Elsevier

Neuropharmacology

Volume 52, Issue 2, February 2007, Pages 476-486
Neuropharmacology

Metabotropic glutamate subtype 5 receptors modulate fear-conditioning induced enhancement of prepulse inhibition in rats

https://doi.org/10.1016/j.neuropharm.2006.08.016Get rights and content

Abstract

Non-startling acoustic events presented shortly before an intense startling sound can inhibit the acoustic startle reflex. This phenomenon is called prepulse inhibition (PPI), and is widely used as a model of sensorimotor gating. The present study investigated whether PPI can be modulated by fear conditioning, whose acquisition can be blocked by the specific antagonist of metabotropic glutamate receptors subtype 5 (mGluR5), 2-methyl-6-(phenylethynyl)-pyridine (MPEP). The results show that a gap embedded in otherwise continuous noise sounds, which were delivered by two spatially separated loudspeakers, could inhibit the startle reflex induced by an intense sound that was presented 50 ms after the gap. The inhibitory effect depended on the duration of the gap, and was enhanced by fear conditioning that was introduced by temporally pairing the gap with footshock. Intraperitoneal injection of MPEP (0.5 or 5 mg/kg) 30 min before fear conditioning blocked the enhancing effect of fear conditioning on PPI, but did not affect either the baseline startle magnitude or PPI if no fear conditioning was introduced. These results indicate that PPI is enhanced when the prepulse signifies an aversive event after fear conditioning. Also, mGlu5Rs play a role in preserving the fear-conditioning-induced enhancement of PPI.

Introduction

The neural substrate of suppressing irrelevant sensory information to ensure useful sensory information processing is called sensory gating. Impaired sensory gating in schizophrenic patients has been assumed to cause thought disorder and emotion abnormality (for reviews see Braff et al., 2001, Geyer et al., 2001, Swerdlow et al., 2001, van den Buuse et al., 2005, Weiss and Feldon, 2001). The startle reflex is the strongest whole-body reflective response (Landis and Hunt, 1939). It can be elicited by intense sensory stimuli with several important features, such as short latency, potent summation, and wide dynamic range (Li and Frost, 1996, Li and Yeomans, 1999, Li et al., 2001). The neural circuit mediating startle is short, and the key structure is the caudal pontine reticular nucleus, in which the giant neurons receive axonal projections from the cochlear nucleus, trigeminal nucleus and vestibular nucleus, and send projections to motor areas of cranial nerve nuclei (e.g. motor neurons in facial nerve nucleus) and the spinal cord (for reviews see Koch and Schnitzler, 1997, Yeomans et al., 2002). The startle reflex is the fast response to threatening stimuli and important for adaptation to the environment, but also has a disruptive effect on cognitive/behavioral performances. For example, the acoustic startle reflex can disrupt perception/motor tasks in humans (Foss et al., 1989) and learned lever-pressing behaviors in rats (Hoffman and Overman, 1971). However, the central nervous system also has neural circuits of inhibiting startle to reduce the disruptive influence to cognition and behavior. Prepulse inhibition (PPI) of the startle reflex is the normal reduction of the startle reflex to an intense startling stimulus when this startling stimulus is shortly preceded by a weaker sensory stimulus (prepulse), and widely recognized as a cross-species model of sensorimotor gating (Braff and Geyer, 1990, Graham, 1975, Hoffman and Ison, 1980, Ison and Hoffman, 1983, Li and Yue, 2002).

Graham proposed a “protection-of-processing” theory for justifying PPI (Graham, 1975): a weak prepulse stimulus followed by an intense stimulus can trigger not only the information processing for the prepulse signal but also a gating mechanism that dampens the information of the intense disruptive stimulus, therefore protects the early process of the prepulse stimulus. This proposal has been supported by several lines of research using human subjects. First, Foss et al. (1989) found that presentation of a weak acoustic stimulus 100 ms prior to a startle-eliciting stimulus significantly reduces startle-produced errors in an aiming task. In addition, the accuracy of discriminating the prepulse stimulus is highly correlated to the degree of suppression of the startle reflex (Filion and Ciranni, 1994, Mussat-Whitlow and Blumenthal, 1997, Norris and Blumenthal, 1995, Norris and Blumenthal, 1996, Perlstein et al., 1989, Perlstein et al., 1993). Finally, the startling sound is perceived as less intense when it is preceded by a prepulse sound (Blumenthal et al., 1996, Perlstein et al., 1993). Thus, PPI of the startle reflex reflects activation of a protective mechanism in the central nervous system.

