditioned aversive stimuli through mechanisms involving the disinhibition of ascending dopaminergic pathways.

Sensorimotor gating and spatial learning in α7‐nicotinic receptor knockout mice

The role of acetylcholine and specific nicotinic receptors in sensorimotor gating and higher cognitive function has been controversial. Here, we used a commercially available mouse with a null mutation in the Chrna7(tm1Bay) gene [α7-nicotinic acetylcholine receptor (nAChR) knockout (KO) mouse] in order to assess the role of the α7-nAChR in sensorimotor gating and spatial learning. We examined prepulse inhibition (PPI) of startle and nicotine-induced enhancement of PPI. We also tested short- and long-term habituation of the startle response as well as of locomotor behaviour in order to differentiate the role of this receptor in the habituation of evoked behaviour (startle) vs. motivated behaviour (locomotion). To address higher cognition, mice were also tested in a spatial learning task. Our results showed a mild but consistent PPI deficit in α7-nAChR KO mice. Furthermore, they did not show nicotine-induced enhancement of startle or PPI. Short- and long-term habituation was normal in KO mice for both types of behaviours, evoked or motivated, and they also showed normal learning and memory in the Barnes maze. Thorough analysis of the behavioural data indicated a slightly higher degree of anxiety in α7-nAChR KO mice; however, this could only be partially confirmed in an elevated plus maze test. In summary, our data suggest that α7-nAChRs play a minor role in PPI, but seem to mediate nicotine-induced PPI enhancement. We found no evidence to suggest that they are important for habituation or spatial learning.

Kami-ondam-tang, a traditional herbal prescription, attenuates the prepulse inhibition deficits and cognitive impairments induced by MK-801 in mice

Ethnopharmacological relevanceKami-ondam-tang (KODT) has been used to treat neuropsychiatric disorders, including neurosis and insomnia, in traditional herbal medicine. However, the mechanisms of this drug have not been well characterized in the treatment of schizophrenia-like behaviors. Aim of the studyWe investigated whether schizophrenia-like behaviors induced by MK-801, a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, could be attenuated by KODT. Materials and methodsAcute systemic administration of MK-801 was used to establish an animal model of schizophrenia. The effects of KODT on the MK-801-induced prepulse inhibition (PPI) deficits, hyperlocomotion, social withdrawal, and cognitive impairment were assessed. We also examined the changes in the expression levels of Akt and extracellular signal-regulated kinase (ERK) after the administration of KODT with MK-801 in the cortical and hippocampal tissues. ResultsThe acoustic startle response test showed that the acoustic startle enhancement and PPI deficits induced by MK-801 were attenuated by KODT. Moreover, KODT ameliorated social and objective recognition impairments that were induced by MK-801 in the social novelty preference test and the novel object recognition test. In addition, the upregulation of phosphorylated Akt or phosphorylated ERK expression induced by MK-801 was blocked by KODT in the cortex. However, MK-801-induced hyperlocomotion was not affected by KODT in the open field test. ConclusionThese findings suggest that KODT attenuates MK-801-induced PPI disruption, social interaction deficits, and cognitive impairments, possibly, by regulating of cortical Akt and ERK signaling.

Gamma butyrolactone (GBL) and gamma valerolactone (GVL): Similarities and differences in their effects on the acoustic startle reflex and the conditioned enhancement of startle in the rat

