Decrease In Transmitter Release Research Articles

Activation of D2-Like Dopamine Receptors Reduces Synaptic Inputs to Striatal Cholinergic Interneurons

Dopamine (DA) plays a crucial role in the modulation of striatal function. Striatal cholinergic interneurons represent an important synaptic target of dopaminergic fibers arising from the substantia nigra and cortical glutamatergic inputs. By means of an electrophysiological approach from corticostriatal slices, we isolated three distinct synaptic inputs to cholinergic interneurons: glutamate-mediated EPSPs, GABAA-mediated potentials, and Acetylcholine (ACh)-mediated IPSPs. We therefore explored whether DA controls the striatal cholinergic activity through the modulation of these synaptic potentials. We found that SKF38393, a D1-like receptor agonist, induced a membrane depolarization (also see Aosaki et al., 1998) but had no effects on glutamatergic, GABAergic, and cholinergic synaptic potentials. Conversely, D2-like DA receptor activation by quinpirole inhibited both GABAA and cholinergic synaptic potentials. These effects of quinpirole were mimicked by omega-conotoxin GVIA, blocker of N-type calcium channels. The lack of effect both on the intrinsic membrane properties and on exogenously applied GABA and ACh by quinpirole supports a presynaptic site of action for the D2-like receptor-mediated inhibition. Moreover, the quinpirole-induced decrease in amplitude was accompanied by an increase in paired pulse facilitation ratio (EPSP2/EPSP1), an index of a decrease in transmitter release. Our findings demonstrate that DA modulates the excitability of cholinergic interneurons through either an excitatory D1-like-mediated postsynaptic mechanism or a presynaptic inhibition of the GABAergic and cholinergic inhibitory synaptic potentials.

Age-related changes in synaptic function: analysis of the effect of dietary supplementation with ω-3 fatty acids

Depolarization-induced transmitter release in synaptosomes prepared from the hippocampus of aged rats is decreased compared with release from young animals. Although the underlying cause of this deficit is not known, some evidence suggests that increased membrane rigidity may contribute to these age-related synaptic changes. One possible consequence of the decreased transmitter release in the hippocampus of aged rats is a reduced ability to sustain long-term potentiation in perforant path–granule cell synapses, a pathway in which maintenance of long-term potentiation and increased glutamate release have been coupled. The observation that there is an age-dependent impairment in long-term potentiation is consistent with this view. If the age-related deficits in release and long-term potentiation are a consequence of increased membrane rigidity, it must be predicted that any manoeuvre which reverses membrane rigidity should reverse these functional deficits. In the present study, we investigated the effect of dietary manipulation of aged rats with ω-3 fatty acids on synaptic function. The data obtained indicate that an eight-week modified feeding schedule reversed the age-related impairments in long-term potentiation and depolarization-induced glutamate transmitter release. We also report that the concentrations of both docosahexanoic acid and arachidonic acid, two main polyunsaturated fatty acids in neuronal membranes, were decreased in the hippocampus of aged rats, and were restored by dietary manipulation. The data are consistent with the hypothesis that these deficits results from a change in membrane composition.

Presynaptic origin of paired-pulse depression at climbing fibre-Purkinje cell synapses in the rat cerebellum.

1. Climbing fibre-mediated excitatory postsynaptic potentials (CF-EPSPs) or currents (CF-EPSCs) were recorded from Purkinje cells in rat cerebellar slices using the whole-cell recording technique. 2. Climbing fibre responses displayed prominent paired-pulse depression (PPD). In the current-clamp recording mode, PPD resulted in a decreased number of spikelets in the second complex spike of the pair, and depression of the after-depolarization and after-hyperpolarization. 3. The mechanism of PPD was examined under voltage clamp. Manipulations that reduce transmitter release significantly affected PPD. These included lowering extracellular Ca2+ concentration and bath application of baclofen or adenosine. 4. Changing the number of stimulated climbing fibres, equivalent to changing the number of release sites, had no effect on PPD. 5. Selective manipulations of postsynaptic responsiveness had no effect on PPD. These included partial blockade of CF-EPSCs by a non-NMDA receptor antagonist, 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX), and changing the holding potential. 6. A rapidly dissociating AMPA receptor antagonist, 2,3-cis-piperidine dicarboxylic acid, inhibited the second CF-EPSC of the pair proportionately more than the first, suggesting that presynaptic release by the second pulse is decreased. 7. PPD at interstimulus intervals of 50 ms or longer (up to 3000 ms) was not significantly affected by manipulations that change postsynaptic glutamate receptor desensitization. 8. Blockade of metabotropic glutamate, GABAB and adenosine receptors had no effect on PPD, suggesting that presynaptic autoreceptors do not contribute to PPD. 9. These results indicate that decreased transmitter release is a major cause of PPD at cerebellar climbing fibre-Purkinje cell synapses.

