Excitatory Nerve Terminals Research Articles

Chapter 6 Neurogenic mechanisms and neuropeptides in chronic pain

This chapter focuses on the neurogenic mechanism and neuropeptides in chronic pain. Neuropeptide-mediated cell signalling is complex, and its function is still unknown. Changes in neuropeptide synthesis and release are related to the pain symptoms that follow chronic inflammation and neuropathic injuries. The chapter discusses these specific features of neuropeptide containing afferent neurones and describes some the properties of sensory neurones. The chapter also discusses the neurogenic effects of the neurokinins that are localized in many afferents and that are most extensive studies. The effects of substance P exemplify the diversity of actions that have been described for sensory neuropeptides. In the spinal dorsal horn, substance P induces changes in excitability of afferent nerve terminals, spinal neurones, and glial cells; events associated with the propagation of nociceptive signals and the modulation of acute and chronic pain responses. It is clear that all features of afferent nerve function can be tempered by their chemical environment and involve dynamic interactions between afferent (and sympathetic) fibres and surrounding tissue. This affects neural excitability, but perhaps more significantly over the long term, there are changes in the peptide composition, concentration, and release.

Lobster swimmerets: Muscle fiber composition and membrane definition of excitatory synapses in a predominantly fast system

AbstractThe abdomen of the lobster Homarus americanus has four pairs of segmental appendages, the swimmerets, whose rhythmic beating functions in swimming, righting responses, creating water currents, and aerating eggs. There are 24 separate muscles in each swimmeret and 21 of these are fast, based on their relatively short (4 μm) sarcomeres and six thin filaments orbiting a single thick filament. Three of the 24 muscles are slow with relatively long (7–12 μm) sarcomeres and 8–11 thin filaments surrounding a thick filament. Of the eight functional groups amongst which the 24 muscles are distributed, six groups have only fast muscles, one group has a mixture of fast and slow muscles, and one group only slow muscles. Thus the number and distribution of fast muscles in the swimmeret makes it a predominantly fast system. Motor innervation of two fast muscles in the power‐stroke group reveals numerous excitatory nerve terminals (recognized by circular synaptic vesicles) with well‐defined synaptic contacts and presynaptic dense bars or active zones. Synaptic contacts appear in the P‐face of the fractured nerve membrane as circular plateaus with sparsely distributed particles and one or two small aggregations of large intramembranous particles (putative calcium channels) representing active zones. In the complementary E‐face, synapses assume spherical outlines and active zones appear as shallow depressions. Attachment sites of synaptic vesicles appear as large pits in P‐face or protuberances in E‐face leaflets along the edge of the active zones. The surface features of excitatory synapses of fast swimmeret muscles are similar to those on other crustacean fast and slow muscles. The packing density of large intramembranous particles in the active zones also resembles that in other crustacean muscles thereby suggesting an optimal packing density for these ion channels. © 1995 Wiley‐Liss, Inc.

GABAA receptor activation and the excitability of nerve terminals in the rat posterior pituitary.

1. The activation of GABAA receptors in nerve terminal membranes gates a Cl- channel. Experiments were conducted to determine how the activation of this receptor influences membrane potentials, action potentials and voltage-activated Na+ and K+ channels. 2. When activation of the GABAA receptor produced only conductance changes and no voltage changes, action potentials changed only slightly. The threshold for action potential generation increased by 15%. GABA reduced the broadening of action potentials caused by high frequency stimulation by only 7%. These results indicate that membrane shunting by GABA-gated Cl- channels plays a relatively minor role. 3. By recording changes in the current through K+ channels in cell-attached patches, the activation of GABAA receptors was shown to depolarize the nerve terminal membrane from rest by 14 mV. The GABAB receptor agonist baclofen produced no change in resting membrane potential as measured by this same technique. 4. In whole-terminal recordings under current clamp, with pipettes containing various Cl- concentrations, the GABA-induced depolarization increased with Ecl. The variation with Ecl provided a basis for evaluating the contributions of leak and K+ current in the balance of currents that determines the magnitude of the GABA-induced depolarization. 5. Based on the GABA-induced voltage change and an evaluation of the other currents of significance in the relevant voltage range, an estimate was obtained for ECl of -48 mV to give an estimate for the intracellular Cl- ion concentration of 20 mM. 6. Under conditions allowing both conductance and voltage to change during Cl- channel gating, GABA prevented action potential responses to current injection. Comparable depolarizations produced by adjusting a steady holding current also blocked action potential responses. 7. A depolarization from -60 to -45 mV under voltage clamp inactivated approximately 90% of the Na+ channels and activated a small amount of K+ current. This suggests that inactivation of Na+ channels makes a major contribution to the inhibition of action potentials by GABA. 8. These results are consistent with the hypothesis that GABA inhibits neurosecretion by retarding impulse propagation into the terminal arborization. These results support a depolarization block mechanism for the inhibition of secretion, in which depolarization inactivates Na+ channels sufficiently to block action potentials.