Gamma butyrolactone (GBL) is metabolized to gamma hydroxybutyrate (GHB) in the body. GHB is a DEA Schedule 1 compound; GBL is a DEA List 1 chemical. Gamma valerolactone (GVL) is the 4-methyl analog of GBL; GVL is metabolized to 4-methyl-GHB; GVL is NOT metabolized to GBL or GHB. The effects of GBL (18.75–150mg/kg), GVL (200–1600mg/kg) or vehicle on the acoustic startle reflex (ASR), and the classically-conditioned enhancement of startle, the Startle Anticipated Potentiation of Startle (SAPS) response were studied in male rats. Both compounds produced a dose-dependent reduction of ASR, with GBL 5–7 times more potent than GVL. In contrast, GBL treatment significantly reduced SAPS at doses that exerted only moderate effects on ASR, whereas GVL exerted little or no effect on the SAPS, except at doses that produced pronounced reductions in Noise Alone ASR. In a second experiment, rats were tested for Noise Alone ASR behavior following treatment with a single mid-range dose of GBL (75mg/kg), GVL (400mg/kg) or vehicle; immediately following startle testing the animals were sacrificed and their brains and blood were collected for determination of GHB, 4-methyl-GHB, GBL and GVL. GHB was found in measurable concentrations in all of the blood specimens and 6 (of 8) of the brain specimens from the GBL-treated subjects. 4-Methyl-GHB was found in measurable concentrations in all of the blood and brain specimens of the GVL-treated subjects; the change in startle amplitude was inversely correlated to the brain concentrations of these compounds. These findings confirm the differences in the metabolic fate of GBL and GVL as pro-drugs for the formation of GHB and 4-methyl-GHB, respectively. Moreover, the dissimilarity in effect profile for GBL and GVL on ASR versus SAPS behaviors suggests that different receptor(s) may be involved in mediating these behavioral effects.

Involvement of noradrenergic and corticoid receptors in the consolidation of the lasting anxiogenic effects of predator stress

The roles of β-NER (β-noradrenergic receptor), GR (glucocorticoid) and mineral corticoid receptors (MR) in the consolidation of anxiogenic effects of predator stress were studied. One minute after predator stress, different groups of rats were injected (ip) with vehicle, propranolol (β-NER blocker, 5 and 10 mg/kg), mifepristone (RU486, GR blocker, 20 mg/kg), spironolactone (MR blocker, 50 mg/kg), propranolol (5 mg/kg) plus RU486 (20 mg/kg) or the anxiolytic, chloradiazepoxide (CPZ, 10 mg/kg). One week later, rodent anxiety was assessed in elevated plus maze, hole board, light/dark box, social interaction and acoustic startle. Considering all tests except startle, propranolol dose dependently blocked consolidation of lasting anxiogenic effects of predator stress in all tests. GR receptor block alone was ineffective. However, GR block in combination with an ineffective dose of propranolol did blocked consolidation of predator stress effects in all tests, suggesting a synergism between β-NER and GR. Surprisingly, MR block prevented consolidation of anxiogenic effects in all tests except the light/dark box. CPZ post stress was ineffective against the anxiogenic impact of predator stress. Study of startle was complicated by the fact that anxiogenic effects of stress on startle amplitude manifested as both an increase and a decrease in startle amplitude. Suppression of startle occurred in stressed plus vehicle injected groups handled three times prior to predator stress. In contrast, stressed plus vehicle rats handled five times prior to predator stress showed increases in startle, as did all predator stressed only groups. Mechanisms of consolidation of the different startle responses appear to differ. CPZ post stress blocked startle suppression but not enhancement of startle. Propranolol post stress had no effect on either suppression or enhancement of startle. GR block alone post stress prevented suppression of startle, but not enhancement. In contrast blocking GR and β-NER together prevented startle enhancement. MR block also prevented startle enhancement. Effects of MR block on startle suppression were not tested. Delay of habituation to startle was found in all stressed rats. Consolidation of delay of habituation was blocked or attenuated by post stress MR block, GR plus β-NER block and CPZ but not by post stress GR or β-NER block alone. Taken together, present findings suggest consolidation of lasting anxiogenic effects of predator stress may share some of the same neurochemical mechanisms implicated in some forms of fear memory consolidation. Implications of these findings for the study of stress-induced changes in affect including posttraumatic stress disorder (PTSD) are discussed.

