Biomedical subjects

D M Caspary

Publications and source records attributed to D M Caspary.

At least 19 recordsLinked to original sources

PubMed1992

GABAA receptor antagonist bicuculline alters response properties of posteroventral cochlear nucleus neurons.

1. The role of GABAergic inhibitory inputs onto posteroventral cochlear nucleus (PVCN) neurons in the anesthetized chinchilla was investigated through iontophoretic application of the GABAA receptor agonist muscimol and the GABAA receptor antagonist bicuculline. The majority of the neurons studied displayed phasic temporal response patterns. 2. All the neurons were sensitive to bicuculline and displayed an increase in discharge rate, which was greatest during the post-onset portion of the response. Most of the tested neurons were also sensitive to muscimol, which appeared to mimic the putative effect of endogenous GABA. 3. Bicuculline reduced the average first-spike latency and the average variability of the first-spike latency. Muscimol had the opposite effect. 4. Bicuculline did not significantly alter the threshold but rather increased discharge rate at suprathreshold intensities. 5. The width of the excitatory response area was not significantly increased by application of bicuculline. The increase in discharge rate occurred within the units' excitatory response areas. 6. The shape of the rate-intensity functions was not altered by bicuculline application. 7. We conclude that GABAergic inhibitory inputs control the post-onset discharge rate of some PVCN neurons. They may suppress tonic activity, resulting in more phasic discharge patterns.

Acoustic Stimulation↗

PubMed1991

Involvement of GABA in acoustically-evoked inhibition in inferior colliculus neurons.

Most criteria for establishing GABA as an inhibitory neurotransmitter in the central nucleus of inferior colliculus (ICc) have been satisfied, but the role of GABA in acoustic coding in ICc is not established. The present study examined this issue by evaluating the effects of iontophoretic application of agents that alter activity at GABA receptors on potential forms of acoustically-evoked inhibition in ICc neurons. Application of the GABAA antagonist, bicuculline, selectively blocked the firing reduction at high intensities observed during non-monotonic rate-intensity functions in ICc neurons. Binaural inhibition was selectively blocked by bicuculline and increased by nipecotic acid. Application of GABA, nipecotic acid (GABA uptake inhibitor) and a benzodiazepine (flurazepam), which enhances the action of GABA, increased the duration and intensity of ipsilateral inhibition and response pause, while bicuculline blocked these acoustically-evoked inhibitory events. Offset inhibition was increased by nipecotic acid application and reduced by bicuculline with the appearance of an offset peak. The present data support an important role for GABA as a neurotransmitter, mediating, in part, non-monotonicity, binaural inhibition, response pause and offset inhibition in ICc neurons. Alterations of these GABA-mediated inhibitory phenomena may occur in auditory dysfunctions observed with aging and audiogenic seizures.

Acoustic Stimulation↗

PubMed1991

Low-frequency neurons in the lateral superior olive exhibit phase-sensitive binaural inhibition.

1. Responses of low characteristic frequency (CF) neurons in the lateral limb of the lateral superior olive (LSO) of chinchilla and rat to binaural stimuli at various interaural phase and intensity differences were examined and compared to responses from previous studies of high CF neurons. 2. Ninety-six LSO neurons from chinchillas and 10 LSO neurons from rats with CFs less than 1,200 Hz were characterized. The majority of these neurons displayed phase-locked tone-evoked temporal discharge patterns to ipsilateral CF stimuli. 3. Similar to high-CF LSO neurons, low-CF LSO neurons were excited by ipsilateral stimuli and inhibited by contralateral stimuli, with discharge rate sensitive to interaural intensity differences (IID). Discharge rate increased as ipsilateral intensity was increased and decreased as contralateral stimulus intensity was increased. 4. Binaural inhibition, inhibition of ipsilaterally evoked activity by contralateral stimuli, was dependent on interaural phase differences (IPD) in the majority of low-CF LSO neurons. Responses of phase-sensitive neurons to binaural stimuli often varied with 90 or 180 degrees changes in IPD from total inhibition to a facilitated response when compared to responses to control ipsilateral stimuli alone. 5. In summary, like high-CF LSO neurons, LSO neurons with low CFs (less than 1,200 Hz) were ipsilaterally excited and contralaterally inhibited (EI) and were sensitive to IID. Unlike most high-CF EI LSO neurons, which are not responsive when the azimuth of the stimulus is directly in front of or directly behind the animal, many low-CF LSO neurons are responsive to these stimuli.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1990

Immunocytochemical and neurochemical evidence for age-related loss of GABA in the inferior colliculus: implications for neural presbycusis.

