Nicotine receptor subtype-specific effects on auditory evoked oscillations and potentials

Background

Individuals with schizophrenia show increased smoking rates which may be due to a beneficial effect of nicotine on cognition and information processing. Decreased amplitude of the P50 and N100 auditory event-related potentials (ERPs) is observed in patients. Both measures show normalization following administration of nicotine. Recent studies identified an association between deficits in auditory evoked gamma oscillations and impaired information processing in schizophrenia, and there is evidence that nicotine normalizes gamma oscillations. Although the role of nicotine receptor subtypes in augmentation of ERPs has received some attention, less is known about how these receptor subtypes regulate the effect of nicotine on evoked gamma activity.

Methodology/Principal Findings

We examined the effects of nicotine, the α7 nicotine receptor antagonist methyllycaconitine (MLA) the α4β4/α4β2 nicotine receptor antagonist dihydro-beta-erythroidine (DHβE), and the α4β2 agonist AZD3480 on P20 and N40 amplitude as well as baseline and event-related gamma oscillations in mice, using electrodes in hippocampal CA3. Nicotine increased P20 amplitude, while DHβE blocked nicotine-induced enhancements in P20 amplitude. Conversely, MLA did not alter P20 amplitude either when presented alone or with nicotine. Administration of the α4β2 specific agonist AZD3480 did not alter any aspect of P20 response, suggesting that DHβE blocks the effects of nicotine through a non-α4β2 receptor specific mechanism. Nicotine and AZD3480 reduced N40 amplitude, which was blocked by both DHβE and MLA. Finally, nicotine significantly increased event-related gamma, as did AZD3480, while DHβE but not MLA blocked the effect of nicotine on event-related gamma.

Conclusions/Significance

These results support findings showing that nicotine-induced augmentation of P20 amplitude occurs via a DHβE sensitive mechanism, but suggests that this does not occur through activation of α4β2 receptors. Event-related gamma is strongly influenced by activation of α4β2, but not α7, receptor subtypes, while disruption of N40 amplitude requires the activation of multiple receptor subtypes.     

No effects of mobile phone electromagnetic field on auditory brainstem response

The present study investigated the possible effects of the electromagnetic field (EMF) emitted by an ordinary GSM mobile phone (902.4 MHz pulsed at 217 Hz) on brainstem auditory processing. Auditory brainstem responses (ABR) were recorded in 17 healthy young adults, without a mobile phone at baseline, and then with a mobile phone on the ear under EMF‐off and EMF‐on conditions. The amplitudes, latencies, and interwave intervals of the main ABR components (waves I, III, V) were compared among the three conditions. ABR waveforms showed no significant differences due to exposure, suggesting that short‐term exposure to mobile phone EMF did not affect the transmission of sensory stimuli from the cochlea up to the midbrain along the auditory nerve and brainstem auditory pathways. Bioelectromagnetics 31:48–55, 2010. © 2009 Wiley‐Liss, Inc.     

Effects of nicotine on precocious evoked auditory potentials of the rat in the presence or absence of endogenous serotonin

In the rat, nicotine bitartrate (100 micrograms/kg) by intraperitoneal route provokes modifications of the brain stem auditory evoked potentials. These changes are complex: a) decrease of the amplitude of waves IV and V, probably by fixation on nicotinic type receptors, neuronal serotonin stores being normal; b) increase of the amplitude of waves I, I' and II, more important when endogenous stores are depleted; c) increase in the latency of these waves when serotonin stores are normal.     

Development of the chloride homeostasis in the auditory brainstem

Inhibitory neurotransmission plays a substantial role in encoding of auditory cues relevant for sound localization in vertebrates. While the anatomical organization of the respective afferent auditory brainstem circuits shows remarkable similarities between mammals and birds, the properties of inhibitory neurotransmission in these neural circuits are strikingly different. In mammals, inhibition is predominantly glycinergic and endowed with fast kinetics. In birds, inhibition is mediated by gamma-Aminobutiric acid (GABA) and too slow to convey temporal information. A further prominent difference lies in the mechanism of inhibition in the respective systems. In auditory brainstem neurons of mammals, [Cl(-)](i) undergoes a developmental shift causing the actions of GABA and glycine to gradually change from depolarization to the 'classic' hyperpolarizing-inhibition before hearing onset. Contrary to this, in the mature avian auditory brainstem Cl(-) homeostasis mechanisms accurately adjust the Cl(-) gradient to enable depolarizing, but still very efficient, shunting inhibition. The present review considers the mechanisms underlying development of the Cl(-) homeostasis in the auditory system of mammals and birds and discusses some open issues that require closer attention in future studies.     

