Startle In Rats Research Articles

Different effects of isolation-rearing and neonatal MK-801 treatment on attentional modulations of prepulse inhibition of startle in rats.

Prepulse inhibition (PPI) is suppression of the startle reflex by a weaker sensory stimulus (prepulse) preceding the startling stimulus. In people with schizophrenia, impairment of attentional modulation of PPI, but not impairment of baseline PPI, is correlated with symptom severity. In rats, both fear conditioning of prepulse and perceptually spatial separation between the conditioned prepulse and a noise masker enhance PPI (the paradigms of attentional modulation of PPI). As a neurodevelopmental model of schizophrenia, isolation rearing impairs both baseline PPI and attentional modulations of PPI in rats. This study examined in Sprague-Dawley male rats whether neonatally blocking N-methyl-D-aspartate (NMDA) receptors specifically affects attentional modulations of PPI during adulthood. Both socially reared rats with neonatal exposure to the NMDA receptor antagonist MK-801 and isolation-reared rats exhibited augmented startle responses, but only isolation rearing impaired baseline PPI. Fear conditioning of the prepulse enhanced PPI in socially reared rats, but MK-801-treated rats lost the prepulse feature specificity. Perceptually spatial separation between the conditioned prepulse and a noise masker further enhanced PPI only in normally reared rats. Clozapine administration during adulthood generally weakened startle, enhanced baseline PPI in neonatally interrupted rats, and restored the fear conditioning-induced PPI enhancement in isolation-reared rats with a loss of the prepulse feature specificity. Clozapine administration also abolished both the perceptual separation-induced PPI enhancement in normally reared rats and the fear conditioning-induced PPI enhancement in MK-801-treated rats. Isolation rearing impairs both baseline PPI and attentional modulations of PPI, but neonatally disrupting NMDA receptor-mediated transmissions specifically impair attentional modulations of PPI. Clozapine has limited alleviating effects.

Acute, but not repeated, administration of the neurotensin NTS1 receptor agonist PD149163 decreases conditioned footshock-induced ultrasonic vocalizations in rats

Neurotensin is an endogenous neuropeptide that has significant interactions with monoamine neurotransmitter systems. To date, neurotensin NTS1 receptor agonists, such as PD149163, have been primarily evaluated for the treatment for schizophrenia, drug addiction, and pain. Recently, PD149163 was found to attenuate fear-potentiated startle in rats, an experimental procedure used for screening anxiolytic drugs. The present study sought to assess these findings through testing PD149163 in a conditioned footshock-induced ultrasonic vocalization (USV) model. Conditioning was conducted in male Wistar rats using chambers equipped with shock grid floors and an ultrasonic vocalization detector. PD149163 and the 5-HT1A receptor partial agonist buspirone produced a statistically significant reduction of 22kHz USV counts. The typical antipsychotic haloperidol also reduced 22kHz USV counts, but did so at cataleptic doses. Ten days of repeated administration of PD149163 abolished the inhibitory effects of PD149163 on 22kHz USVs. These findings further support an anxiolytic profile for PD149163. However, tolerance to these effects may limit the utility of these drugs for the treatment of anxiety.

Corticotropin-releasing factor (CRF) and α2 adrenergic receptors mediate heroin withdrawal-potentiated startle in rats

Anxiety is one of the early symptoms of opioid withdrawal and contributes to continued drug use and relapse. The acoustic startle response (ASR) is a component of anxiety that has been shown to increase during opioid withdrawal in both humans and animals. We investigated the role of corticotropin-releasing factor (CRF) and norepinephrine (NE), two key mediators of the brain stress system, on acute heroin withdrawal-potentiated ASR. Rats injected with heroin (2mg/kg s.c.) displayed an increased ASR when tested 4h after heroin treatment. A similar increase in ASR was found in rats 10-20h into withdrawal from extended access (12h) to i.v. heroin self-administration, a model that captures several aspects of heroin addiction in humans. Both the α 2 adrenergic receptor agonist clonidine (10μg/kg s.c.) and CRF1 receptor antagonist N,N-bis(2-methoxyethyl)-3-(4-methoxy-2-methylphenyl)-2,5-dimethyl-pyrazolo[1,5-a] pyrimidin-7-amine (MPZP; 20mg/kg s.c.) blocked heroin withdrawal-potentiated startle. To investigate the relationship between CRF1 and α 2 adrenergic receptors in the potentiation of the ASR, we tested the effect of MPZP on yohimbine (1.25mg/kg s.c.)-potentiated startle and clonidine on CRF (2μg i.c.v.)-potentiated startle. Clonidine blocked CRF-potentiated startle, whereas MPZP partially attenuated but did not reverse yohimbine-potentiated startle, suggesting that CRF may drive NE release to potentiate startle. These results suggest that CRF1 and α 2 receptors play an important role in the heightened anxiety-like behaviour observed during acute withdrawal from heroin, possibly via CRF inducing the release of NE in stress-related brain regions.