Startling facts about emotion in Parkinson's disease: blunted reactivity to aversive stimuli

The amygdala is closely linked to basal ganglia circuitry and plays a key role in danger detection and fear-potentiated startle. Based on recent findings of amygdalar abnormalities in Parkinson's disease, we hypothesized that non-demented patients with this illness would show blunted reactivity during aversive/unpleasant events, as indexed by diminished emotional modulation of the startle eyeblink response. To test this hypothesis, 23 idiopathic patients with Parkinson's disease and 17 controls viewed standardized sets of aversive, pleasant and neutral pictures for 6 s each. During this time, white noise bursts (50 ms, 95 db) were binaurally presented to elicit startle eyeblink responses, measured from electrodes over the orbicularis oculi. After viewing each picture, subjects provided ratings of valence and arousal. The Parkinson's disease patients were in the early to middle stages of their disease, not demented or depressed, and were tested 'on' dopaminergic medication. The two groups were similar in age, education, gender and cognitive screening status. The control group had larger startle responses when viewing negative, aversive pictures than neutral or pleasant pictures. As predicted, startle enhancement during aversive pictures was significantly muted in the Parkinson's disease patients. This blunting was not due to abnormalities in the mechanics of the startle eyeblink per se. Nor was it related to depression symptoms, medications (psychotropics), or failure to perceive/appreciate the negative meaning of aversive pictures (i.e. normal valence ratings). Reduced startle reactivity in the disease group was related to disease severity (Hoehn-Yahr) and occurred in the context of reduced arousal ratings of aversive pictures. These findings of blunted startle reactivity add to the literature on emotional changes associated with Parkinson's disease. The basis for this muted reactivity is unknown but may involve an amygdala-based translational defect whereby the results of cognitive appraisal are not appropriately transcoded into somato-motor-arousal responses normally associated with an aversive motivational state. This may arise from faulty dopaminergic gating of the amygdala, resulting in 'inhibition' of the amygdala in the manner described by Marowsky et al. (Marowsky A, Yanagawa Y, Obata K, Vogt E. Neuron 2005; 48: 1025-37). More broadly, the findings of muted reactivity to aversive stimuli may reflect a 'bradylimbic' affective disturbance in patients with Parkinson's disease. Future studies are needed to address whether the physiologic blunting observed here might be a useful correlate of apathy.

Protein synthesis and the mechanisms of lasting change in anxiety induced by severe stress

Brief, unprotected exposure of rats to cats (predator stress) may be lastingly anxiogenic in a variety of tests of rodent anxiety. Recent findings suggest that predator stress induced plasticity in neural circuitry implicated in fear learning underlies some of these anxiogenic effects. In addition, recent work implicates a consolidation-like process in the impact of predator stress on anxiety in that effects of predator stress may be interrupted by immediate post stressor pharmacological interventions. The present study tested whether “consolidation” of the anxiogenic effects of predator stress were dependent on protein synthesis. In addition, the study examined whether a protein synthesis dependent reconsolidation-like process was at work when rats were exposed to a cat twice. Anisomycin (210 mg/kg) or vehicle (Tween 80 in saline) was injected subcutaneously 1 min after a single cat exposure (consolidation test paradigm) or a 1 min after a second cat exposure (reconsolidation test paradigm) and behavior tested 7–8 days after predator stress. In the consolidation test paradigm, anisomycin blocked the anxiogenic effects of predator stress in the elevated plus maze (EPM) measured with open arm exploration. Moreover, anisomycin blocked the potentiation of startle by predator stress when rats were startled in the light, but not when startled in the dark. In contrast, the delay of habituation of startle produced by predator stress was unaffected by anisomycin. Suppression of risk assessment in the EPM by predator stress was not affected by anisomycin either. In startle testing, vehicle injection 1 min after predator stress led to a lasting suppression, rather than enhancement of startle response. Vehicle plus predator stress enhanced and prolonged corticosterone level changes sampled over 30–180 min after treatment when compared to handled or predator stressed only rats. In addition, predator stress plus vehicle suppression of startle was blocked by a benzodiazepine anxiolytic (chloradiazepoxide) or the glucorticoid receptor (GR) blocker RU486. Both drugs returned startle to the predator stressed only heightened levels. It is argued that an added anxiogenic effect of vehicle injection plus predator stress leads to a suppression, rather than enhancement of startle. Startle suppression appears to be mediated, in part, by activation of GR by corticosterone which engages a protein synthesis dependent process, since anisomycin blocked the startle suppressive effects of vehicle. Startle suppression also appeared to be independent of the startle enhancing effect of predator stress and in competition with it. Since predator stress may model aspects of hyperarousal associated with post traumatic stress disorder (PTSD), implications of these findings for understanding of mechanisms of initiation of the disorder and for treatment are discussed.