Action of thiamine on auditory evoked potentials in the guinea pig

A technique is proposed for quantifying the effects of physiologically active substances at the periphery of the auditory analyzer. It was found that applying 1×10^–11 to 1×10^–3 M thiamine to the membrane of guinea pig cochlear round window (fenestra rotunda) produces a rise in the amplitude and a reduction in the latency of the N₁ and N₂ components of auditory nerve action potentials, waves I and II of brainstem auditory evoked potentials occurring in response to an acoustic stimulus. It is suggested that this effect is produced by facilitated synaptic transmission at synapses between hair cells and spiral ganglia neurons under the action of thiamine penetrating into the cochlea.A. V. Palladin Institute of Biochemistry, Academy of Sciences of the Ukrainian SSR, Kiev. A. I. Kolomiichenko Research Institute of Otolaryngology, Ministry of Public Health of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 18, No. 5, pp. 654–660, September–October, 1986.     

Developmental nicotine exposure enhances inhibitory synaptic transmission in motor neurons and interneurons critical for normal breathing

Nicotine exposure in utero negatively affects neuronal growth, differentiation, and synaptogenesis. We used rhythmic brainstems slices and immunohistochemistry to determine how developmental nicotine exposure (DNE) alters inhibitory neurotransmission in two regions essential to normal breathing, the hypoglossal motor nucleus (XIIn), and preBötzinger complex (preBötC). We microinjected glycine or muscimol (GABA_A agonist) into the XIIn or preBötC of rhythmic brainstem slices from neonatal rats while recording from XII nerve roots to obtain XII motoneuron population activity. Injection of glycine or muscimol into the XIIn reduced XII nerve burst amplitude, while injection into the preBötC altered nerve burst frequency. These responses were exaggerated in preparations from DNE animals. Quantitative immunohistochemistry revealed a significantly higher GABA_A receptor density on XII motoneurons from DNE pups. There were no differences in GABA_A receptor density in the preBötC, and there were no differences in glycine receptor expression in either region. Nicotine, in the absence of other chemicals in tobacco smoke, alters normal development of brainstem circuits that are critical for normal breathing. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 337–354, 2016     

Intensity dependence of auditory evoked potentials in behaving cats

The intensity dependence of auditory evoked potentials (AEPs) recorded epidurally over the primary (AI) and secondary (AII) areas of the auditory cortex was studied in behaving cats during wakefulness, sleep and anesthesia. Four kHz tones of 50, 60, 70, and 80 dB SPL, presented in random order every 2 ± 0.2 s by a bone conductor, elicited clear changes of the AEP amplitudes with increasing stimulus intensity, but individual components displayed different responses curves. AEP components from the AI region showed saturation of their amplitude with stimulus intensity (P13, P34) or no amplitude increase (N19), while amplitude and intensity were linearly related in the AII area. The intensity dependence of the first positive component (P12/P13) was consistently stronger for the AEP recorded from the AI than from the AII area, while later components exhibited no difference between AI and AII. During slow wave sleep, the intensity dependence of this first positive component increased in the two areas, while that of later components decreased. Pentobarbital anesthesia abolished almost all later components and depressed the intensity dependence of the first positive component both in the AI and AII area. These results indicate that (1) clear intensity dependence of AEP exists in the cat auditory cortex and (2) this intensity dependence, especially that of the first positive AEP component, shares functional similarities to the human augmenting/reducing phenomenon in the auditory modality concerning regional differences and sleep-waking cycle.     

Age differences of event-related potentials in the perception of successive and spatial components of auditory information

The perception of spatial and successive contexts of auditory information develops during child ontogeny. We compared event-related potentials (ERPs) recorded in 5- to 6-year-old children (N = 15) and adults (N = 15) in response to a digital series with omitted digits to explore age differences in the perception of successive auditory information. In addition, ERPs in response to the sound of a falling drop presented binaurally were obtained to examine the spatial content of auditory information. The ERPs obtained from the omitted digits significantly differed in the amplitude and latency of the N200 and P300 components between adults and children, which supports the hypothesis that the perception of a successive auditory structure is less automatic in children compared to adults. Although no significant differences were found in adults, the sound of a falling drop presented to the left ears of children elicited ERPs with earlier latencies and higher amplitudes of the P300 and N400 components in the right temporal area. Stimulation of the right ear caused an increasing amplitude of the N100 component in children. Thus, the observed differences in the auditory ERPs of children and adults reflect developmental changes in the perception of spatial and successive auditory information.     