The present study describes substantial, selective, age-related loss of the putative inhibitory neurotransmitter GABA in the central nucleus of the inferior colliculus (CIC) of rat based on immunocytochemical and neurochemical data. For immunocytochemistry, neurons in the CIC were immunolabeled using an antibody against a GABA conjugate in young adult (2- to 7-month-old) and aged (18- to 29-month-old) Fischer-344 rats. Computer-assisted morphometry was then used to generate maps of GABA-immunoreactive neurons in the CIC. The number of GABA-positive neurons was reduced 36% in the ventrolateral portion of the CIC of aged animals (93 neurons/mm2) compared to their matched young adult cohorts (145 neurons/mm2; p less than 0.01). For neurochemistry, basal and K(+)-evoked release of the endogenous amino acids GABA, glutamate (Glu), aspartate (Asp), and tyrosine (Tyr) from micropunches of the CIC were measured in 8 age-paired animals from the 2 age groups using high-performance liquid chromatography. Overflow of radiolabeled acetylcholine (3H-ACh) was also determined. In both age groups, K(+)-evoked release of GABA, Glu, Asp, and 3H-ACh from CIC punches was significantly enhanced above basal efflux (+200, +215, +163, and +309%, respectively), while Tyr release was unchanged. Evoked release of 3H-ACh and all amino acids except Tyr showed substantial Ca2+ dependence. A significant (p less than 0.05) age-related reduction in both basal (-35%) and K(+)-stimulated (-42%) efflux of GABA from the CIC was observed. A corresponding decrease in postrelease tissue content of GABA in CIC of aged rats was observed (-30%, p less than 0.05). In contrast, tissue content as well as basal and evoked release of Glu, Asp, Tyr, and 3H-ACh was similar between the 2 age groups. Age-related GABA neurochemical changes described in the CIC were not observed in the release of the other amino acids or 3H-ACh from either the rostral ventrolateral medulla or the somatosensory cortex, 2 brain regions involved in processing non-auditory sensory input. These data support previous findings that GABA, Glu, Asp, and ACh may subserve neurotransmission in the CIC. Additionally, these data provide clear evidence for a pronounced, region- and neurotransmitter-selective, age-related reduction of GABA in the CIC. These findings support the hypothesis that impairment of inhibitory GABAergic neurotransmission in the CIC may contribute to abnormal auditory perception and processing seen in neural presbycusis.

Acetylcholine↗

PubMed1989

Non-N-methyl-D-aspartate receptors may mediate ipsilateral excitation at lateral superior olivary synapses.

Principal cells of the lateral superior olivary nucleus (LSO) are thought to receive a direct excitatory input from spherical bushy cells located in the ipsilateral ventral cochlear nucleus (VCN) and an indirect input from the contralateral VCN globular bushy cells via a secure synapse in the medial nucleus of the trapezoid body (MNTB). MNTB bushy cells project to the somata and proximal dendrites of LSO principal cells. LSO neurons display phasic 'chopper' temporal response patterns to ipsilateral tone-burst stimuli at characteristic frequency (CF), while binaural stimuli suppress this ipsilaterally evoked activity. This suppression is sensitive to interaural differences in intensity, phase and time, suggesting a role for these neurons in the localization of sound in space. In the present study, the nature of the neurotransmitter mediating fast ipsilateral excitation of LSO neurons was examined using iontophoretic application of excitant amino acid (EAA) agonists and antagonists. N-methyl-D-aspartate (NMDA) and quisqualate (QUIS) were used as agonists, while the selective NMDA receptor antagonist D. L-2-amino-5-phosphonovaleric acid (APV), and the non-selective receptor EAA antagonist cis-2,3-piperidine-dicarboxylic acid (PDA) were used to study ipsilaterally evoked neuronal responses. In 3 additional experiments the selective non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) replaced PDA. Ipsilateral, tone-evoked and spontaneous activities were generally enhanced by EAA agonists while partial blockade of tone-evoked, ipsilateral excitation was observed with EAA antagonists. Both PDA and DNQX more effectively blocked ipsilateral tone-evoked excitations and spontaneous activity than did the NMDA-receptor antagonist, APV.(ABSTRACT TRUNCATED AT 250 WORDS)

Acoustic Stimulation↗

PubMed1989

On the role of GABA as an inhibitory neurotransmitter in inferior colliculus neurons: iontophoretic studies.