The nucleus locus coeruleus/subcoeruleus contributes to antinociception during freezing behavior following the air-puff startle in rats

An air puff elicits a startle response in mammals. Following the startle response, rats react with a defensive-like, immobile posture (DIP) of approximately 2–5s in length. We have previously reported that air-puff stimulation (APS) activates the nucleus locus coeruleus/subcoeruleus (LC/SC) so that the DIP is induced. The LC/SC is one of the structures that plays an important role in endogenous pain control. Our particular interest is whether APS induces nociceptive modulation. Rats were tested for behavioral nociception with heating of the tail. Rats whisked their tail following heating and then bit the heat source when the tail could not escape heating by tail flick. The tail flick latency (TFL) and the bite latency (BL) were measured as an indicator of nociception. Compressed house air (14.4psi in strength, 0.1s in duration) was presented for APS. Two weeks before the experiment, the rats received bilateral injections of 6μg of the neurotoxin 6-hydroxydopamine to specifically lesion noradrenaline-containing neurons of the LC/SC. APS produced prolongation of the TFL and the BL. In both the TFL and the BL, APS-induced prolongation was not observed in rats with the LC/SC lesions. When BLs were plotted against DIP periods, the BL was almost constant regardless of the change in the DIP period. These results suggest that (1) APS produces nociceptive modulation, (2) the LC/SC is involved in APS-induced nociceptive modulation, and (3) two APS-induced events, the DIP and nociceptive modulation, are a parallel phenomenon.

Group III Metabotropic Glutamate Receptors Inhibit Startle-Mediating Giant Neurons in the Caudal Pontine Reticular Nucleus But Do Not Mediate Synaptic Depression/Short-Term Habituation of Startle

Short-term habituation is a basic form of learning that is analyzed in different species and using different behavioral models. Previous studies on mechanisms of short-term habituation yielded evidence for a potential role of group III metabotropic glutamate receptors (mGluRIIIs). Here we tested the hypothesis that mGluRIII mediate short-term habituation of startle in rats, combining electrophysiological experiments in vitro with behavioral studies in vivo. We applied different mGluRIII agonists and antagonists on rat brainstem slices while recording from startle-mediating neurons in the caudal pontine reticular nucleus (PnC) and monitoring synaptic depression presumably underlying habituation. Furthermore, we injected the mGluRIII antagonist (RS)-alpha-phosphonophenylglycine (MPPG) and the agonist L-(+)-2-amino-4-phosphonobutyric acid (L-AP4) into the PnC of rats in vivo and measured its effect on startle habituation. Our results show that activation of mGluRIIIs in the PnC strongly inhibits startle-mediating giant neurons in vitro. Accordingly, L-AP4 reduced startle responses in vivo. However, synaptic depression in the slice was not disrupted by mGluRIII antagonists or agonists. Correspondingly, the in vivo application of the mGluRIII antagonist MPPG failed to show any effect on short-term habituation of startle responses. We therefore conclude that mGluRs are expressed within the primary startle pathway and that they inhibit startle responses upon activation; however, this inhibition does not play any role in synaptic depression and short-term habituation of startle. This is in contrast to the role of mGluRIIIs in other forms of habituation and supports the notion that there are different mechanisms involved in habituation of sensory-evoked behaviors.

