Measuring the middle-ear reflex: A quantitative method to assess effects of industrial solvents on central auditory pathways.

Volatile organic solvents are frequently present in industrial atmospheres. Their lipophilic properties mean they quickly reach the brain following inhalation. Acute exposure to some solvents perturbs the middle ear reflex, which could jeopardize cochlear protection against loud noises. As the physiological mechanisms involved in this protective reflex are highly complex, in vivo rodent models are required to allow rapid and reliable identification of any adverse effects of solvents on the middle ear reflex (MER). In this study, MER amplitude was measured in anesthetized Brown-Norway rats by monitoring the decrease in distortion product otoacoustic emissions (DPOAEs) caused by a contralateral stimulation. Our screening test consisted in measuring the impact of inhalation of solvent vapors at 3000 ppm for 15 min on the MER amplitude. We had previously studied a selection of aromatic solvents with this model; here, we extended the analysis to volatile compounds from other chemical families. The results obtained shed light on the mechanisms involved in the interactions between solvents and their neuronal targets. Thus, benzene and chlorobenzene had the greatest effect on MER (≥ + 1.8 dB), followed by a group composed of toluene, styrene, p-xylene, m-xylene, tetrachloroethylene and cyclohexane, which had a moderate effect on the MER (between + 0.3 and + 0.7 dB). Finally, trichloroethylene, n-hexane, methyl-ethyl-ketone, acetone, o-xylene, and ethylbenzene had no effect on the MER. Thus, the effect of solvents on the MER is not simply linked to their lipophilicity, rather it depends on specific interactions with neuronal targets. These interactions appear to be governed by the compound's chemical structure, e.g. the presence of an aromatic ring and its steric hindrance. In addition, perturbation of the MER by a solvent is independent of its toxic effects on cochlear cells. As the MER plays a protective role against exposure to high-intensity noises, these findings could have a significant impact in terms of prevention for subjects exposed to both noise and solvents.

A Clinical Trial of Proton Pump Inhibitors to Treat Children with Chronic Otitis Media with Effusion.

OBJECTIVE: Gastroesophageal reflux (GER) is considered a cause of otitis media with effusion (OME). This study aimed to investigate whether OME can be effectively treated with a proton pump inhibitor (PPI), therefore implicating GER as a causative factor of OME. MATERIALS AND METHODS: A PPI or placebo was randomly administered to enrolled subjects for 4-8 weeks. To monitor effusion status, subjects underwent monthly pneumatic otoscopy and acoustic reflectometry. At enrollment and at completion of treatment, subjects underwent an audiogram and tympanogram for assessing changes in hearing due to altered fluid levels in the middle ear. After the treatment period, tympanostomy tube placement was recommended for subjects with unresolved effusion. RESULTS: This study enrolled 16 patients with an average age of 5.17 years. Between the treatment and placebo groups, there was no significant difference in the need for tympanostomy tubes. At completion of this study, patients receiving Lansoprazole demonstrated a significant improvement in pure tone average (p<0.01) and speech recognition thresholds (p=0.04). Four patients (25%) from the cohort dropped out of the study. Eight patients (50%) from the cohort required tympanostomy tube placement. CONCLUSION: Owing to difficulties with recruitment and small sample size, this study was unable to demonstrate the use of PPI in treating OME. A larger study is needed for further evaluation of this process.

Characterization of Behavioral, Signaling and Cytokine Alterations in a Rat Neurodevelopmental Model for Schizophrenia, and Their Reversal by the 5-HT6 Receptor Antagonist SB-399885.