Nociceptin Inhibits T-Type Ca2+Channel Current in Rat Sensory Neurons by a G-Protein-Independent Mechanism

Nociceptin (orphanin FQ) is a novel, opioid-like, heptadecapeptide that is an endogenous ligand for the opioid receptor-like (ORL1) receptor. Unlike classical opioids, nociceptin can produce hyperalgesia when injected intracerebroventricularly into mice. Despite this, nociceptin has been reported to decrease transmitter release, activate an inwardly rectifying K+ conductance, and suppress high-voltage-activated Ca2+ channel conductances (HVA gCa) in much the same way as micro-, delta-, and kappa-opioids. We report an action of nociceptin that is not shared by morphine: the suppression of low-voltage-activated, transient calcium (barium) current (IBa,T) in acutely dissociated rat dorsal root ganglion (DRG) neurons (EC50 = 100 nM). This effect was reflected as inhibition of bursts of action potentials that can be evoked in "medium-sized" DRG neurons. Experiments with GTP-gamma-S (100 microM), GDP-beta-S (2 mM), or aluminum fluoride (AlF3) (100 microM) in the patch pipette failed to provide evidence for G-protein involvement in nociceptin-induced IBa,T suppression. By contrast, both morphine and nociceptin suppressed HVA gCa, and the latter response was affected by intracellular GTP-gamma-S, GDP-beta-S, and AlF3 in ways that confirmed G-protein involvement. The selective effect of nociceptin on IBa,T may therefore be relevant to understanding why its behavioral actions differ from those of other opioids. This G-protein-independent effect of the action of nociceptin may reflect a new general mechanism of action for opioid peptides within the nervous system.

Synaptic depression: a dynamic regulator of synaptic communication with varied functional roles

It appears that a bewildering array of processes can contribute to the mechanism of synaptic depression. Markram and Tsodyks argued that the depression they observed in cortical cells was probably dependent on the amount of transmitter released, as indicated in the model (Fig. 1Fig. 1), although changes in the affinity of postsynaptic glutamate receptors could not be excluded[9xMarkram, H. and Tsodyks, M. Nature. 1996; 882: 807–810Crossref | Scopus (510)See all References[9]. However, in studies of the visual cortex several postsynaptic factors have been eliminated because synaptic depression at excitatory synapses is unaffected by postsynaptic receptor blockade with the non-NMDA receptor antagonist CNQX or by reduction of receptor desensitization by cyclohexemide (J.A. Varela et al., unpublished observations). In developing muscle afferent–motoneuron contacts a presynaptic mechanism for depression has also been implicated because depression is abolished when transmitter release is decreased by low extracellular Ca2+ concentrations or bath-application of the GABAB agonist, baclofen[5xLev-Tov, A. and Pinco, M. J. Physiol. 1992; 447: 149–169Crossref | PubMedSee all References[5]. In cultured spinal cord neurons transmitter depletion is probably also responsible for synaptic depression at some synapses. However, at other synapses in such cultures, the depression might be due to failure of the presynaptic action potential to invade all of the terminals[6xStreit, J., Luscher, C., and Luscher, H-R. J. Neurophysiol. 1992; 68: 1793–1803PubMedSee all References[6]. It has also been proposed that synaptic depression might be caused by a form of negative feedback. This can occur if excess transmitter leaks from synaptic sites to engage presynaptic autoreceptors which decrease transmitter release[8xDeisz, R.A. and Prince, D.A. J. Physiol. 1989; 412: 513–541PubMedSee all References, 21xScanziani, M. et al. Nature. 1997; 385: 630–634Crossref | PubMed | Scopus (357)See all References], or by an activity-dependent reduction in the presynaptic calcium currents responsible for transmitter release[22xJia, M. and Nelson, P.G. J. Neurophysiol. 1986; 56: 1257–1267PubMedSee all References[22]. Finally, alterations in the sensitivity of postsynaptic receptors have also been implicated in synaptic depression[23xNumann, R.E. and Wong, R.K. Neurosci. Lett. 1984; 47: 289–294Crossref | PubMed | Scopus (58)See all References[23].It should be clear from this review that synaptic depression has the potential to be an important contributor to the properties and function of networks. But are these interesting properties actually engaged in active networks? This will be a difficult question to answer because it will require modifying the degree of synaptic depression within a network and documenting the effects on the network output. This may be easier to accomplish in rhythmically active networks whose output can be easily measured. It will be considerably more difficult to establish whether or not synaptic depression actually enhances the dynamic sensitivity of networks, both for experimental reasons and because we do not know how such information is actually used in functioning networks.Finally, it will be important in future studies to establish whether synaptic depression is actively regulated by the nervous system and whether or not its effects can be modified by events in the postsynaptic cell. For example, it is possible that active conductances in dendrites might be capable of compensating or modifying the effects of depression at some synapses.Perhaps many different classes of synapse can express both depression and facilitation. Certainly, there is evidence that both processes can be co-expressed at the same synapse. Can the nervous system control the relative expression of either process at individual synapses? Is synaptic depression a property that is regulated retrogradely by the postsynaptic cell, as has been proposed for developing synapses in the spinal cord[24xSeebach, B.S. and Mendell, L.M. J. Neurophysiol. 1996; 76: 3875–3885PubMedSee all References[24]?