Information processing in the auditory brainstem.

The past year has seen significant advances in our understanding of the structural (circuitry and chemistry of synaptic connections) and functional characteristics of the auditory brainstem. Some of the findings that shed light on the mechanisms underlying complex auditory information processing are highlighted.     

Brainstem auditory evoked potentials in the fetal sheep, in utero

We studied brainstem auditory evoked potentials (BAEPs) in 8 fetal sheep in utero, ranging in gestational age from 105 to 142 days gestation (normal term 147 days). We could not elicit BAEPs prior to 117 days of gestation. After this age rapid maturation was seen, with three discernible peaks observed prior to 120 days and five peaks after 120 days. A significant (P less than 0.05) gestational age related fall in peak latencies and interpeak latencies was observed. The rate of stimulus presentation that could be tolerated without significant changes in wavepeak latency or amplitude also increased with advancing gestational age. In older fetuses (greater than 125 days), where a differentiated electrocorticogram (ECOG) was observed, differences were seen in latency and amplitude of several of the BAEP wavepeaks dependent upon the state. In high voltage ECOG states the amplitudes of wave IV and V were significantly (P less than 0.05) greater than in the low voltage ECOG state and the latencies of wave I, II and V were significantly (P less than 0.05) longer in low as compared to high voltage ECOG state. The BAEP, being obtainable over very short periods of time, appears to provide a useful indice of neural maturation for the sheep fetus in utero.     

The effects of nicotine administration on the pathophysiology of rat aortic wall

Abdominal aortic aneurysm (AAA) is the progressive dilation of the abdominal aorta. Nicotine is reported to be associated with the development and rupture of AAA, but the pathological effects of nicotine on normal rat aorta have not been determined. We investigated pathological changes in the aortic wall of rats caused by the administration of nicotine. Nicotine administration weakened the vascular wall, increased gelatinolytic activity and promoted the destruction of elastin and collagen in the rat abdominal aorta. There were no differences in the areas positive for matrix metalloproteinase (MMP)-2 and MMP-9 between the control and nicotine treated groups. The areas positive for MMP-12 in the nicotine group were significantly greater than for the control group. Gelatinolytic activity in the aortic wall was increased significantly in the nicotine group. Our findings suggest that MMP-12 is sensitive to nicotine exposure in rats.     

高胆红素血症新生大鼠脑干听觉诱发电位快慢成分的变化

目的：探讨高胆红素血症新生大鼠脑干听觉诱发电位快成分（FC-BAEP）和慢成分（SC-BAEP）及脑干神经元线粒体超微结构的异常变化。方法：生后7天SD大鼠随机分为对照组（C组,17只）和两个实验组（T1和T2组,各17只）。T1和T2组大鼠生后7天和10天腹腔注射2g/L胆红素溶液,第二次腹腔注射6h后随机抽出7只断头取血用微量胆红素仪检测血清胆红素,其余大鼠生后17天和20天用诱发电位仪检测FC-BAEP和SC-BAEP,生后20天灌注固定、取耳蜗核进行透射电镜观察。结果：T1和T2组大鼠于生后10天腹腔注射6h后,血清胆红素浓度明显升高;T1和T2组大鼠生后17天三种刺激重复率（10/s,40/s,80/s）引导的FC-BAEP,除Ⅱ-Ⅳ波峰间潜伏期（IPL）外,各波波峰潜伏期（PL）和IPL显著延长,且T2组大鼠各波PL较T1组显著延长;T1和T2组大鼠生后20天三种刺激重复率引导的FC-BAEP,除刺激重复率10/s和40/s引导的Ⅱ-ⅣIPL外,各波PL和IPL显著延长;T1和T2组大鼠生后17天与20天刺激重复率10/s引导的SC-BAEP的PL显著延长,且T2组大鼠生后17天SC-BAEP的PL较T1组显著延长;T1和T2组大鼠耳蜗核电镜观察可见神经元线粒体肿胀变形、膜模糊不清和嵴断裂等。结论：高胆红素血症新生大鼠FC-BAEP和SC-BAEP及脑干神经元线粒体超微结构有显著异常变化,FC-BAEP与SC-BAEP的PL和IPL是早期监测胆红素诱发的听觉和脑损伤的客观灵敏指标。     

Properties of auditory brainstem responses evoked by intra-operative electrical stimulation of the cochlear nucleus in human subjects