Post-weaning social isolation of rats produces neuroanatomical, neurochemical and behavioral alterations resembling some core features of schizophrenia. This study examined the ability of the 5-HT6 receptor antagonist SB-399885 to reverse isolation-induced cognitive deficits, then investigated alterations in hippocampal cell proliferation and hippocampal and frontal cortical expression of selected intracellular signaling molecules and cytokines. Male Lister hooded rats (weaned on post-natal days 21-24 and housed individually or in groups of 3-4) received six i.p. injections of vehicle (1% Tween 80, 1 mL/kg) or SB-399885 (5 or 10 mg/kg) over a 2-week period starting 40 days post-weaning, on the days that locomotor activity, novel object discrimination (NOD), pre-pulse inhibition of acoustic startle and acquisition, retention and extinction of a conditioned freezing response (CFR) were assessed. Tissue was collected 24 h after the final injection for immunohistochemistry, reverse-phase protein microarray and western blotting. Isolation rearing impaired NOD and cue-mediated CFR, decreased cell proliferation within the dentate gyrus, and elevated hippocampal TNFα levels and Cdc42 expression. SB-399885 reversed the NOD deficit and partially normalized CFR and cell proliferation. These effects were accompanied by altered expression of several members of the c-Jun N-terminal Kinase (JNK) and p38 MAPK signaling pathways (including TAK1, MKK4 and STAT3). Although JNK and p38 themselves were unaltered at this time point hippocampal TAK1 expression and phosphorylation correlated with visual recognition memory in the NOD task. Continued use of this neurodevelopmental model could further elucidate the neurobiology of schizophrenia and aid assessment of novel therapies for drug-resistant cognitive symptoms.

Pharmacological Rescue of Hippocampal Fear Learning Deficits in Fragile X Syndrome.

Fragile X Syndrome (FXS) is the leading cause of autism spectrum disorder and intellectual disability and results from loss of Fragile X mental retardation protein (FMRP). In neurons, FMRP controls the translation of synaptic plasticity proteins that are implicated in learning and memory. FMRP also regulates development- and experience-dependent actin cytoskeleton remodeling within dendritic spines through the small Rho GTPase Rac1. Modulation of Rac1 activity is critical during synaptic plasticity as well as learning and memory. We have previously shown that FXS mouse models exhibit learning and memory deficits as well as hyperactive Rac1 in the hippocampus. To determine whether pharmacological inhibition of Rac1 in FXS improves cognitive impairment, FXS mice were treated with the specific Rac1 inhibitor NSC23766, followed by fear conditioning. Whereas non-cognitive functions were unaffected, hippocampus-related memory improved in FXS mice treated with the Rac1 inhibitor. Furthermore, long-term potentiation in hippocampal slices from FXS mice was increased after incubation with the Rac1 inhibitor. Together, these observations indicate that modulation of Rac1 may provide a novel therapeutic target in the treatment of cognitive impairment in FXS.

The Middle Ear Muscle Reflex in Rat: Developing a Biomarker of Auditory Nerve Degeneration.

OBJECTIVES: The long-term goal of this research is to determine whether the middle ear muscle reflex can be used to predict the number of healthy auditory nerve fibers in hearing-impaired ears. In this study, we develop a high-impedance source and an animal model of the middle ear muscle reflex and explore the influence of signal frequency and level on parameters of the reflex to determine an optimal signal to examine auditory nerve fiber survival. DESIGN: A high-impedance source was developed using a hearing aid receiver attached to a 0.06 diameter 10.5-cm length tube. The impedance probe consisted of a microphone probe placed near the tip of a tube coupled to a sound source. The probe was calibrated by inserting it into a syringe of known volumes and impedances. The reflex in the anesthetized rat was measured with elicitor stimuli ranging from 3 to 16 kHz presented at levels ranging from 35 to 100 dB SPL to one ear while the reflex was measured in the opposite ear containing the probe and probe stimulus. RESULTS: The amplitude of the reflex increased with elicitor level and was largest at 3 kHz. The lowest threshold was approximately 54 dB SPL for the 3-kHz stimulus. The rate of decay of the reflex was greatest at 16 kHz followed by 10 and 3 kHz. The rate of decay did not change significantly with elicitor signal level for 3 and 16 kHz, but decreased as the level of the 10-kHz elicitor increased. A negative feedback model accounts for the reflex decay by having the strength of feedback dependent on auditory nerve input. The rise time of the reflex varied with frequency and changed with level for the 10- and 16-kHz signals but not significantly for the 3-kHz signal. The latency of the reflex increased with a decrease in elicitor level, and the change in latency with level was largest for the 10-kHz stimulus. CONCLUSIONS: Because the amplitude of the reflex in rat was largest with an elicitor signal at 3 kHz, had the lowest threshold, and yielded the least amount of decay, this may be the ideal frequency to estimate auditory nerve survival in hearing-impaired ears.