Protein kinase C and transmitter release.

1. Protein kinase C (PKC) is an important second messenger-activated enzyme. In noradrenergic nerves it appears to be tonically activated by diacylglycerol (DAG) to facilitate transmitter release and the steps in this involve activation of phospholipase C, generation of DAG and activation of PKC. It is suggested that the subsequent facilitation of transmitter release is due to the phosphorylation of proteins involved in the release process distal to Ca2+ entry, presumably those involved in vesicle dynamics. 2. There are differences between central noradrenergic neurons and sympathetic nerves. In central neurons PKC appears to be tonically active and its inhibition results in a decrease in noradrenaline release under most, if not all, conditions. 3. In sympathetic nerves PKC inhibitors only decrease transmitter release during high-frequency stimulation and not during low-frequency stimulation. At high frequency there is a gradual increase in the effect of PKC inhibitors on transmitter release during the first 15 s of a stimulation train. It is suggested that this is due to a progressive rise in intracellular Ca2+ and a consequent activation of PKC. 4. Activation of PKC by phorbol esters produces a large enhancement in action potential-evoked noradrenaline release in both the central nervous system and in peripheral tissues. The structural requirements of the phorbol esters for maximal effect suggest that the phorbol esters must access the interior of the nerve terminal to activate PKC and the neural membrane acts as a barrier for highly lipophilic phorbol esters, thereby reducing their activity. Activation of PKC represents one of the most powerful ways to enhance transmitter release and may have therapeutic potential.

Membrane delimited and intracellular soluble pathways in the somatostatin modulation of ACH release

The signal transduction cascade between the activation of the somatostatin (SOM) receptor and modulation of transmitter release was study using Acetylcholine (ACh) release measurements and patch clamp recordings of Ca 2+ current from acutely dissociated St 40 ciliary ganglion neurons. As in intact synapses, somal ACh release was blocked by 100 nM SOM or 100 μM dibutyril cGMP, and the SOM-mediated inhibition could be reversed by 10 μM 1-NAME (a selective inhibitor of nitric oxide synthase, NOS) or 100 μM Rp-8p-CPT-cGMPs (a selective inhibitor of a cGMP protein dependent kinase, PKG). In whole cell recordings, SOM inhibition of Ca 2+ current rapidly relaxes to control levels but is sustained in perforated patch recordings which decreases cell dialysis. Inhibition of NOS or PKG in perforated patch recordings, however caused SOM effects to become transient again. We hypothesize that PKG alters the characteristics of the membrane-delimited G protein inhibition of Ca 2+ current. Therefore SOM receptors trigger a membrane-delimited signal transduction cascade that is modulated by soluble messengers, converging on voltage activated Ca 2+ channels. When both pathways are active together, SOM causes a sustained inhibition of neuronal Ca 2+ current leading to a decrease in transmitter release.