Significant neurochemical, immunocytochemical, and ligand binding studies support a role for GABA as an inhibitory neurotransmitter in the inferior colliculus (IC). The present study attempted to satisfy some of the remaining criteria for establishing transmitter identity by utilizing iontophoretic application onto IC neurons of agents affecting the action of gamma-aminobutyric acid (GABA). The agents examined include GABA, a GABAB agonist (baclofen), a GABAA antagonist (bicuculline), a GABA uptake inhibitor (nipecotic acid), and a benzodiazepine (flurazepam), thought to exert its actions on the GABA receptor complex. Application of GABA results in inhibition of the spontaneous firing and acoustically evoked responses of inferior colliculus neurons. The inhibitory effect of GABA is enhanced by the simultaneous application of nipecotic acid or flurazepam. These agents as well as baclofen produce firing reductions when applied alone in higher doses. The effect of GABA can be blocked by application of bicuculline, and acoustically evoked (binaural) inhibition can also be selectively blocked by low doses of this GABAA antagonist. These data along with previous studies utilizing different techniques fulfill many of the criteria for establishment of GABA as an important inhibitory transmitter in the inferior colliculus.

Acoustic Stimulation↗

PubMed1989

Effects of excitant amino acids on acoustic responses of inferior colliculus neurons.

Iontophoretic application of the excitant amino acids (EAAs), glutamate, aspartate and N-methyl-D-aspartate (NMDA) resulted in increased acoustically evoked and spontaneous firing of most neurons in the central nucleus of inferior colliculus (ICC). The excitatory effects of these EAAs were blocked by simultaneous application of EAA antagonists which selectively block the NMDA receptor subtype, 2-amino-5-phosphonovalerate or D-alpha-aminoadipate and to a lesser extent with non-selective EAA antagonists, such as glutamic acid diethylester. Application of NMDA receptor-selective EAA antagonists alone greatly reduced the firing of most ICC neurons examined, but non-selective EAA antagonists either increased or produced little change in firing of most ICC neurons examined. In this and previous studies cholinergic agonists were found to increase the firing of ICC neurons, but the cholinergic agonists were less effective in exciting ICC neurons than EAA agonists. Cholinergic antagonists in a previous study were considerably less effective in inhibiting the discharge of ICC neurons than were the EAA antagonists in the present study. These results, in conjunction with previous neurochemical and anatomical localization studies, support a possible role of an EAA as a candidate for afferent excitatory transmitter in neurons of the inferior colliculus.

2-Amino-5-phosphonovalerate↗

PubMed1989

Synaptic potentials of chinchilla lateral superior olivary neurons.

Neurons in the lateral superior olive (LSO) were characterized in vivo, by extracellular and intracellular recordings. Principal neurons of the LSO are excited by ipsilateral auditory stimuli and exhibit binaural inhibition, as observed in extracellular recordings. In subsequent intracellular recordings, ipsilateral acoustic stimuli evoked robust excitatory postsynaptic potentials (epsps), while contralateral stimuli evoked large inhibitory postsynaptic potentials (ipsps). The contralaterally evoked ipsps were reversed when the cell was polarized below resting membrane potential and when current was injected into neurons recorded with chloride-filled electrodes. The ipsp is probably a reflection of contralaterally evoked release of glycine acting through glycinergic receptors on the somata and proximal dendrites of these neurons. The properties of the epsps are consistent with data suggesting that ipsilaterally evoked excitation may be mediated by an excitatory amino acid-like substance acting through quisqualate or kainate receptors at dendritic locations.

Amino Acids↗

PubMed1989

Presbycusis.

Explore the source record for details and available documents.

Aged↗

PubMed1987

Strychnine alters the fusiform cell output from the dorsal cochlear nucleus.