The effects of the dopamine D2 agonist sumanirole on prepulse inhibition in rats

Dopamine agonists reduce prepulse inhibition (PPI) of startle in rats. While it is used to predict antipsychotic efficacy, the specific receptor subtypes mediating this effect of dopamine agonists remain unclear. We characterized the effects of sumanirole, a highly selective D2 agonist, on PPI in rats. Sumanirole decreased PPI at 60-120 ms prepulse intervals, and increased PPI at 10-20 ms intervals. PPI deficits were antagonized by low doses of the preferential D2 antagonist L741626, supporting a D2 mechanism of action. Sumanirole is a valuable tool for parsing the role of dopamine receptor subtypes in the regulation of PPI.

Retrograde amnesia for fear-potentiated startle in rats after complete, but not partial, hippocampal damage

We assessed the involvement of the hippocampus in recall of learned fear of a discrete visual stimulus using a fear-potentiated startle (FPS) procedure. Recall was measured by an increase in acoustic startle in the presence of a light that was paired with footshock. In Experiment 1, rats either received sham, dorsal, ventral, or complete (dorsal and ventral) NMDA-induced damage of the hippocampus following FPS acquisition. During the post-surgery retention test, only the rats with complete hippocampal damage showed a significant FPS deficit. In Experiment 2, we examined whether recent and remote memory for FPS would be differentially affected by complete hippocampal damage. Rats received sham or complete hippocampal damage 1- or 4-wk after FPS acquisition. During the retention test, sham rats exhibited significant FPS, whereas rats with hippocampal damage showed a large FPS deficit that was equivalent for recent and remote memories. In Experiment 3, we found that rats with complete hippocampal damage induced before conditioning showed levels of FPS that did not significantly differ from sham rats. Combined, these findings suggest that extensive damage to the hippocampus causes retrograde amnesia for a memory involving a light–shock association that is not temporally graded. The same damage does not cause anterograde amnesia in the same memory task. Partial damage of the hippocampus, whether of the dorsal or ventral region, was insufficient to cause retrograde amnesia. Thus, the hippocampus normally has a critical and long-lasting role enabling recall of fear conditioning to a discrete visual stimulus. In the absence of the hippocampus other memory systems support new learning.

Role of corticosterone in trace and delay conditioned fear-potentiated startle in rats.

Emotional events often lead to particularly strong memory formation. Corticosterone, the final product of hypothalamic-pituitary-adrenal (HPA)-axis activation, has been suggested to play a critical role in this effect. Although a great deal of work has implicated the amygdala as a necessary structure for the effects of corticosterone, other studies have suggested a critical role for the hippocampus in determining the involvement of corticosterone. The current experiments examined this question by disrupting corticosterone synthesis with administration of metyrapone (25 or 100 mg/kg) prior to training in either dorsal hippocampus-independent delay fear conditioning or dorsal hippocampus-dependent trace fear conditioning. Metyrapone administration 2 hrs prior to training significantly attenuated corticosterone secretion during training, but these effects were transient as corticosterone levels were similar to control subjects following the test session. As hypothesized, only trace fear conditioning was impaired. This suggests that only fear conditioning tasks that are dependent on the dorsal hippocampus require HPA-axis activation in order to be learned.

Intra-amygdaloid infusion of Ginkgo biloba leaf extract (EGb761) facilitates fear-potentiated startle in rats

Ginkgo biloba extract, EGb761, is one of the most commonly used herbal supplements throughout Western society. It has been used in the treatment of various common geriatric complaints including short-term memory loss. We showed that acute systemic administration of EGb761 enhanced fear-potentiated startle (FPS) in rats. Little is known about the behavioral effects of centrally administered EGb761 on FPS. The current study was performed to evaluate the involvement of basolateral nucleus of amygdala (BLA) in the EGb761 facilitation effect on FPS. Male adult SD rats were used. EGb761 was infused into cerebroventricle or basolateral nucleus of amygdala 10 min prior to fear conditioning. Animals were then tested for FPS 24 h later. Results showed that (1) intra-cerebroventricular infusion of EGb761 (0.1, 1.0, or 3.0 microg/3.0 microl per side, bilaterally) and intra-amygdaloid infusion of EGb761 (1.0, 14.0, or 28.0 ng/microl per side, bilaterally) 30 and 10 min prior to fear conditioning, respectively, facilitated FPS in a dose-dependent manner. (2) Administration of EGb761 did not impair an animal's basal startle response or pain perception. (3) Subsequent control experiment's results indicated that the facilitation effect of EGb761 on the acquisition was not due to anxiogenic effect or non-specific effect. These results suggested that a single dose of EGb761 also has memory-enhancing effects in young animals. In addition, BLA is the central locus for EGb761 facilitation effect on FPS.