Effect of chronic morphine treatment on transmitter release from sympathetic varicosities of the mouse vas deferens.

1 Transmitter release from sympathetic varicosities of mouse vasa deferentia removed from animals which were chronically treated with morphine for 7 to 9 days has been evaluated. 2 In control preparations increasing the extracellular calcium concentration ([Ca2+]o) from 1 to 2 mM increased transmitter release by 3 fold while increasing [Ca2+]o from 6 to 8 mM increased transmitter release by about 0.9 fold. Introduction of morphine (1.0 microM) produced a uniform decrease in transmitter release, shifting the relationship between transmitter release and [Ca2+]o to the right. 3 Only sympathetic varicosities with probabilities of transmitter release greater than 0.01 were chosen for this study. In these varicosities the decrease in transmitter release induced by morphine in control preparations (bathed in [Ca2+]o 2.0 mM) was not observed following 7 to 9 days of morphine treatment. When the morphine was acutely withdrawn from these preparations transmitter release was more than 6 times the average level of transmitter release from control preparations. 4 The morphine induced increase in facilitation of transmitter release while stimulating with short trains of nerve impulses was not observed when the preparations were removed from animals which had been exposed to morphine for 7 to 9 days. When these preparations were acutely withdrawn from morphine there was a further decrease in the level of facilitation and a significant increase in depression of transmitter release when compared to control. 5 The morphine induced decrease in probability of transmitter release when naive sympathetic varicosities in vitro were bathed with morphine (1 microM) was not observed following chronic morphine treatment of the animals for 7 to 9 days. When the morphine was acutely withdrawn from chronically morphine treated preparations the underlying increase in probabilities of transmitter release of sympathetic varicosities was unmasked.

Some Effects of d-Tubocurarine Alone and Combined with Halothane or Isoflurane on Neuromuscular Transmission

The mechanisms contributing to the neuromuscular block produced by nondepolarizing muscle relaxants and inhaled anesthetics include:1) receptor blockade, 2) open or closed ion channel block, 3) decreased transmitter release, and 4) receptor desensitization. In this study we investigated the contributions of receptor and ion channel block. We used the two microelectrode voltage clamp to evaluate miniature end-plate currents (MEPCs) for amplitude and time constant of decay (tau) before and after the application of 1) d-Tubocurarine (DTC) (10-7-10-6 M) alone, and then 2) the same concentration of DTC plus 0.5% or 1.0% halothane or isoflurane delivered by passing compressed air through a flow and temperature compensated vaporizer. The electrodes were maintained in the same cell for the entire experiment. DTC alone decreased MEPC amplitude to 91.3% +/- 4.5% and 65.1% +/- 5.6% of control at 10-7 and 10-6 M, respectively. MEPC amplitude with 10-6 M DTC decreased further to 52.4% +/- 7.6% and 37.4% +/- 7.0% of control after the addition of 0.5% and 1.0% halothane, respectively. After the application of DTC 10-7 M tau was 94.7% +/- 3.1% of control and decreased to 73.7% +/- 7.1% of control with 10-6 M DTC. After the application of DTC 10 (-6) M the addition of 0.5% and 1% halothane decreased tau to 52.4% +/- 7.6% and 30.0% +/- 5.9% of control. Isoflurane produced similar changes. This study provides evidence that at least some of the augmentation of nondepolarizing relaxants by inhaled anesthetics can be explained by the additive effect of nondepolarizing muscle relaxants and inhaled anesthetics on MEPC amplitude and tau. (Anesth Analg 1995;81:763-7)

Some effects of d-tubocurarine alone and combined with halothane or isoflurane on neuromuscular transmission.