Repeated shock stress facilitates basolateral amygdala synaptic plasticity through decreased cAMP-specific phosphodiesterase type IV (PDE4) expression.

Previous studies have shown that exposure to stressful events can enhance fear memory and anxiety-like behavior as well as increase synaptic plasticity in the rat basolateral amygdala (BLA). We have evidence that repeated unpredictable shock stress (USS) elicits a long-lasting increase in anxiety-like behavior in rats, but the cellular mechanisms mediating this response remain unclear. Evidence from recent morphological studies suggests that alterations in the dendritic arbor or spine density of BLA principal neurons may underlie stress-induced anxiety behavior. Recently, we have shown that the induction of long-term potentiation (LTP) in BLA principal neurons is dependent on activation of postsynaptic D1 dopamine receptors and the subsequent activation of the cyclic adenosine 5'-monophosphate (cAMP)-protein kinase A (PKA) signaling cascade. Here, we have used in vitro whole-cell patch-clamp recording from BLA principal neurons to investigate the long-term consequences of USS on their morphological properties and synaptic plasticity. We provided evidence that the enhanced anxiety-like behavior in response to USS was not associated with any significant change in the morphological properties of BLA principal neurons, but was associated with a changed frequency dependence of synaptic plasticity, lowered LTP induction threshold, and reduced expression of phosphodiesterase type 4 enzymes (PDE4s). Furthermore, pharmacological inhibition of PDE4 activity with rolipram mimics the effects of chronic stress on LTP induction threshold and baseline startle. Our results provide the first evidence that stress both enhances anxiety-like behavior and facilitates synaptic plasticity in the amygdala through a common mechanism of PDE4-mediated disinhibition of cAMP-PKA signaling.

Effects of thiocolchicoside, a commonly used myorelaxant, on the acoustic reflex.

OBJECTIVE: To determine whether thiocolchicoside, a commonly used myorelaxant, may impair the acoustic reflex. METHODS: Forty-two patients scheduled to receive thiocolchicoside treatment for different reasons were enrolled in the study. Acoustic reflex thresholds at 500, 1000, 2000 and 4000 Hz were determined and analysed statistically pre-treatment and on the 5th day of treatment. RESULTS: Increases were observed in the mean acoustic reflex thresholds on the 5th day of treatment compared to pre-treatment, at all frequencies, except right contralateral thresholds at 500 and 2000 Hz. These increases were statistically significant for right ipsilateral thresholds at 2000 and 4000 Hz, left ipsilateral thresholds at 500, 1000, 2000 and 4000 Hz, and left contralateral thresholds at 2000 and 4000 Hz (p ≤ 0.05), but not at other frequencies (p > 0.05). CONCLUSION: Muscle relaxant drugs, especially those affecting the central nervous system, may weaken the stapedial muscle so that the ability of noise to cause acoustic trauma may become evident. For this reason, physicians should advise their patients to avoid loud noises when muscle relaxant therapy is prescribed.

Membrane fluidity does not explain how solvents act on the middle-ear reflex.

Some volatile aromatic solvents have similar or opposite effects to anesthetics in the central nervous system. Like for anesthetics, the mechanisms of action involved are currently the subject of debate. This paper presents an in vivo study to determine whether direct binding or effects on membrane fluidity best explain how solvents counterbalance anesthesia's depression of the middle-ear reflex (MER). Rats were anesthetized with a mixture of ketamine and xylazine while also exposed to solvent vapors (toluene, ethylbenzene, or one of the three xylene isomers) and the amplitude of their MER was monitored. The depth of anesthesia was standardized based on the magnitude of the contraction of the muscles involved in the MER, determined by measuring cubic distortion product oto-acoustic emissions (DPOAEs) while triggering the bilateral reflex with contralateral acoustic stimulation. The effects of the aromatic solvents were quantified based on variations in the amplitude of the DPOAEs. The amplitude of the alteration to the MER measured in anesthetized rats did not correlate with solvent lipophilocity (as indicated by logKow values). Results obtained with the three xylene isomers indicated that the positions of two methyl groups around the benzene ring played a determinant role in solvent/neuronal cell interaction. Additionally, Solid-state Nuclear Magnetic Resonance (NMR) spectra for brain microsomes confirmed that brain lipid fluidity was unaffected by solvent exposure, even after three days (6h/day) at an extremely high concentration (3000ppm). Therefore, aromatic solvents appear to act directly on the neuroreceptors involved in the acoustic reflex circuit, rather than on membrane fluidity. The affinity of this interaction is determined by stereospecific parameters rather than lipophilocity.