Olfactory-mediated fear conditioning in mice: simultaneous measurements of fear-potentiated startle and freezing.

This study demonstrates that mice display olfactory-cued fear as measured with both freezing and fear-potentiated startle. Following a preconditioning test to measure any unconditioned responses to odor, mice received 5 pairings of a 10-s odor with a 0.25-s, 0.4-mA footshock. The next day, startle and freezing were measured in the presence and absence of the odor. Both fear measures increased after training with amyl acetate (Experiment 1) and acetophenone (Experiment 2). The enhancement of startle did not occur when the same number of odors and shocks were presented in an unpaired fashion (Experiment 3). Furthermore, mice were able to discriminate between an odor paired with shock and a nonreinforced odor (Experiment 4).

The substantia nigra pars reticulata mediates the enhancement of startle by the dopamine D1 receptor agonist SKF 82958 in rats.

Several studies have shown that the substantia nigra pars reticulata (SNr) is a critical site of action mediating dopamine agonist effects on motor behaviors. Because dopaminergic and GABA ergic mechanisms may interact in the SNr, we tested the contribution of both dopamine and GABA receptors in the SNr on the enhancement of startle by the dopamine D1 agonist SKF 82958. Male Sprague-Dawley rats were implanted with cannulae into the SNr and 1 week later infused with either the D1 antagonist SCH 23390 (0.1, 1 microg) or the GABA(A) antagonist bicuculline (0.1 microg), followed by a systemic challenge with the D1 agonist SKF 82958 (1 mg/kg). Other rats were infused with the GABA(A) agonist muscimol (0.1 microg) or SKF 82958 (0.1, 1, 5 microg). Both SCH 23390 and bicuculline infused into the SNr completely blocked the enhancement of startle by systemic SKF 82958. Muscimol infused into the SNr produced a significant increase in startle by itself, whereas SKF 82958 had no effect. These results suggest that activation of D1 receptors in the SNr is necessary for the enhancement of startle by SKF 82958, but that activation of these receptors alone is not sufficient to increase startle. These results also suggest that GABA transmission in the SNr may be involved in the enhancement of startle by SKF 82958. Based on these data, we propose that activation of striatonigral neurons by D1 receptor agonists facilitates GABA release in the SNr to produce the observed enhancement of startle.

Nicotine and ethanol enhancements of acoustic startle reflex are mediated in part by dopamine in C57BL/6J mice

Nicotine has been shown to have additive as well as antagonistic effects on behavior stimulated by ethanol. Here, we examine the effects of nicotine, ethanol, and the coadministration of each drug on acoustic startle responding in C57BL/6J mice. Mice were tested at a range of decibel levels (80–115 dB, 5 dB increments), with administration of 0.031, 0.062, 0.125, and 0.25 mg/kg nicotine or 0.5, 1.0, 1.5, and 2.0 g/kg ethanol. Nicotine and ethanol each caused an increase in the acoustic startle response at the highest and lowest doses tested, respectively. Mecamylamine, a nicotinic receptor antagonist, administered in combination with nicotine or ethanol attenuated these increases in acoustic startle responding. Nicotine and ethanol, administered together, did not produce greater enhancement of startle than when administered alone. Haloperidol (1 mg/kg) was administered in combination with nicotine or ethanol to investigate if dopamine modulated nicotine or ethanol enhancement of acoustic startle. It was found that the increase in acoustic startle responses observed with ethanol or nicotine was attenuated by haloperidol. Thus, ethanol or nicotine may enhance the acoustic startle reflex through a common dopaminergic mechanism.

Acoustic startle, conditioned startle potentiation and the effects of 8-OH-DPAT and buspirone in rats selectively bred for differences in 8-OH-DPAT-induced hypothermia.