The mechanisms contributing to the neuromuscular block produced by nondepolarizing muscle relaxants and inhaled anesthetics include: 1) receptor blockade, 2) open or closed ion channel block, 3) decreased transmitter release, and 4) receptor desensitization. In this study we investigated the contributions of receptor and ion channel block. We used the two microelectrode voltage clamp to evaluate miniature end-plate currents (MEPCs) for amplitude and time constant of decay (tau) before and after the application of 1) d-Tubocurarine (DTC) (10(-7)-10(-6) M) alone, and then 2) the same concentration of DTC plus 0.5% or 1.0% halothane or isoflurane delivered by passing compressed air through a flow and temperature compensated vaporizer. The electrodes were maintained in the same cell for the entire experiment. DTC alone decreased MEPC amplitude to 91.3% +/- 4.5% and 65.1% +/- 5.6% of control at 10(-7) and 10(-6) M, respectively. MEPC amplitude with 10(-6) M DTC decreased further to 52.4% +/- 7.6% and 37.4% +/- 7.0% of control after the addition of 0.5% and 1.0% halothane, respectively. After the application of DTC 10(-7) M tau was 94.7% +/- 3.1% of control and decreased to 73.7% +/- 7.1% of control with 10(-6) M DTC. After the application of DTC 10(-6) M the addition of 0.5% and 1% halothane decreased tau to 52.4% +/- 7.6% and 30.0% +/- 5.9% of control. Isoflurane produced similar changes. This study provides evidence that at least some of the augmentation of nondepolarizing relaxants by inhaled anesthetics can be explained by the additive effect of nondepolarizing muscle relaxants and inhaled anesthetics on MEPC amplitude and tau.

Synaptic depression in visual cortex tissue slices: an in vitro model for cortical neuron adaptation.

Synaptic depression was assessed from intracellular recordings in cortical tissue slices. Evoked postsynaptic potentials exhibited synaptic depression with an exponential or double exponential decrease (time constants: < 1-30 s) in amplitude during repetitive afferent stimulation by short trains of suprathreshold stimuli. Depressed synaptic responses with an exponential time course (time constants: 10 s-8 min) during presentation of similar short trains of stimuli every 5 or 10 s. Cortical cells recorded extracellularly in cat visual cortex show similar time constants of response decrement during adaptation to moving stripes. Postsynaptic voltage- or ion-regulated conductances and chloride conductances do not appear to be involved in synaptic depression. Input resistance changes and effects of injection of chloride indicate a lack of GABAA receptor-mediated effects. Hyperpolarizing or depolarizing neurons, and pairing polarization with afferent stimulation, also did not affect synaptic depression. This distinguishes these processes from long-term depression and long-term potentiation. Our results suggest that the most likely mechanisms of synaptic depression and adaptation in cortical cells are presynaptic decrease in transmitter release and/or receptor desensitization. Short-term postsynaptic changes may also occur after synaptic depression.

Postsynaptic Induction and Presynaptic Expression of Hippocampal Long-Term Depression

Long-term depression (LTD) is an activity-dependent decrease in synaptic efficacy that together with its counterpart, long-term potentiation, is thought to be an important cellular mechanism for learning and memory in the mammalian brain. The induction of LTD in hippocampal CA1 pyramidal neurons in neonatal rats is shown to depend on postsynaptic calcium ion entry through L-type voltage-gated calcium channels paired with the activation of metabotropic glutamate receptors. Although induced postsynaptically, LTD is due to a long-term decrease in transmitter release from presynaptic terminals. This suggests that LTD is likely to require the production of a retrograde messenger.

Functional uncoupling of inhibitory interneurons plays an important role in short-term sensitization of Aplysia gill and siphon withdrawal reflex

Attempts to explain learning-associated potentiation of synaptic transmission in model systems such as withdrawal reflexes in the mollusk Aplysia or the hippocampus of vertebrates have focused on the mechanisms by which transmitter release is increased in the principal elements of the circuit. Increased transmission in neuronal networks such as the gill and siphon withdrawal reflex (GSWR) of Aplysia may, however, also be caused by a decrease of transmitter release by inhibitory interneurons. The importance and function of cholinergic inhibitory transmission in the GSWR network were investigated. Central application of the nicotinic cholinergic antagonist d-tubocurarine (d-TC) considerably potentiated gill contractions, evoked either by nerve stimulation or by tactile stimulation of the siphon. Compound EPSPs evoked in motoneurons upon siphon nerve stimulation were also significantly prolonged following application of d-TC, but were unaffected by hexamethonium, a blocker of excitatory ACh receptors in Aplysia. Recordings from excitatory interneurons showed that they received excitation followed by powerful inhibitory input upon stimulation of the siphon nerve. Application of d-TC completely blocked this rapid inhibition, thus prolonging the compound EPSPs evoked in the interneurons. These effects were obtained at a concentration of d-TC (100 microM) that almost totally blocked fast inhibitory cholinergic transmission, but was without effect on monosynaptic connections between sensory neurons and motoneurons of the reflex. Facilitation of (1) compound EPSCs in motoneurons and (2) evoked excitatory interneuronal firing was reduced in preparations already disinhibited by pretreatment with d-TC. Facilitation of sensory-motor synapses, however, was not reduced in the presence of d-TC, indicating that facilitatory interneurons are still activated under cholinergic blockade. These data show that transmission through the GSWR neuronal network is gated by a feedback inhibitory mechanism. They also suggest that a reduction of cholinergic inhibition onto excitatory interneurons may be a mechanism through which transmission within the GSWR network is increased during various forms of learning, such as sensitization. These data place new emphasis on the important role of inhibitory interneurons in determining the plastic properties of neuronal networks, in both invertebrates and vertebrates.