Repeated amphetamine injections alter behavior and induce a delayed behavioral sensitization modulated by reactivity to novelty: Similarities and differences with trauma consequences.

Supporting our hypothesis of common biological bases for post-traumatic stress disorder (PTSD) and addiction, we recently reported that rats exposed to a single prolonged stress (SPS), a PTSD model, develop a delayed behavioral sensitization of the noradrenergic system, similar to that observed in mice after four repeated drug administrations. However, sensitization after trauma was modulated by reactivity to novelty, and this aspect that had not been explored in the addiction model. The first aim of the paper was thus to investigate the influence of reactivity to novelty on delayed behavioral sensitization in rats after four repeated amphetamine injections. Injections were either distributed over 4 days, as conducted in mouse models of addiction, or massed during a single session, reproducing SPS conditions. The second aim was to investigate whether repeated amphetamine injections have similar behavioral consequences to those induced by PTSD. Our results showed that massed amphetamine injections induced more anxiety than distributed injections, and led to avoidance of drug-associated cues avoidance, while distributed injections somewhat reduced the startle response, such as is seen in SPS. In addition, massed amphetamine injections induced a delayed behavioral sensitization clearly affected by the reactivity to novelty, reproducing results observed following exposure to traumatic events. Finally, all rats receiving repeated amphetamine injections exhibited a behavioral sensitization in response to exposure to drug-associated cues. Taken together, these data strengthen the position that drug addiction and PTSD share some common mechanisms that we tried to clarify in this paper.

Effect of JWH-250, JWH-073 and their interaction on "tetrad", sensorimotor, neurological and neurochemical responses in mice.

JWH-250 and JWH-073 are two synthetic cannabinoid agonists with nanomolar affinity at CB1 and CB2 receptors. They are illegally marketed within "herbal blend" for theirs psychoactive effects greater than those produced by Cannabis. Recently, we analyzed an "herbal" preparation containing a mixture of both JWH-250 and JWH-073. The present study was aimed at investigating the in vitro and in vivo pharmacological activity of JWH-250 and JWH-073 in male CD-1 mice. In vitro competition binding experiments performed on mouse and human CB1 and CB2 receptors revealed a nanomolar affinity and potency of the JWH-250 and JWH-073. In vivo studies showed that JWH-250 and JWH-073, administered separately, induced a marked hypothermia, increased pain threshold to both noxious mechanical and thermal stimuli, caused catalepsy, reduced motor activity, impaired sensorimotor responses (visual, acoustic and tactile), caused seizures, myoclonia, hyperreflexia and promote aggressiveness in mice. Moreover, microdialysis study in freely moving mice showed that systemic administration of JWH-250 and JWH-073 stimulated dopamine release in the nucleus accumbens in a dose-dependent manner. Behavioral, neurological and neurochemical effects were fully prevented by the selective CB1 receptor antagonist/inverse agonist AM 251. Co-administration of ineffective doses of JWH-250 and JWH-073 impaired visual sensorimotor responses, improved mechanical pain threshold and stimulated mesolimbic DA transmission in mice, living unchanged all other behavioral and physiological parameters. For the first time the present study demonstrates the overall pharmacological effects induced by the administration of JWH-250 and JWH-073 in mice and it reveals their potentially synergistic action suggesting that co-administration of different synthetic cannabinoids may potentiate the detrimental effects of individual compounds increasing their dangerousness and abuse potential.

Neuropharmacological and cochleotoxic effects of styrene. Consequences on noise exposures.