Anatomical and physiological evidence suggests that fusiform cells, the major output neurons of the dorsal cochlear nucleus (DCN), receive significant inhibitory input. Fusiform cells often display strongly non-monotonic rate-intensity functions and pauser-buildup or buildup tone-evoked temporal responses, patterns which may be mediated by inhibitory neurotransmitters. Other neurons located within the fusiform cell layer or in the more superficial molecular layer display varied rate-intensity functions and temporal responses. Neurons displaying response properties characteristic of fusiform cells are sensitive to iontophoretic application of the inhibitory amino acid neurotransmitter, glycine. Application of the glycine receptor antagonist, strychnine, alters the non-monotonic portion of the rate-intensity function at doses which do not alter spontaneous activity or near-threshold tone-evoked responses. These neurons are also sensitive to GABA and the GABAB agonist, (-)-baclofen, but are insensitive to the GABAA antagonist, bicuculline. DCN neurons which display monotonic rate-intensity functions and temporal response properties different than those associated with fusiform cells are sensitive to bicuculline, (-)-baclofen, and GABA. These data suggest that a glycinergic input onto fusiform cells may control the non-monotonic nature of the response of these neurons near characteristic frequency and therefore may contribute significantly to the nature of the output of the DCN.

Acoustic Stimulation↗

PubMed1986

Inferior colliculus neuronal response abnormalities in genetically epilepsy-prone rats: evidence for a deficit of inhibition.

The genetically epilepsy-prone rat (GEPR) is abnormally susceptible to induction of seizures by acoustic stimulation. The inferior colliculus (IC) is critically important to audiogenic seizure susceptibility. The GEPR is more susceptible to induction of audiogenic seizures at 12 kHz than at other pure tone frequencies. IC neurons in the GEPR exhibit significantly elevated response thresholds and broader tuning characteristics than normal. These findings along with previous neurophysiological and anatomical data suggest that a hearing deficit occurs in the GEPR. IC neurons in the GEPR exhibit a significantly elevated incidence of a response pattern with a peak of activity at the beginning and end of the stimulus, the onset-offset response. This response pattern occurs at 12 kHz and at characteristic frequency with high stimulus intensities and may represent an afterdischarge phenomenon. The onset-offset pattern may be a manifestation of central mechanisms developed to compensate for reduced peripheral auditory input that appears to be involved in the hearing deficit of the GEPR. Such compensatory mechanisms may involve alterations of the actions of neurotransmitters of the brain-stem auditory nuclei. GABA is implicated as an inhibitory transmitter in the IC. Iontophoretic application of GABA or a benzodiazepine produces significantly less inhibition of IC neurons of the GEPR than of the normal rat. Endogenous sound-induced (binaural) inhibition which is suggested to be GABA-mediated is also significantly reduced in IC neurons of the GEPR. Iontophoresis of the GABAA antagonist, bicuculline, often converts normal response patterns in the IC to onset-offset responses seen with high incidence in GEPR IC neurons, suggesting that the decreased effectiveness of GABA may lead to the onset-offset prevalence. This reduced effectiveness of inhibition may be unable to compensate for the rise in the putative excitatory transmitter, aspartate, in IC during high intensity acoustic stimulation in the GEPR. These altered transmitter actions may be important mechanisms subserving initiation of audiogenic seizures in the genetically epilepsy-prone rat.

Acoustic Stimulation↗

PubMed1986

Neuronal response abnormalities in the inferior colliculus of the genetically epilepsy-prone rat.

The genetically epilepsy-prone (GEP) rat is susceptible to seizure induction by acoustic stimuli. The inferior colliculus (IC) has been implicated as being critically important in audiogenic seizure susceptibility based on lesion, electrical stimulation, and focal implantation experiments. The current study determined that GEP rats were most susceptible to seizure induction by pure tone bursts at 100 dB at a frequency of 12 kHz. IC neurons in the GEP rat exhibited a significantly elevated incidence of a particular response pattern at 12 kHz and at characteristic frequency. This pattern consisted of a peak at the beginning and end of the stimulus (onset-offset response). This response pattern only occurred with high intensity stimuli approximating those which induce seizures and may represent an afterdischarge phenomenon. The response threshold was significantly elevated and tuning characteristics were also significantly altered in IC neurons of GEP rats as compared to normal IC neurons. The latter two findings may be related to the deficit of hearing which is reported in the GEP rat. The increased incidence of onset-offset responses may be due to a decreased efficacy of inhibition in the GEP rat neurons as compared to normal rat neurons.