Evidence for the Action of Endogenous Adenosine in the Rabbit Retina: Modulation of the Light‐Evoked Release of Acetylcholine

Much evidence has accumulated supporting the hypothesis that the purine nucleoside adenosine may indeed function as a neuromodulator in the mammalian retina, but to date no reports have directly illustrated a physiological role for this nucleoside. In other regions of the CNS, adenosine agonists decrease transmitter release, whereas antagonists increase release. A similar role for adenosine in the retina is now apparent. The cholinergic amacrine cells of the rabbit retina were labeled with [3H]choline, and the effects of enzymatic adenosine degradation or adenosine antagonists on the light-evoked efflux of acetylcholine were evaluated. When endogenous adenosine was degraded by addition of adenosine deaminase, the light-evoked release of radioactivity derived from [3H]choline was significantly increased compared with control values. A similar response was observed when rabbit eyecups were superfused with a selective adenosine A1 receptor antagonist. The effect elicited by adenosine deaminase could be almost completely reversed by addition of cyclopentyladenosine, a highly selective A1 receptor agonist. These effects were observed in either the presence or the absence of picrotoxin. The results demonstrate a modulation of retinal physiology by adenosine.

Excitatory and inhibitory amino acids involved in the high pressure nervous syndrome: Epileptic activity and hyperexcitability

Epileptic-like activities are observed in mammals exposed to ambient pressures higher than 20 atm. These symptoms are part of the so called "high pressure nervous syndrome". In the search of the cellular mechanisms of this syndrome, we examined synaptic and intrinsic pressure-induced changes in the in vitro hippocampal slice preparation in the rat. We found that pressure (80 atm) depresses the efficiency of excitatory amino acidergic and inhibitory GABA synaptic transmissions, while it increases the intrinsic excitability of the CA1 pyramidal cells and induced multiple population spikes. The changes were associated with a selective increase in the effects of NMDA andL-homocysteate, while the postsynaptic effects of GABA was unchanged. NMDA antagonists and GABA synergistic drugs antagonized the pressure-induced hyperexcitability and multiple population spikes. These results suggest that pressure would decrease transmitter release at the tested excitatory and inhibitory synapses and would facilitate NMDA postsynaptic mechanisms. Thus, changes in both NMDA and GABA processes might be involved in the development of the high pressure nervous syndrome.

Patch clamp analysis of excitatory synapses in mammalian spinal cord slices

Excitatory synaptic transmission to visually identified alpha-moto neurones was studied in thin slice preparations of the neonatal rat spinal cord. Excitatory postsynaptic currents (EPSCs) elicited by stimulation of intraspinal presynaptic fibres were recorded using the whole-cell patch clamp technique, following blockade of inhibitory transmission by bath application of strychnine and bicuculline. The EPSCs could be separated pharmacologically into N-methyl-D-aspartate- (NMDA) and non-NMDA-receptor-mediated components, where the contribution of the NMDA-mediated component was significant only at holding potentials more positive than -50 mV. Graded stimulation of intraspinal fibres showed that the NMDA- and the non-NMDA-mediated EPSCs were evoked by activation of presynaptic fibres with similar sensitivities to the stimulation intensity, suggesting that the same presynaptic fibres released the excitatory amino-acid (EAA) activating the two sub-sets of receptors. Studies of the amplitude fluctuations of EPSCs elicited by stimulation of a presumed single fibre revealed similar proportions of transmission failures and similar distributions of both the NMDA- and the non-NMDA-mediated components. These similarities suggest that the EAA transmitter activating the two sub-types of receptors is released from the same set of synaptic boutons and that the receptors are therefore post-synaptically co-localized. In addition the gamma aminobutyric acidB (GABAB) receptor agonist L-baclofen, which is known to decrease transmitter release, changed the amplitude distributions of non-NMDA- and NMDA-receptor-mediated EPSCs into unimodal distributions without affecting the amplitude of the presumed unitary event. The similarity between the transmitter release profiles of the two EAA components further supports the notion of postsynaptic receptor co-localization.