Electrically evoked auditory brainstem response (EABR) testing can aid placement of the stimulating electrodes during surgical implantation of an auditory brainstem implant (ABI). To facilitate efficient testing, this study of EABR properties examined the effects of various stimulating and recording parameters on the magnitude and clarity of the EABRs obtained from 9 successive ABI patients during intra-operative monitoring. Both stimulus polarities elicited EABRs; the response waveforms were similar and no significant differences between the latencies were found. Stimulus-response relationships displayed thresholds and non-linear growth, characteristic of neural activity, and provided a stimulus amplitude that elicited readily detectable EABRs in all subjects. The stimulus rate could be increased without degrading the EABRs, but usually 50 Hz was used with a 10 ms sampling sweep so that muscle responses, which occurred later than EABRs, could be detected. When 3 stimulating electrodes in a line were tested, the pair with the largest separation consistently provided the largest response. A recording filter passband of 10–3000 Hz was useful for attenuating interference signals because there is negligible energy in the EABR at frequencies above 3 kHz, but there is some energy below 100 Hz.     

Deficiency of neural recognition molecule NB-2 affects the development of glutamatergic auditory pathways from the ventral cochlear nucleus to the superior olivary complex in mouse

Neural recognition molecule NB-2/contactin 5 is expressed transiently during the first postnatal week in glutamatergic neurons of the central auditory system. Here, we investigated the effect of NB-2 deficiency on the auditory brainstem in mouse. While almost all principal neurons are wrapped with the calyces of Held in the medial nucleus of the trapezoid body (MNTB) in wild type, 8% of principal neurons in NB-2 knockout (KO) mice lack the calyces of Held at postnatal day (P) 6. At P10 and P15, apoptotic principal neurons were detected in NB-2 KO mice, but not in wild type. Apoptotic cells were also increased in the ventral cochlear nucleus (VCN) of NB-2 KO mice, which contains bushy neurons projecting to the MNTB and the lateral superior olive (LSO). At the age of 1 month, the number of principal neurons in the MNTB and of glutamatergic synapses in the LSO was reduced in NB-2 KO mice. Finally, interpeak latencies for auditory brainstem response waves II-III and III-IV were significantly increased in NB-2 KO mice. Together, these findings suggest that NB-2 deficiency causes a deficit in synapse formation and then induces apoptosis in MNTB and VCN neurons, affecting auditory brainstem function.     

Identification of auditory brainstem responses

Auditory brainstem evoked responses are routinely used in audiology and otoneurology. An automatic method can be used to roughly classify the responses into probably normal, probably abnormal, and uncertain cases. Interpretation of the auditory brainstem response is a multistage process. Essential tasks are to detect individual peaks in the waveform and to choose representatives examples as medically interesting Jewett components. Our method is based on the comparison of detected peaks and normal values by means of an evaluation function, choosing representatives so that the values of this function will be maximized. We have studied the effects of some evaluation functions on the ability to correctly classify an evoked response. It turns out that the choice of an appropriate evaluation function is crucial in some problematic cases.     

A dipole localization method in analyzing the auditory brain-stem evoked potential]

The localization of generators of brainstem auditory evoked response (BAER) has been studied in one patient using the method of dipole localization based on the spatial distribution of BAER over the surface of the head. It has been found that in formation of all BAER waves the activity of several generators overlaps. It is especially marked for the peaks I', II', III and III'--their potential distribution can not be described by single-dipole model, thus preventing the defining of their generation site. Distribution of potential for other peaks corresponds to the single-dipole model. The coordinates of the equivalent sources of these peaks are in the vicinity of the auditory structures: I--near the distal part of the auditory nerve, II--near the auditory nerve in the place of its entering the brainstem, V--near contralateral auditory pontine structures, V--near lateral lemniscus while V', VI and VI'--near mesencephalic auditory structures.     

EphB signaling regulates target innervation in the developing and deafferented auditory brainstem

Precision in auditory brainstem connectivity underlies sound localization. Cochlear activity is transmitted to the ventral cochlear nucleus (VCN) in the mammalian brainstem via the auditory nerve. VCN globular bushy cells project to the contralateral medial nucleus of the trapezoid body (MNTB), where specialized axons terminals, the calyces of Held, encapsulate MNTB principal neurons. The VCN-MNTB pathway is an essential component of the circuitry used to compute interaural intensity differences that are used for localizing sounds. When input from one ear is removed during early postnatal development, auditory brainstem circuitry displays robust anatomical plasticity. The molecular mechanisms that control the development of auditory brainstem circuitry and the developmental plasticity of these pathways are poorly understood. In this study we examined the role of EphB signaling in the development of the VCN-MNTB projection and in the reorganization of this pathway after unilateral deafferentation. We found that EphB2 and EphB3 reverse signaling are critical for the normal development of the projection from VCN to MNTB, but that successful circuit assembly most likely relies upon the coordinated function of many EphB proteins. We have also found that ephrin-B reverse signaling repels induced projections to the ipsilateral MNTB after unilateral deafferentation, suggesting that similar mechanisms regulate these two processes.     