Effects of tryptophan deficiency on prepulse inhibition of the acoustic startle in rats

Serotonin (5-HT) plays a key role in the pathophysiology of psychotic disorders, presumably through a modulation of dopamine (DA) transmission. Reduction of 5-HT signaling has been suggested to enhance dopaminergic responses in animal models of psychosis. An intriguing naturalistic strategy to reduce 5-HT brain content is afforded by the dietary restriction to its precursor, l-tryptophan (TRP). We investigated the impact of a TRP-deficient diet in rats on the prepulse inhibition of the startle (PPI), a measure of sensorimotor gating which is typically impaired by psychotomimetic substances. After either short-term (6 h) or long-term (14 days) TRP deprivation, rats were tested for startle reflex and PPI. Moreover, we assessed the impact of both TRP deprivation regimens on PPI reduction induced by the psychotomimetic substance d-amphetamine (AMPH). Both TRP-deficient regimens failed to significantly affect PPI responses. However, chronic, but not short-term, TRP-deficient diet induced a significant sensitization to the effects of AMPH (1.25-2.5 mg/kg, subcutaneous). The enhanced predisposition to PPI disruption elicited by prolonged TRP deprivation was completely reversed 24 h after reinstatement of TRP in the diet, as well as pretreatment with antipsychotic drugs haloperidol (0.1 mg/kg, intraperitoneal) and clozapine (5 mg/kg, intraperitoneal), which exert their therapeutic action mostly through blockade of DA D(2) receptors. The present results confirm and extend previous findings on the impact of serotonergic signaling in the modulation of DA transmission in schizophrenia and point to chronic TRP deprivation as a potential model of environmental manipulation that may produce a sensitization to psychotic-like symptoms induced by dopaminergic activation.

In vivo pharmacological characterization of the structurally novel, potent, selective mGlu2/3 receptor agonist LY404039 in animal models of psychiatric disorders

Data from both preclinical and clinical studies have provided proof of concept that modulation of limbic and forebrain glutamate, via mGlu2/3 receptor agonists, might provide therapeutic benefits in many psychiatric disorders including schizophrenia and anxiety. The aim of this study was to assess the efficacy of a structurally novel, potent, selective mGlu2/3 receptor agonist with improved bioavailability (LY404039) in animal models predictive of antipsychotic and anxiolytic efficacy. LY404039 was assessed in amphetamine- and phencyclidine-induced hyperlocomotion, conditioned avoidance responding, fear-potentiated startle, marble burying, and rotarod behavioral tests. Monoamine release and turnover were assessed using microdialysis and ex vivo tissue levels. LY404039 attenuated amphetamine- and phencyclidine-induced hyperlocomotion (3-30 and 10 mg/kg, respectively). LY404039 (3-10 mg/kg) inhibited conditioned avoidance responding. LY404039 also reduced fear-potentiated startle in rats (3-30 microg/kg) and marble burying in mice (3-10 mg/kg), indicating anxiolytic-like effects. Importantly, LY404039 did not produce sedative effects or motor impairment as measured by rotarod performance and lack of escape failures in the conditioned avoidance task (at doses up to 30 and 10 mg/kg, respectively). LY404039 (10 mg/kg) also increased dopamine and serotonin release/turnover in the prefrontal cortex. These results demonstrate the broad preclinical efficacy of LY404039 across multiple animal models of antipsychotic and anxiolytic efficacy. Additionally, this compound modulates mesocortical neurotransmission and provides a novel mechanism for the treatment of psychiatric disorders that may be associated with improved efficacy and reduced incidence of undesirable side effects. As glutamatergic dysfunction has been linked to the etiology of schizophrenia, clinical studies with more potent mGlu2/3 agonists, such as LY404039, may be useful to explore the validity of this hypothesis.