Acoustic Stimulation↗

PubMed1986

Decreased effectiveness of GABA-mediated inhibition in the inferior colliculus of the genetically epilepsy-prone rat.

The inferior colliculus (IC) is a critical site for induction of audiogenic seizures in the genetically epilepsy-prone rat (GEPR). Abnormal response properties observed in inferior colliculus neurons of that strain include a high incidence of onset-offset responses which may be a form of afterdischarge. These response abnormalities may involve altered actions of neurotransmitters in that region of the brain. GABA is implicated as a transmitter in endogenous sound-induced inhibition in the inferior colliculus. Endogenous inhibition and the actions of agents that affect GABA receptors were examined in inferior colliculus neurons in epileptic and normal rats. The iontophoretic dose (current) of GABA required to suppress neuronal firing in the epilepsy-prone rat was significantly greater than that required in neurons of the normal rat. A form of endogenous (binaural) inhibition in inferior colliculus neurons, which is proposed to be GABA-mediated, was also significantly reduced in the epilepsy-prone rat as compared with the normal rat. A benzodiazepine (flurazepam) which enhances the action of GABA in many brain sites including the inferior colliculus was significantly less effective than normal when applied iontophoretically onto the same neurons of the epilepsy-prone rat. The GABAA antagonist, bicuculline, which blocks the effect of GABA on inferior colliculus neurons, frequently induced the onset-offset response in neurons not previously exhibiting this pattern. These findings suggest that the reduction of GABA-mediated inhibition in the genetically epilepsy-prone rat may result in the increased incidence of afterdischarges in neurons of the inferior colliculus and may serve as an important mechanism of epileptogenesis in audiogenic seizures in this genetic form of epilepsy.

Animals↗

PubMed1985

Comparative effects of convulsant drugs on the sensory responses of neurons in the amygdala and brainstem reticular formation.

The sensory responses of neurons in the amygdala and mesencephalic reticular formation in the cat were enhanced following the intravenous administration of subconvulsant doses of bicuculline, strychnine, bemegride, pentylenetetrazol and physostigmine. The degree and intensity of the enhancement of the response was considerably greater in the reticular formation than in the amygdala. The latency of the response in simultaneously-recorded pairs of neurons in the amygdala and reticular formation was significantly shorter in the mesencephalic reticular formation. The enhancement induced by convulsants does not appear to be transmitter-specific, since enhancement was produced with sequential administration of convulsant drugs which affect gamma-aminobutyric acid (GABA), glycine or acetylcholine. These findings suggest that the reticular formation is involved, to a larger degree than the amygdala, in the ability of sensory stimuli to initiate generalized convulsive seizures in animals treated with these convulsant drugs. The enhancement of the response in the hippocampus and cortex, which has previously been shown to exhibit a longer latency and a lower degree of enhancement than the reticular formation, coupled with the findings in the amygdala, suggest that the reticular formation may mediate the enhancement of the response of these other regions of the brain. The spread of the enhancement of the response to other structures in the brain via the widely distributed output pathways from the reticular formation may lead to initiation of generalized seizures by a recruitment-like process, which may involve enlargement of the sensory hyperresponsive neural network of the brain until a critical neural mass is reached and initiation of seizures results.

Amygdala↗

PubMed1985

Mechanisms of sensory seizures: brain-stem neuronal response changes and convulsant drugs.