HDS and LDS rats are the result of selective breeding for differences in the hypothermic effects of the 5-hydroxytryptamine-1A (5-HT1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT); HDS (high DPAT sensitivity) rats exhibit a much greater hypothermic response than do LDS (low DPAT sensitivity) rats. It is possible that this genetically-based difference in sensitivity to the hypothermic effects of the 5-HT1A agonist is associated with a change in other behaviours modulated by 5-HT neurotransmission. The present study examined the acoustic startle response, the classically conditioned enhancement of startle, and the effects of 8-OH-DPAT and buspirone treatments on these measures, in HDS and LDS rats. On four test sessions, HDS and LDS rats were exposed to 20 acoustic startle stimuli (115 dB; 40 ms in duration). For each test session, 10 trials were presented in the dark (Noise Alone trials) and 10 were presented at the end of a 3500 ms presentation of a 15 W signal light (Light + Noise trials). LDS rats exhibited greater startle amplitude than did HDS rats on Noise Alone trials. Initially, there was no difference in startle amplitude on the Light + Noise versus Noise Alone trials in either LDS or HDS rats. By the end of the first test session, however, and continuing throughout the remainder of the four test sessions, startle amplitude on the Light + Noise trials was significantly greater than in the Noise Alone trials. The magnitude of this startle-potentiated startle (SPS) effect did not differ in HDS versus LDS rats. SPS testing was continued for three additional sessions; in these sessions the effects of acute treatment with the 8-OH-DPAT (125 microg/kg, subcutaneously (s.c.)), the novel anxiolytic buspirone (4 mg/kg, intraperitoneally (i.p.)) or vehicle (distilled water) were determined. Both 8-OH-DPAT and buspirone treatment increased baseline (Noise Alone) startle amplitude in LDS rats but not in HDS rats. With respect to the conditioned enhancement of startle, buspirone reduced the SPS effect in both HDS and LDS rats, whereas 8-OH-DPAT did not change the conditioned enhancement effect in either rat line. These findings suggest that the selective breeding for differences in 8-OH-DPAT-induced hypothermia has resulted in changes in other behaviours and also changes in the response to 5-HT1A agonist treatment. Moreover, these findings are consistent with the hypotheses that: (a) 5-HT1A agonist actions underlie the buspirone-induced and 8-OH-DPAT-induced increases in Noise Alone startle amplitude; whereas (b) the buspirone-induced reduction in potentiated startle is not the result of 5-HT1A agonist actions of this compound.

Inhibition of amygdaloid dopamine D 2 receptors impairs emotional learning measured with fear-potentiated startle

Considerable advances have been made in understanding the neurocircuitry underlying the acquisition and expression of Pavlovian conditioned fear responses. Within the complex cellular and molecular processes mediating fearfulness, amygdaloid dopamine (DA), originating from cells in the ventral tegmental area (VTA) of the midbrain, is thought to contribute to fear-motivated responding. Considering that blockade of DA D 2 receptors is a common mechanism of action for antipsychotic agents, we hypothesized that inhibition of D 2 receptors in the amygdala may be involved in the antiparanoid effects of these drugs. To assess the role of amygdaloid DA D 2 receptors in aversive emotionality, the D 2 receptor antagonist raclopride was infused into the amygdala prior to Pavlovian fear conditioning. Potentiated startle was used as a behavioral indicator of fear and anxiety. Classical fear conditioning and acoustic startle testing were conducted in a single session allowing for the concomitant assessment of shock reactivity with startle enhancement. Depending on dose, the results found conditioned fear acquisition and retention to be impaired following administration of raclopride into the amygdala. Additionally, the learning deficit was dissociated from shock detection and from fear expression assessed with the shock sensitization of acoustic startle. These findings further refine the known neural mechanisms of amygdala-based emotional learning and memory and were interpreted to suggest that, along with D 1 receptors, D 2 receptors in the amygdala may mediate the formation and the retention of newly-acquired fear associations.