Motivated attention and prepulse inhibition of startle in rats: Using conditioned reinforcers as prepulses.

In humans, prepulse inhibition (PPI) of startle is greater during attended prestimuli than it is during ignored prestimuli, whereas in rats, most work has focused on passive PPI, which does not require attention. In the work described in this article, researchers developed a paradigm to assess attentional modification of PPI in rats using motivationally salient prepulses. Water-deprived rats were either conditioned to attend to a conditioned stimulus (CS; 1-s, 7-dB increase in white noise) paired with water (CS(+) group), or they received uncorrelated presentations of white noise and water (CS0 group). After 10 conditioning sessions, startle probes (50 ms, 115 dB) were introduced, with the CS serving as a continuous prepulse. Three experiments examined PPI across a range of prepulse intensities (4-10 dB) and stimulus onset asynchronies (SOAs; 30-960 ms). PPI was consistently reduced in the CS(+) group, particularly with a 10-dB prepulse and a 60-ms SOA. Thus, PPI in rats differed between attended and ignored prestimuli, but the effect was reversed in the results of research with humans. A fourth study eliminated the group difference by reversing the CS-water contingency. Methodological and motivational hypotheses regarding the current findings are discussed.

Pharmacokinetic and behavioral characterization of a long-term antipsychotic delivery system in rodents and rabbits

Non-adherence with medication remains the major correctable cause of poor outcome in schizophrenia. However, few treatments have addressed this major determinant of outcome with novel long-term delivery systems. The aim of this study was to provide biological proof of concept for a long-term implantable antipsychotic delivery system in rodents and rabbits. Implantable formulations of haloperidol were created using biodegradable polymers. Implants were characterized for in vitro release and in vivo behavior using prepulse inhibition of startle in rats and mice, as well as pharmacokinetics in rabbits. Behavioral measures demonstrate the effectiveness of haloperidol implants delivering 1 mg/kg in mice and 0.6 mg/kg in rats to block amphetamine (10 mg/kg) in mice or apomorphine (0.5 mg/kg) in rats. Additionally, we demonstrate the pattern of release from single polymer implants for 1 year in rabbits. The current study suggests that implantable formulations are a viable approach to providing long-term delivery of antipsychotic medications in vivo using animal models of behavior and pharmacokinetics. In contrast to depot formulations, implantable formulations could last 6 months or longer. Additionally, implants can be removed throughout the delivery interval, offering a degree of reversibility not available with depot formulations.

Effects of Topiramate on the Prepulse Inhibition of the Acoustic Startle in Rats

The anticonvulsant topiramate (TPM) has been recently proposed as a novel adjuvant therapy for bipolar disorder and schizophrenia, yet its efficacy remains controversial. As both disorders are characterized by gating deficits, we tested the effects of TPM on the behavioral paradigm of prepulse inhibition (PPI) of the acoustic startle response, a validated animal model of sensorimotor gating. TPM (10, 18, 32, 58, 100 mg/kg, intraperitoneal, i.p.) enhanced PPI in rats in a dose-dependent fashion, prevented the PPI reduction mediated by the dopaminergic agonist apomorphine (0.25 mg/kg, subcutaneous, s.c.) and potentiated the effects of the antipsychotic drugs haloperidol (0.05, 0.1 mg/kg, i.p.) and clozapine (2.5, 5 mg/kg, i.p.). Conversely, TPM elicited no significant effect on the PPI disruption mediated by the NMDA receptor antagonist dizocilpine (0.05, 0.1 mg/kg, s.c.) and surprisingly antagonized the attenuation of dizocilpine-induced PPI disruption mediated by clozapine (5 mg/kg, i.p.). Our results suggest that TPM may exert diverse actions on the neural substrates of sensorimotor gating. While the pharmacological mechanisms of such effects are still elusive, our findings might contribute to shed light on some controversies on the therapeutic action of TPM, and point to this drug as a putative novel adjuvant therapy for some clusters of gating disturbances.