Occupational noise exposure can damage workers' hearing, particularly when combined with exposure to cochleotoxic chemicals such as styrene. Although styrene-induced cochlear impairments only become apparent after a long incubation period, the pharmacological impact of styrene on the central nervous system (CNS) can be rapidly measured by determining the threshold of the middle-ear acoustic reflex (MER) trigger. The aim of the study was to evaluate the effects of a noise (both continuous and impulse), and a low concentration of styrene [300ppm<(threshold limit value×10) safety factor] on the peripheral auditory receptor, and on the CNS in rats. The impact of the different conditions on hearing loss was assessed using distortion product oto-acoustic emissions, and histological analysis of cochleae. Although the LEX,8h (8-hour time-weighted average exposure) of the impulse noise was lower (80dB SPL sound pressure level) than that of the continuous noise (85dB SPL), it appeared more detrimental to the peripheral auditory receptors. A co-exposure to styrene and continuous noise was less damaging than exposure to continuous noise alone. In contrast, the traumatic effects of impulse noise on the organ of Corti were enhanced by co-exposure to styrene. The pharmacological effects of the solvent on the CNS were discussed to put forward a plausible explanation of these surprising results. We hypothesize that CNS effects of styrene may account for this apparent paradox. Based on the present results, the temporal structure of the noise should be reintroduced as a key parameter in hearing conservation regulations.

Long-term impacts of adolescent risperidone treatment on behavioral responsiveness to olanzapine and clozapine in adulthood.

This preclinical study investigated how a short-term risperidone treatment in adolescence impacts antipsychotic response to olanzapine and clozapine in adulthood. Antipsychotic effect was indexed by a drug's suppressive effect on avoidance responding in a rat conditioned avoidance response (CAR) model. Male adolescent Sprague-Dawley rats were first treated with risperidone (1.0mg/kg, sc) or sterile water and tested in the CAR model for 5 consecutive days from postnatal days P 40 to 44. After they became adults (~P 80-84), they were switched to olanzapine (0.5mg/kg, sc), clozapine (5.0mg/kg, sc) or vehicle treatment and tested for avoidance for 5days. During the adolescent period, repeated risperidone treatment produced a persistent inhibition of avoidance response. Throughout the 5days of adulthood drug testing, rats previously treated with risperidone in adolescence made significantly fewer avoidance responses than the vehicle ones when they all were switched to olanzapine, indicating a risperidone-induced enhancement of behavioral sensitivity to olanzapine. In contrast, when switched to clozapine, rats previously treated with risperidone made significantly more avoidance responses than the vehicle rats, indicating a risperidone-induced decrease of behavioral sensitivity to clozapine. Performance in the prepulse inhibition of acoustic startle response in adulthood was not altered by adolescent risperidone treatment. Collectively, adolescent risperidone exposure induced a long-term change in behavioral sensitivity to other atypical antipsychotic drugs, with the specific direction of change (i.e., increase or decrease) dependent on the drug to be switched to. These long-lasting changes are likely mediated by drug-induced neuroplastic changes and may also have significant clinical implications for antipsychotic treatment of chronic patients with an early onset of psychotic symptoms.

Neurobehavioral phenotype of C57BL/6J mice prenatally and neonatally exposed to cigarette smoke.

Although maternal cigarette smoking during pregnancy is a well-documented risk factor for a variety of adverse pregnancy outcomes, how prenatal cigarette smoke exposure affects postnatal neurobehavioral/cognitive development remains poorly defined. In order to investigate the cause of an altered behavioral phenotype, mice developmentally exposed to a paradigm of 'active' maternal cigarette smoke is needed. Accordingly, cigarette smoke exposed (CSE) and air-exposed C57BL/6J mice were treated for 6h per day in paired inhalation chambers throughout gestation and lactation and were tested for neurobehavioral effects while controlling for litter effects. CSE mice exhibited less than normal anxiety in the elevated zero maze, transient hypoactivity during a 1h locomotor activity test, had longer latencies on the last day of cued Morris water maze testing, impaired hidden platform learning in the Morris water maze during acquisition, reversal, and shift trials, and impaired retention for platform location on probe trials after reversal but not after acquisition or shift. CSE mice also showed a sexually dimorphic response in central zone locomotion to a methamphetamine challenge (males under-responded and females over-responded), and showed reduced anxiety in the light-dark test by spending more time on the light side. No differences on tests of marble burying, acoustic startle response with prepulse inhibition, Cincinnati water maze, matching-to-sample Morris water maze, conditioned fear, forced swim, or MK-801-induced locomotor activation were found. Collectively, the data indicate that developmental cigarette smoke exposure induces subnormal anxiety in a novel environment, impairs spatial learning and reference memory while sparing other behaviors (route-based learning, fear conditioning, and forced swim immobility). The findings add support to mounting evidence that developmental cigarette smoke exposure has long-term adverse effects on brain function.