PPI can be modulated in animals by manipulations of neural activity of various forebrain structures, including the amygdala (Bouwmeester et al., 2002, Daenen et al., 2003, Decker et al., 1995, Fendt et al., 2000, Stevenson and Gratton, 2004, Wan and Swerdlow, 1997; for reviews see Li and Shao, 2003, Swerdlow et al., 2001). For example, either large lesions of the amygdala or focal lesions of the basolateral amygdala significantly reduce PPI (Decker et al., 1995, Wan and Swerdlow, 1997). It has been well known that the lateral nucleus of the amygdala (LA) mediates auditory fear conditioning (AFC) (Hitchcock and Davis, 1986, Romanski and LeDoux, 1992, Maren, 1996, Fendt, 2001, Goosens and Maren, 2001, Tazumi and Okaichi, 2002). Auditory inputs to LA originate mainly from the medial geniculate nucleus (MGN) and auditory association cortex (AAC) (LeDoux et al., 1990, Turner and Herkenham, 1991, Romanski and LeDoux, 1993, Mascagni et al., 1993, Doron and LeDoux, 1999, Woodson et al., 2000). Interestingly, the amygdala also plays a role in developing neuronal plasticity in the MGN during AFC (Maren et al., 2001, Poremba and Gabriel, 2001). The MGN has been suggested to be an auditory structure that modulates PPI (Zhang et al., 1999). It would be intriguing and important to know whether AFC can have certain influence to PPI. When a prepulse stimulus becomes a signal informing aversive events following AFC, does it grow to be more potent in inhibiting the startle reflex? However, to our knowledge, this issue has not been investigated before.

Metabotropic glutamate receptors (mGluRs) are coupled to various second messenger cascades, and involved in synaptic plasticity associated with learning and memory (for reviews see Riedel, 1996, Simonyi et al., 2005). The group I metabotropic glutamate receptors subtype 5 (mGluR5) are critical for formation of AFC (Schulz et al., 2001, Fendt and Schmid, 2002, Lee et al., 2002, Rodrigues et al., 2002). Some studies have confirmed that systemic administration of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), the non-competitive, selective, and systemically active antagonist of mGluR5 (Gasparini et al., 1999), does not effect either PPI or the acoustic startle reflex (Henry et al., 2002, Kinney et al., 2003, Schulz et al., 2001, Spooren et al., 2000). For example, Schulz et al. (2001) have reported that oral administration of MPEP did not affect PPI and the magnitude of the acoustic startle reflex at the dosage of 3.0 mg/kg, short-term habituation of startle at the dosage of 0.3, 3.0, or 30.0 mg/kg, and sensitization of startle by footshock at the dosage of 3.0 mg/kg. Therefore, MPEP would be an ideal pharmacological agent used for studying the modification of PPI by AFC.

This study was to investigate whether PPI, the model of sensorimotor gating, can be modified by AFC, which is induced by explicitly pairing the prepulse stimulus with footshock. In addition, this study was also to investigate whether MPEP affects the effect of AFC on PPI. The prepulse stimulus used in the present study was a gap (a transient drop in sound level) embedded in otherwise continuous background noise sounds (Leitner and Girten, 1997, Barsz et al., 1998, Barsz et al., 2002, Ison et al., 1998, Ison et al., 2002, Ison and Bowen, 2000).

Section snippets

Animals

Fifty-three young adult male albino Sprague–Dawley rats (weighted between 160–180 g), provided by Beijing Vital River Experimental Animals Technology Ltd., were used in this study. They were housed individually in plastic cages and placed on a 12 h light/dark cycle, with food and water freely available. These male rats used for this study had become adults before they were purchased. They did not experience social isolation during their early ages. They were allowed at least 1 week to adapt to the

Mean prepulse inhibition across 53 rats before treatments

In each of the 53 rats used in the present study, the intense 10-ms noise burst could reliably elicit whole-body startle responses, whose latencies of primary peak components were about 15 ms after the onset of the startling noise burst (Fig. 2).

For all the 53 rats, compared to the startle responses under the zero-gap condition (gap duration = 0 ms), startle responses, which were measured on the fourth day, were significantly inhibited by gap presentations at each of the 6 gap-size conditions (5 ms:

Gap induced prepulse inhibition

The temporal resolution of the auditory system, that is, the ability to discriminate rapid changes in the envelope of a sound, is important for processing the sound. A common way of investigating temporal resolution in both humans and animals is the measurement of the threshold of detecting a gap embedded in an otherwise continuous sound. The gap detection ability is determined in part by the rate of decay of neural activity during the gap and in part by sensitivity to the signal increment at

Acknowledgement

This work was supported by the Chinese National Natural Sciences Grant (30200080), Key Project of China Natural Science Foundation (60535030), the Ministry of Science and Technology of China (2002CCA01000), the Ministry of Education of China (grant No. 02170), and a “985” grant from Peking University. The authors thank Fei Luo for technical supervision and Xian Liu for developing computer programs.

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