Effects of long-term heat exposure on the auditory nerve-brainstem evoked responses

1. 1.|The purpose of this study was to determine whether chronic latency changes were induced in the auditory nerve-brainstem potentials (ABR) during long-term heat exposure (acclimation).

2. 2.|Latency prolongations of the ABR were observed during acute (5 days) heat exposure. This was followed by a shortening of latencies and amplitude elevation after long-term (2 months) heat exposure (acclimation).

3. 3.|It was concluded that long-term exposure to heat induces chronic changes in nervous activity.

The detrimental effects of potassium bromate and thioglycolate on auditory brainstem response of guinea pigs

Potassium bromate (KBrO3) is known to be an oxidizing agent that is used not only as a food additive, mainly in the bread-making process, but also as a neutralizer in thioglycolate containing hair curling set. Although it has been shown that bromate poisoning could cause severe and irreversible sensorineural hearing loss as well as renal failure, the action mechanism of bromate-induced otoneurotoxicity especially its combination with thioglycolate remains to be studied. In this study, we attempted to investigate the toxic effects of KBrO3 in combination with or without thioglycolate on the auditory brainstem response (ABR) system in the guinea-pigs which was claimed to be very susceptible to the xenobiotics. In a preliminary test, we have found that after consecutive 2 weeks administration, KBrO3 caused a significant prolongation of wave I-III and the interwave latencies of ABR as well as significantly elevated the threshold of hearing, suggesting that the conduction velocity of the peripheral auditory nerve was delayed. By contrast, the absolute latency of wave IV/V and the interwave latency of wave III-V were not significantly prolonged, suggesting that KBrO3 had no effect on the brainstem. This oto-neurotoxic effect of KBrO3 was markedly enhanced by combining with thioglycolate. Our data also indicated that KBrO3 combined with thioglycolate but not KBrO3 alone prominantly caused a decrease of body weight. However, enzymatic activities (including Na+/K+-ATPase and Ca2+-ATPase) and the level of nitric oxide (NO) was significantly affected in the brainstem. Based on these findings, we tentatively conclude that whether KBrO3 alone or KBrO3 combined with thioglycolate induced oto-neurotoxicity majorly through the peripheral auditory nerve rather than via the central brainstem intoxication.     

Differential effects of nicotine and aging on splenocyte proliferation and the production of Th1- versus Th2-type cytokines

Nicotine has a multitude of biological actions in the central and peripheral nervous systems where nicotinic acetylcholine receptors are found. Nicotinic acetylcholine receptors have also been identified on immune cells, but the effects of nicotine on immune responses are not well characterized. These studies tested the hypotheses that nicotine has an effect on both T-lymphocyte proliferation and the production of cytokines by activated T cells, processes that are necessary for effective T-cell-mediated immune responses. In addition, the effects of nicotine on these immune responses in aging animals and the effects of nicotine exposure prior to immunostimulation were investigated. Murine splenocytes were exposed to nicotine and stimulated with concanavalin A (ConA). The highest concentration of nicotine (128 microg/ml) significantly depressed proliferation of T cells both when nicotine and ConA were added concurrently and when nicotine was added 3 hr prior to ConA. Nicotine, added concurrently with ConA at concentrations between 0. 25 and 64 microg/ml, significantly inhibited the production of IL-10 by splenocytes from young adult mice, whereas the inhibition of production of IL-10 by splenocytes from old mice was significantly inhibited, but the response was more variable, depending on the nicotine concentration. In contrast, the production of IFN-gamma by splenocytes from either young adult or old mice was not affected when nicotine (0.016-64 microg/ml) was added concurrently with ConA. Pre-exposure to 1 microg/ml of nicotine for 3 hr significantly enhanced the production of IFN-gamma by splenocytes from young adult mice, whereas pre-exposure to 0.016 microg/ml of nicotine tended to but did not significantly enhance IFN-gamma production. Nicotine is now being used as an over-the-counter drug by people who differ in age and general immunocompetence. Therefore, the effects of nicotine on immune responses, independent from the effects of the other chemicals found in tobacco, need to be investigated.