Enhancement of the acoustic startle response by dopamine agonists after 6-hydroxydopamine lesions of the substantia nigra pars compacta: corresponding changes in c-Fos expression in the caudate–putamen

Rats with 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway show enhanced locomotor and stereotyped behaviors when challenged with direct and indirect dopamine (DA) agonists due to the development of postsynaptic supersensitivity. To determine if this phenomenon generalizes to other motor behaviors, we have used this rat model of Parkinson’s disease to examine the effects of the direct dopamine D 1 receptor agonist SKF 82958 and the indirect DA agonist l-3,4-dihydroxyphenylalanine ( l-DOPA) on the acoustic startle response. In addition, we used the expression of c-Fos protein as a marker of neuronal activity to assess any corresponding drug-induced changes in the caudate–putamen (CPu) after l-DOPA administration. Male Sprague–Dawley rats received bilateral injections of 6-OHDA into the substantia nigra pars compacta and 1 week later were tested for startle after systemic administration of SKF 82958 (0.05 mg/kg) or l-DOPA (1, 5, 10 mg/kg). SKF 82958 produced a marked enhancement of startle with a rapid onset in 6-OHDA-lesioned but not SHAM animals. l-DOPA produced a dose- and time-dependent enhancement of startle in 6-OHDA-lesioned rats that had no effect in SHAM animals even at the highest dose (10 mg/kg). Furthermore, l-DOPA produced a dramatic induction of c-Fos in the CPu in 6-OHDA-lesioned animals. Consistent with other literature, these data suggest that neurons in the CPu become supersensitive to the effects of DA agonists after 6-OHDA-induced denervation of the nigrostriatal pathway and that supersensitive dopamine D 1 receptors may mediate the enhancement of startle seen in the present study.

Synergistic enhancement of the acoustic startle reflex by dopamine D1 and 5-HT1A agonists and corresponding changes in c-Fos expression in the dorsal raphe of rats.

Several studies have reported an increase in dopamine (DA)-stimulated behavioral responses after manipulations that reduce brain serotonin (5-hydroxytryptamine, 5-HT) levels. Because others have shown that systemic administration of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) reduces 5-HT levels throughout the brain, we tested the effects of 8-OH-DPAT on the enhancement of the acoustic startle reflex by the dopamine D1 receptor agonist SKF 82958. In addition, we used the expression of the c-Fos protein as a marker of neuronal activity to assess any corresponding drug-induced changes within the dorsal raphe (DR). Male Sprague-Dawley rats pretreated (10 min) with 8-OH-DPAT (0.5 mg/kg) showed a marked potentiation of the enhancement of startle by SKF 82958 (0.1 mg/kg). Furthermore, SKF 82958 produced a dramatic induction of c-Fos in the DR, an effect that was blocked by 8-OH-DPAT. Double-labeling immunohistochemistry for c-Fos and 5-HT showed that SKF 82958-induced expression of c-Fos, and its blockade by 8-OH-DPAT, occurred in a percentage of 5-HT-containing cells of the DR. These data suggest the possibility that inhibition of the DR by 8-OH-DPAT mediates the potentiation of startle by SKF 82958, perhaps through a reduction in 5-HT release in the striatum. Such an interpretation is consistent with the hypothesis of an inhibitory role of the 5-HT system on DA-mediated behaviors.

GABA in the Deep Layers of the Superior Colliculus/Mesencephalic Reticular Formation Mediates the Enhancement of Startle by the Dopamine D1Receptor Agonist SKF 82958 in Rats

GABA transmission in the deep layers of the superior colliculus/deep mesencephalic reticular formation (deep SC/Me) mediates several motor responses, including those expressed after systemic administration of dopamine agonists. In the present study we examined the role of the deep SC/Me in the modulation of the acoustic startle reflex and its enhancement by the dopamine D(1) agonist SKF 82958. Rats were implanted with bilateral cannulas into the deep SC/Me or superficial layers of the SC (super SC) and 1 week later were infused with various compounds. The GABA(A) antagonist bicuculline (0, 5, and 10 ng) produced a dose- and time-dependent enhancement of startle after infusion into the deep SC/Me, but not the super SC. Infusion of the GABA(A) agonist muscimol (0.1 microg) into the deep SC/Me, but not the super SC, blocked the enhancement of startle by systemic SKF 82958 (1 mg/kg) but had no effect on baseline startle by itself. This effect was not produced by infusion of the D(1) antagonist SCH 23390(1 microg) or the glutamate antagonist NBQX (0.1 microg). Deposits of FluoroGold into the deep SC/Me, combined with immunohistochemistry for glutamic acid decarboxylase (GAD), confirmed a direct GABAergic input from the substantia nigra pars reticulata (SNr) to the deep SC/Me. These results suggest that GABA tone in the deep SC/Me modulates the expression of startle as well as the enhancement of startle by dopamine D(1) agonists. On the basis of these data and previous work, we have proposed a striatonigral-tectal-reticular neural pathway mediating the effects of dopamine D(1) agonists on startle.