Neurotoxic lesions of the dorsal and ventral hippocampus impair acquisition and expression of trace-conditioned fear-potentiated startle in rats

Pavlovian delay conditioning, in which a conditioned stimulus (CS) and unconditioned stimulus (US) co-terminate, is thought to reflect non-declarative memory. In contrast, trace conditioning, in which the CS and US are temporally separate, is thought to reflect declarative memory. Hippocampal lesions impair acquisition and expression of trace conditioning measured by the conditioned freezing and eyeblink responses, while having little effect on the acquisition of delay conditioning. Recent evidence suggests that lesions of the ventral hippocampus (VH) impair conditioned fear under conditions in which dorsal hippocampal (DH) lesions have little effect. In the present study, we examined the time-course of fear expression after delay and trace conditioning using the fear-potentiated startle (FPS) reflex, and the effects of pre- and post-training lesions to the VH and DH on trace-conditioned FPS. We found that both delay- and trace-conditioned rats displayed significant FPS near the end of the CS relative to the unpaired control group. In contrast, trace-conditioned rats displayed significant FPS throughout the duration of the trace interval, whereas FPS decayed rapidly to baseline after CS offset in delay-conditioned rats. In experiment 2, both DH and VH lesions were found to significantly reduce the overall magnitude of FPS compared to the control group, however, no differences were found between the DH and VH groups. These findings support a role for both the DH and VH in trace fear conditioning, and suggest that the greater effect of VH lesions on conditioned fear might be specific to certain measures of fear.

Actions of Novel Antipsychotic Agents on Apomorphine-Induced PPI Disruption: Influence of Combined Serotonin 5-HT1A Receptor Activation and Dopamine D2 Receptor Blockade

The dopamine D1/D2 agonist apomorphine (0.63 mg/kg) disrupted prepulse inhibition (PPI) of acoustic startle in rats, a model of sensorimotor gating deficits observed in schizophrenia. All current antipsychotics, which antagonize D2 receptors, prevent this apomorphine-induced deficit. A novel class of antipsychotics possesses, in addition to D2 antagonist property, various levels of 5-HT1A agonist activity. Considering that the latter itself produces PPI deficits, it appeared necessary to assess the potential of this novel class of antipsychotics to reverse apomorphine-PPI deficits. Potent D2 antagonists, like haloperidol (0.63-2.5 mg/kg), risperidone (0.63-10 mg/kg), and olanzapine (0.63-40 mg/kg) prevented apomorphine PPI disruption. The atypical antipsychotics, clozapine (40 mg/kg), nemonapride (0.01-2.5 mg/kg), ziprasidone (10 mg/kg), and aripiprazole (0.01 and 10 mg/kg), which all exhibit 5-HT1A agonist properties, reversed PPI deficits at some doses only, whereas the anti-dyskinetic agent sarizotan (0.16-10 mg/kg), an efficacious 5-HT1A agonist, did not. New generation antipsychotics with marked 5-HT1A agonist properties, such as SLV313 and SSR181507 (0.0025-10 mg/kg and 0.16-10 mg/kg, respectively) did not reverse these deficits whereas bifeprunox (0.04-2.5 mg/kg) did. To reveal the contribution of 5-HT1A agonist properties in the lack of effects of SLV313 and SSR181507, we pretreated rats with the 5-HT1A antagonist WAY100635 (0.63 mg/kg). Under these conditions, significant reversal of PPI deficit was observed, indicating that D2 antagonist properties of SLV313 and SSR181507 are now sufficient to overcome the disruptive effects of apomorphine. To summarize, antipsychotics possessing agonist efficacy at 5-HT1A receptors exhibit diverse profiles against apomorphine-induced PPI deficits, depending on the balance between D2 and 5-HT1A activities, suggesting that they may display distinct activity on some aspects of gating deficits in schizophrenic patients.