Long-Term Adaptation of a Phasic Extensor Motoneurone in Crayfish

ABSTRACT Long-term adaptation (LTA), a phenomenon previously studied in the crayfish claw, was examined in one of the motoneurones innervating the phasic abdominal extensor muscles. The motoneurone was conditioned by electrically stimulating the second root of the third abdominal ganglion in situ for 4 h per day, using trains of stimuli with an average impulse frequency of 2·5 Hz. In juvenile crayfish, 3 days of conditioning produced a marked (81%) reduction in EPSP amplitude, which recovered only slightly during the succeeding 7 days. The quantal content of synaptic currents also decreased (by an average of 65 %). Estimated values of the binomial parameter p were lower for conditioned neurones than for controls, suggesting that the observed decrease in transmitter release involves a decrease in release probability. Conditioned neurones also displayed less synaptic depression than controls during repetitive stimulation at 5 Hz. In adult crayfish, conditioning for 7 days also produced a marked (74%) reduction in EPSP amplitude and resistance to synaptic depression. These results differ from those of previous work with the phasic axon of the claw closer muscle, which shows virtually no synaptic changes in adults after conditioning for 2 weeks. The ability to exhibit LTA, therefore, is not lost with age in all neurones.

Ethanol-Induced Effects on the Central Nervous System: A Short Review

Ethanol in sufficient concentrations will affect the central nervous system (CNS) and disturb several physiologic functions. During prolonged exposure to the drug, tolerance and dependence may develop, and finally the CNS may be damaged. The mechanisms mediating these effects remain to be elucidated. Data indicate that ethanol dissolves in the neuronal membrane and disorders its structure. As a consequence, the protein complexes associated with important membrane functions may be altered, and activities such as ion movements, enzymatic activity, and receptor-mediated translation of information may be impaired. Studies using electrophysiologic techniques have reported cellular changes proposed to be underlying the behavioral pattern of ethanol intoxication. A reduction of presynaptic depolarization-induced Ca++ entry has been related to ethanol-induced decrease of transmitter release. Generally, enzymes and receptors do not seem sensitive to ethanol in concentrations compatible with life. Interesting excep...

Effects of synthetic ω-conotoxin, a new type Ca 2+ antagonist, on frog and mouse neuromuscular transmission

A new type Ca 2+ antagonist, synthetic ω-conotoxin (ω-CgTX) decreased the peak height of the endplate potential (EPP) in frog muscle but had no effect on the mouse neuromuscular junction. The reduction of endplate potential in frogs was due to a decrease in transmitter release, since the mean quantal content estimated by variance of EPPs (m) and from the peak heights of EPPs and miniature EPPs (m 1) was reduced by ω-CgTX, but the postsynaptic sensitivity to ACh was unaltered. The decrease of mean quantal content caused by ω-CgTX was reversed by 4-aminopyridine, guanidine and Bay K 8644. Also, the effect of ω-CgTX was weakened in the presence of 10 mM Ca 2+ or 12 mM Mg 2+. Statistical analysis revealed that ω-CgTX decreased the number of quanta available (n) whereas the probability of release (p) remained unaffected.

Presynaptic inhibitory effect of geographutoxin II, a new peptide toxin from Conus geographus venom, in the guinea-pig vas deferens

Geographutoxin II (GTX II), a new peptide toxin, isolated from Conus geographyus venom, caused a dose-dependent inhibition of the contractile response of the guinea-pig vas deferens to transmural stimulation at concentrations of 3 × 10 −8 to 10 −6 M. The dose-response curves for noradrenaline, acetylcholine and KC1 were not affected by GTX II (2 × 10 −7 to 10 −6 M). The release of noradrenaline induced by veratridine was strongly inhibited by GTX II. These results suggest that the GTX II-induced inhibition of the vas deferens may be a presynaptic effect causing a decrease of transmitter release.