Generalized convulsive seizures can be triggered by sensory stimuli in animals treated with subthreshold levels of convulsant drugs. The sensory responses of the brain-stem reticular formation (RF) are extensively enhanced before seizure initiation with bicuculline, strychnine, pentylenetetrazol, physostigmine, and several other convulsants. The responses of RF neurons are more greatly enhanced than other nonprimary neurons in the hippocampus, amygdala, and cortex. The action of systemically administered convulsants involves direct effects on reticular neurons, because RF response enhancement is also seen with iontophoresis. RF neuronal response enhancement does not appear to involve actions of convulsants on specific neurotransmitters, because agents that act on different transmitters enhance the responses of the same RF neuron when given sequentially. Anticonvulsant drugs reverse the effects of convulsants on reticular neurons. The convulsant-induced response enhancement in the RF may involve blockade of inhibitory postsynaptic potentials and/or threshold reduction, effects observed in vitro. RF neurons may be most susceptible to convulsant action because these agents block habituation and other mechanisms that normally restrict RF neuronal responsiveness. The massive synchronization of reticular neuronal firing by sensory stimuli may induce seizures by intense output over widespread RF projection pathways analogous to the afterdischarge seizures seen with electrical stimulation of the RF.

Animals↗

PubMed1984

Effects of iontophoretic application of convulsants on the sensory responses of neurons in the brain-stem reticular formation.

Iontophoretic or pneumatic application of convulsants produced enhancement of the sensory responses of brain-stem reticular formation (RF) neurons in cat and rat. Enhanced sensory responsiveness is observed with visual, auditory, somatosensory and vibrissa manipulation following application of strychnine, bicuculline or pentylenetetrazol. The effect was not transmitter-specific, since it could be produced by sequential application of bicuculline and strychnine which are thought to affect different neurotransmitters. Intravenous administration of convulsant also enhanced the responsiveness of RF neurons which had previously been affected by application of a different convulsant. Both systemic and iontophoretic effects could be antagonized by application of GABA and glycine. These data, coupled with previous findings in primary sensory pathways, indicate that sensory response enhancement in the RF induced by intravenous administration of these convulsants is in large part due to actions on synaptic elements of reticular formation neurons.

Animals↗

PubMed1984

Baclofen reduces tone-evoked activity of cochlear nucleus neurons.

Recent evidence suggests that an excitant amino acid may be a neurotransmitter at acoustic nerve synapses in cochlear nucleus (CN). Release of excitant amino acids is reportedly reduced by baclofen, a lipophilic GABA-mimetic used to treat the spasticity of multiple sclerosis and spinal injury. Microiontophoresis of (-)baclofen suppressed spontaneous and tone-evoked activity in CN neurons. GABA inhibited the responses of most neurons responsive to (-)baclofen. However, iontophoresis of these two substances onto the same CN neuron resulted in dramatic differences in time course to maximum effect and to recovery. Onset and offset of (-)baclofen-induced firing reduction were gradual at all doses (currents), but even the highest doses rarely caused total suppression of firing. Inhibition of firing by GABA was abrupt, and total suppression was frequently observed over the range of doses used. GABA desensitization (fading) commonly occurred while the (-)baclofen response never faded. The same CN neurons were also suppressed by D-alpha-aminoadipate, which blocks certain excitatory amino acid receptors, while the GABA antagonist bicuculline had no effect on the (-)baclofen response. These findings support the hypothesis that an excitant amino acid may be a transmitter at acoustic nerve synapses in CN.

2-Aminoadipic Acid↗

PubMed1983

Bicuculline-induced enhancement of sensory responses and cross-correlations between reticular formation and cortical neurons.

The visual, auditory and somatosensory responses of neurons in the brain stem reticular formation (RF) and pericruciate cortex of the cat are enhanced by intravenous administration of subconvulsant doses of bicuculline. The degree of enhancement in RF neurons is somewhat greater in magnitude and occurs in a greater percentage of RF neurons. The latency of response is shorter in the RF than in the cortex in 70% of cases. A large percentage of simultaneously recorded RF and cortical neurons which became responsive to the same stimulus exhibited consistent convulsant-induced cross-correlations of firing which were not present before drug treatment. The latency and correlation data are consistent with the possibility that the RF may subserve the cortical enhancement. Auditory response thresholds in RF neurons are reduced by bicuculline administration. Enhancement of RF neuronal responsiveness has previously been observed with several other convulsant drugs which are thought to act on different neurotransmitters suggesting that it may reflect a general action of these agents beyond the effects on specific neurotransmitters. The bicuculline-induced correlation of firing of RF and pericruciate neurons may be involved in the mechanism of initiation of convulsant-mediated seizure generalization induced by sensory stimuli.

Animals↗