Central Oxytocin, Vasopressin, and Corticotropin-Releasing Factor Receptor Densities in the Basal Forebrain Predict Isolation Potentiated Startle in Rats

Individual differences in resiliency to particular stressors may be mediated by specific neuropeptide receptor patterns in the brain. Here, we explored this issue by using a multivariate approach to identify brain sites in which oxytocin (OTR), vasopressin (V1aR), and corticotropin-releasing factor type 1 (CRF1) or type 2 receptor binding covaried with a measure of isolation-induced anxiety: isolation potentiated startle (IPS). Partial least squares (PLS) analysis identified three binding sites, the shell of the nucleus accumbens (AccSh), lateral bed nucleus of the stria terminalis, and intermediate zone of the lateral septum, in which CRF1, V1aR, and OTR receptors, respectively, covaried with IPS. Multiple regression analysis demonstrated that the three binding sites accounted for more of the variation in IPS as a linear combination than when considered individually. Using the same multiple regression model, the linear combination of the same three binding sites/peptide receptors measured in a new group of animals successfully predicted their IPS values. There were no differences in binding between grouped and isolated animals, suggesting that the patterns are trait effects rather than a consequence of isolation. Based on the finding that CRF1 receptors in the AccSh were positively correlated with IPS, we infused CRF directly into the AccSh and found that it significantly potentiated startle after a short isolation period but not under grouped conditions. This result directly supported the predictions made by the combined PLS/regression approach. These results suggest that the integrated activity of neuropeptide systems mediating both social behavior and anxiety underlie IPS.

Kappa Opioid Receptor Activation Disrupts Prepulse Inhibition of the Acoustic Startle in Rats

Compelling evidence indicates that kappa opioid receptor (KOR) agonists produce perceptual distortions in animals and humans, yet the mechanism of action and clinical relevance of such effects remain unclear. Since abnormalities in preattentional functions and informational processing are hypothesized to underlie psychotic disorders, the present study has been designed to assess the role of KOR on sensorimotor gating. The effects of the selective KOR agonist U50488 were evaluated on the behavioral paradigm of prepulse inhibition (PPI) of the acoustic startle reflex (ASR). U50488 (1.25, 2.5, and 5 mg/kg, subcutaneous [SC]) induced a dose-dependent reduction of PPI, which was efficiently prevented by the selective KOR antagonist norbinaltorphimine (nor-BNI, 10 mg/kg, SC), as well as by the atypical antipsychotic clozapine (5, 8 mg/kg, intraperitoneal [IP]) but not by the typical antipsychotic haloperidol (.1, .5 mg/kg, IP). Conversely, nor-BNI (10 mg/kg, SC) failed to reverse the PPI disruption mediated by both apomorphine (.25 mg/kg, SC) and dizocilpine (.1 mg/kg, SC). Our results support a pivotal role of KOR in the regulation of preattentional functions and sensorimotor gating, pointing to these receptors as a possible neurobiological substrate especially relevant to the clusters of psychosis unresponsive to typical antipsychotics.

Activation of group II metabotropic glutamate receptors induces depotentiation in amygdala slices and reduces fear-potentiated startle in rats

There is a close correlation between long-term potentiation (LTP) in the synapses of lateral amygdala (LA) and fear conditioning in animals. We predict that reversal of LTP (depotentiation) in this area of the brain may ameliorate conditioned fear. Activation of group II metabotropic glutamate receptors (mGluR II) with DCG-IV induces depotentiation in the LA. The induction of depotentiation is independent of NMDA receptors, L-type Ca++ channels, and calcineurin activity, but requires presynaptic activity and extracellular Ca++. (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV) depotentiation is accompanied by a decrease in the frequency but not the amplitude of miniature excitatory post-synaptic currents (mEPSCs) and could be mimicked by endogenously released glutamate. DCG-IV inhibited the release of glutamate evoked by 4-AP but not that evoked by ionomycin, suggesting that the effect of DCG-IV is not mediated by an action downstream of Ca++ entry. Intra-amygdala infusion of mGluR II agonist blocks the consolidation of fear memory measured with fear-potentiated startle. Taken together, the present results characterize the properties of DCG-IV depotentiation and reveal a close parallel between depotentiation in the amygdala slice and the reduction of conditioned fear in animals.

Prepulse lost and regained: a commentary on “Weak prepulses inhibit but do not elicit startle in rats and humans” Biological Psychiatry 55:98–101

Prepulse lost and regained: a commentary on “Weak prepulses inhibit but do not elicit startle in rats and humans” Biological Psychiatry 55:98–101