Inhaled toluene can modulate the effects of anesthetics on the middle-ear acoustic reflex.

Toluene (Tol) is an organic solvent widely used in the industry. It is also abused as an inhaled solvent, and can have deleterious effects on hearing. Recently, it was demonstrated that Tol has both anticholinergic and antiglutamatergic effects, and that it also inhibits voltage-dependent Ca(2+) channels. This paper describes a study of the effects of inhaled Tol on rats anesthetized with isoflurane, pentobarbital, or a mixture of ketamine/xylazine. Hearing was tested using distortion product oto-acoustic emissions (DPOAEs) associated with a contralateral noise to evaluate contraction of the middle-ear muscles. This allowed us to assess the interactions between the effects of Tol and anesthesia on the central nervous system (CNS). Although both anesthetics and Tol are known to inhibit the middle-ear acoustic reflex, our data indicated that inhaled Tol counterbalances the effects of anesthetic in a dose-dependent manner. In other terms, Tol can increase the amplitude of the middle-ear reflex in anesthetized rats, whatever the nature of the anesthetic used. This indicates that inhaling Tol (a Ca(2+)-channel-blocking drug) modifies the potency of anesthesia, and thereby the amplitude of the middle-ear reflex.

Acoustic stapedius muscle reflex in mercury-exposed Andean children and adults.

CONCLUSION: The results suggested mercury (Hg)-induced anomalies in the brainstem-mediated acoustic stapedius muscle reflex in children. OBJECTIVES: Hg exposure has been associated with hearing impairment and brainstem anomalies. Acoustic stapedius reflex (ASR) thresholds, growth functions, decay/adaptation times, and behavioral auditory thresholds were used to screen Andean children and adults for Hg-induced auditory brainstem and facial nerve impairment. METHODS: Fifty-one participants, which included 22 children (aged 6-17 years) and 29 adults (aged 19-83 years) living in gold mining areas of Ecuador where Hg is widely used in amalgamation, were screened using ASR immittance procedures. RESULTS: Mean blood mercury (HgB) level in the children was 15.6 µg/L (SD, 21.3; median, 7 µg/L; range, 2.0-89 µg/L), and in the adults 8.5 µg/L (SD, 7.1; median, 6 µg/L; range, 2.0-32 µg/L). Mean contralateral ASR thresholds (ASRT) for the screening frequency of 2000 Hz in the children (39 ears) was 92.9 dB HL (SD, 6.1; range, 80-105 dB HL), and in the adults (53 ears) 90.0 dB HL (SD, 6.4; range, 65-105 dB HL). The ASRT in the children increased significantly with HgB level (rho = 0.433; p = 0.008).

Cochlear hearing loss in patients with Laron syndrome.

The aim of this prospective clinical study was to test auditory function in patients with Laron syndrome, either untreated or treated with insulin-like growth factor I (IGF-I). The study group consisted of 11 patients with Laron syndrome: 5 untreated adults, 5 children and young adults treated with replacement IGF-I starting at bone age <2 years, and 1 adolescent who started replacement therapy at bone age 4.6 years. The auditory evaluation included pure tone and speech audiometry, tympanometry and acoustic reflexes, otoacoustic emissions, loudness dynamics, auditory brain stem responses and a hyperacusis questionnaire. All untreated patients and the patient who started treatment late had various degrees of sensorineural hearing loss and auditory hypersensitivity; acoustic middle ear reflexes were absent in most of them. All treated children had normal hearing and no auditory hypersensitivity; most had recordable middle ear acoustic reflexes. In conclusion, auditory defects seem to be associated with Laron syndrome and may be prevented by starting treatment with IGF-I at an early developmental age.

Assessment of auditory brainstem function in lead-exposed children using stapedius muscle reflexes.