Enhancement of the acoustic startle response in rats by the dopamine D1 receptor agonist SKF 82958.

The present series of experiments was conducted in order to assess the nature of dopaminergic modulation of the acoustic startle response using agonists and antagonists specific for dopamine D1 and D2 receptors. The objective of the present study was to demonstrate an enhancement of the acoustic startle response by dopamine D1 receptor agonists and to characterize this effect pharmacologically in terms of dose-response and selective antagonism at both the dopamine D1 and D2 receptor using a varied range of startle-eliciting intensities. Male Sprague-Dawley rats were injected subcutaneously with the dopamine D1 receptor agonist SKF 82958 (0, 0.01, 0.1, 1, or 3 mg/kg) or SKF 81297 (3 mg/kg) and their startle response was measured across a range of startle-eliciting intensities. For testing with the dopamine D1 or D2 receptor antagonists, animals received injections of either SCH 23390 (0.01 and 0.1 mg/kg) or raclopride (0.1 and 1 mg/kg) 10 min before the challenge with SKF 82958 (1 mg/kg). Systemic administration of SKF 82958 produced a marked enhancement of startle over a wide range of startle intensities. This effect was dose-dependent, with a dose of 1 mg/kg producing the maximal amount of startle enhancement at each intensity. SKF 81297 (3 mg/kg) also produced a robust enhancement of startle. Pretreatment with SCH 23390 produced a dose-dependent blockade of the enhancement of startle by SKF 82958. Pretreatment with raclopride blocked the enhancement of startle by SKF 82958 at the low intensities and attenuated the enhancement at the high intensities. These data suggest that dopamine D1 receptor agonists enhance the acoustic startle response. Furthermore, this effect is dependent on a cooperative type of D1/D2 receptor interaction whereby D2 receptor activation is necessary for the full expression of the D1 receptor-mediated enhancement of startle.

Effects of Nicotine and Stress on Startle Amplitude and Sensory Gating Depend on Rat Strain and Sex

We recently reported that 14 days of nicotine administration (12 mg/kg/day) reduced acoustic startle reflex amplitude and impaired prepulse inhibition (PPI) of startle in male and female Long–Evans rats (24). These findings contrasted with reports of nicotine-induced enhancement of startle and PPI in Sprague–Dawley (a different strain) male rats (2–4). The present experiment administered 0, 6, or 12 mg/kg/day nicotine via osmotic minipump for 14 days to 120 Sprague–Dawley rats (male and female) and to 120 Long–Evans rats (male and female) and examined ASR and PPI. Half of the subjects also were stressed by immobilization once each day to examine nicotine–stress interactions. Nicotine enhanced ASR and PPI responses of Sprague–Dawley rats but impaired these responses in Long–Evans rats, regardless of sex. Effects of stress were complex and depended on strain, sex, and drug dose. These findings indicate that effects of nicotine on measures of reactivity (ASR) and sensory gating (PPI) depend on genotype and that nicotine–stress interactions depend on genotype, sex, and nicotine dosage.

Corticotropin-releasing factor in the caudal pontine reticular nucleus mediates the expression of fear-potentiated startle in the rat.

The fear-potentiated startle paradigm is a valuable model for the investigation of the neuronal basis of fear. Previous studies have demonstrated that the neuropeptide corticotropin-releasing factor (CRF) plays an important role in fear-related processes, notably in the potentiation of the acoustic startle response. The present study investigated the role in fear-potentiated startle of CRF in the caudal pontine reticular nucleus, a brain nucleus that mediates the acoustic startle response. First, we showed that the central nucleus of the amygdala gives rise to a CRFergic projection to the caudal pontine reticular nucleus. In the second experiment, we iontophoretically applied CRF to caudal pontine reticular nucleus neurons and extracellularly recorded the activity of these neurons. CRF had a mainly excitatory effect on the tone-evoked activity of the neurons. In our third experiment, we injected the CRF antagonist alpha-helical CRF into the caudal pontine reticular nucleus of awake rats. Here, alpha-helical CRF dose-dependently blocked fear-potentiated startle, but had no effect on the baseline startle amplitude. The present results show that CRF-containing neurons which project from the central nucleus to the caudal pontine reticular nucleus are important for the enhancement of startle by fear, and further characterize the hypothetical neuronal circuitry underlying the expression of fear-potentiated startle.

Modification of acoustic and tactile startle by single microwave pulses

Single microwave pulses at 1.25 GHz were delivered to the head and neck of male Long-Evans rats as a prestimulus to acoustic and tactile startle. For acoustic startle, pulses averaging 0.96 μs in duration were tested with two specific absorption rate (specific absorption) ranges, 15.0–30.0 kW/kg (16.0–44.2 mJ/kg) and 35.5–86.0 kW/kg (66.6–141.8 mJ/kg), delivered 201, 101, 51, 3, and 1 ms before and 1 ms after onset of a startling noise. The low-intensity pulse did not affect peak amplitude, integral, or latency of the whole-body startle response. The high-intensity pulse at 101 and 51 ms inhibited the startle response by decreasing peak amplitude and integral; at 201 and 51 ms latency was increased. The high-intensity pulse at 1 ms enhanced the startle response by increasing peak amplitude and at 3 ms by increasing integral. For tactile startle, either microwave pulses averaging 7.82 μs in duration and 55.9–113.3 kW/kg (525.0–1055.7 mJ/kg) or 94 dB SPL clicks were delivered 157, 107, 57, and 7 ms before and 43 ms after onset of a startling air burst. The microwave pulse at 57 ms inhibited the startle response by decreasing peak amplitude; at 157, 107, 57, and 7 ms it increased latency. The microwave pulse at 43 ms after onset enhanced the startle response by increasing peak amplitude. The acoustic click at 157 and 57 ms inhibited the startle response by decreasing peak amplitude; at 157, 107, and 57 ms it increased latency. The microwave pulse inhibition and enhancement of startle were similar to previously reported effects of sensory stimuli delivered at similar lead times, indicating the possibility that action was mediated by sensory stimulation.

Effects of haloperidol and SCH 23390 on acoustic startle and prepulse inhibition under basal and stimulated conditions

Schwarzkopf, Steven B., John P. Bruno, and Tanmoy Mitra: Differential Effects of Haloperidol and SCH 23390 on Acoustic Startle and Prepulse Inhibition Under Basal and Stimulated Conditions. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1993, 17(6): 1023–1036. 1. 1. Adult Sprague-Dawley rats underwent startle testing for assessment of baseline startle amplitude and prepulse inhibition (PPI) of the startle reflex. 2. 2. Animals were tested after administration of either: saline, a selective D1 dopamine (DA) receptor antagonist, a relatively selective D2 DA antagonist, or combined low dose D1 and D2 antagonists. 3. 3. Changes due to antagonists were assessed with and without administration of the D1 D2 agonist apomorphine. 4. 4. Testing without apomorphine stimulation showed that both D1 and D2 antagonists reduce baseline startle and enhance PPI. Further, the two antagonists exhibited a synergistic interaction. 5. 5. Testing with apomorphine showed that D1 and D2 antagonists reduce apomorphineinduced startle enhancement. Again, the two exhibited a synergistic interaction. 6. 6. For PPI, the D2 but not D1 antagonist reduced the apomorphine effect. However, the D1 antagonist potentiated the effect of the D2 antagonist.