The purpose of this study was to investigate the neurological integrity and physiological status of the auditory brainstem tracts and nuclei in children with chronic lead (Pb) exposure using non-invasive acoustic stapedius reflex (ASR) measurements of afferent and efferent-neuromuscular auditory function. Following audiological examinations, uncrossed (ipsilateral) and crossed (contralateral) brainstem ASR responses were evoked by pure tone (500, 1000, and 2000 Hz), and broadband noise (bandwidth: 125-4000 Hz) stimulus activators. The ASR threshold (ASRT), amplitude growth, and decay/fatigue were measured by conventional clinical middle ear immittance methods in a group of Andean children (age range: 2-18 years) with a history of chronic environmental Pb exposure from occupational Pb glazing. Blood lead (PbB) levels of the study group (n=117) ranged from 4.0 to 83.7 µg/dL with a mean PbB level of 33.5 µg/dL (SD: 23.6; median: 33.0: CDC III Classification). The PbB distribution data indicated that 77.8% (n=91) of the children had PbB levels greater than the CDC action line of 10 µg/dL. Repeatable, normal ASRTs were elicited for ipsilateral (mean: ≤90 dB HL) and contralateral (mean: ≤97 dB HL) stimulation for each acoustic activator. Spearman Rho correlation analysis indicated no significant association between PbB level and ipsilateral or contralateral ASRT for any of the stimulus activators. The ASR amplitude growth results showed typical growth functions with no Pb-associated aberrations. No statistical association was found between ASR decay/adaptation (ASRD) and PbB level for any of the stimulus activators. The results of stapedius muscle reflex testing using several stimulus activators showed no significant relationship between PbB level and the physiological integrity of the auditory brainstem mediated ASR responses in children with chronic Pb exposure and elevated PbB levels.

[The delayed sensitization of CRH response developed after chronic variable stress on the acoustic startle reflex].

Substantial evidence indicates that brain neurons containing and secreting norepinephrine (NE) and corticotrophin-releasing hormone (CRH) are activated during stress. The acoustic startle reflex (ASR) can be enhanced by CRH neuronal activity in the central nucleus of the amygdala. Our previous study demonstrates an augmentation of the footshock-induced ASR (f-ASR) 1 day after chronic variable stress (CVS) for 13 days. In this study, to evaluate a long-term neural plasticity in NE-CRH systems after CVS, we examined f-ASR 1, 8 or 15 days after CVS. The augmented magnitude of the f-ASR 15 day after CVS was potentiated and delayed compared with that 1 day after CVS. The delayed augmentation of f-ASR was inhibited by repeated treatment with desipramine, maprotiline or paroxetine for 14 days after CVS. A single treatment with any antidepressant agent had no influence the f-ASR while a marked inhibition by a single dose of alprazolam, CRH1-receptor antagonist, prazosin and propranolol was observed. The decreased tyrosine hydroxylase activity in the locus coeruleus and the beta-adrenoceptor down-regulation in the amygdaloid complex might be involved in the inhibiton of the delayed augmentation of f-ASR by repeated antidepressant treatment, leading to the possibility that the delayed sensitization of CRH response to stress after CVS might contribute to the biological mechanism underlying the formation of pathological states such as anxiety and depressive disorders.

Acetylcholine receptor and behavioral deficits in mice lacking apolipoprotein E.

Apolipoprotein E (apoE) is involved in the risk to develop sporadic Alzheimer's disease (AD). Since impaired central acetylcholine (ACh) function is a hallmark of AD, apoE may influence ACh function by modulating muscarinic ACh receptors (mAChRs). To test this hypothesis, mAChR binding was measured in mice lacking apoE and wild type C57BL/6J mice. Mice were also tested on the pre-pulse inhibition, delay eyeblink classical conditioning, and 5-choice serial reaction time tasks (5-SRTT), which are all modulated by ACh transmission. Mice were also given scopolamine to challenge central mAChR function. Compared to wild type mice, mice lacking apoE had reduced number of cortical and hippocampal mAChRs. Scopolamine had a small effect on delay eyeblink classical conditioning in wild type mice but a large effect in mice lacking apoE. Mice lacking apoE were also unable to acquire performance on the 5-SRTT. These results support a role for apoE in ACh function and suggest that modulation of cortical and hippocampal mAChRs might contribute to genotype differences in scopolamine sensitivity and task acquisition. Impaired apoE functioning may result in cholinergic deficits that contribute to the cognitive impairments seen in AD.