Inhibitory axoaxonal and neuromuscular synapses in the crayfish opener muscle: Membrane definition and ultrastructure

The specific inhibitory motoneuron to the crayfish (Procambarus clarkii) opener muscle provides neuromuscular synapses to the muscle fibers and axoaxonal synapses to the excitatory motor nerve terminals. Freeze fracture of the membrane in both types of synapses show that the presynaptic active zone consists of clusters of large particles (putative calcium channels), which are often encircled by large depressions representing fused synaptic vesicles on the internal leaflet or P face of the presynaptic membrane. Corresponding pits and protrusions mark the external leaflet or E face of the presynaptic membrane. The postsynaptic receptor-bearing surface, characterized for neuromuscular synapses only, consists of rows of particles on both leaflets of the muscle membrane. The organization differs from that seen at excitatory synapses where particles occur only on the E-face leaflet. Serial thin sections of nerve terminals reveal that neuromuscular synapses are significantly larger in proximal fibers than in their central counterparts and support a greater number of presynaptic dense bars (active zones). Axoaxonal synapses also show regional differences; almost three times as many occur in the proximal region compared with the central region. Most synapses possess a single dense bar. The majority of synapses formed by the inhibitory axon are neuromuscular; a minority are axoaxonal. The latter occur in various locations along the excitatory nerve terminals as well as on branches of the axon itself. This preterminal or "off-shore" location could act to cut off entire populations of excitatory synapses or reduce the amplitude of the preterminal action potential.

Phosphorylation and dephosphorylation modulate a Ca(2+)‐activated K+ channel in rat peptidergic nerve terminals.

1. Ca(2+)-activated K+ channels regulate the excitability of many nerve terminals. A Ca(2+)-activated K+ channel present in the membranes of rat posterior pituitary nerve terminals runs down following the formation of excised patches. This run-down process reflects enzymatic dephosphorylation. 2. Both Mg-ATP and the protein phosphatase inhibitor okadaic acid prevented run-down of channel activity in excised patches. The okadaic acid sensitivity suggests that run-down resulted from dephosphorylation by a type 1 protein phosphatase. 3. Guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) accelerated run-down by accelerating okadaic acid-sensitive dephosphorylation. GTP gamma S had no effect on the activity of the protein kinase in these patches. These results suggest a direct coupling between a G-protein and a protein phosphatase. 4. After run-down, channel activity could be restored by Mg-ATP; restoration depended on ATP hydrolysis, but did not require Ca2+ or a second messenger. Restoration of channel activity by ATP was blocked by staurosporine and 1-(5-isoquinolinylsulphonyl)-3-methylpiperizine, but not by more specific inhibitors of protein kinases. 5. Restoration of channel activity by phosphorylation was very sensitive to membrane potential; increasing the voltage by as little as 10 mV could dramatically enhance recovery. 6. Ca2+ and voltage acted synergistically to enhance phosphorylation; higher [Ca2+] permitted phosphorylation at more negative potentials. 7. During trains of high frequency stimulation under current clamp, action potentials were influenced by both the protein phosphatase and protein kinase, indicating that enzymatic modulation of channel gating occurs under physiological conditions. An important implication of these results is that voltage-dependent phosphorylation could play a role in use-dependent depression of secretion from nerve terminals.

Cloning and expression of a spinal cord- and brain-specific glycine transporter with novel structural features.

A novel glycine transporter (GLYT2) was cloned from a rat brain cDNA library. GLYT2 is about 48 and 50% homologous to the previously cloned mouse glycine transporter (GLYT1) and rat proline transporter (PROT), respectively. GLYT2 differs from GLYT1 in molecular structure, tissue specificity, and pharmacological properties. The cDNA of GLYT2 encodes for 799 amino acid residues with an extended amino-terminal peptide containing 200 amino acids before the first transmembrane domain. Potential phosphorylation sites for protein kinase C, cAMP-dependent kinase, and calmodulin-dependent kinase were identified in the amino-terminal region. GLYT2 mRNA was shown to be specifically localized in spinal cord, brain stem, and to a lesser extent in the cerebellum. In contrast, GLYT1 mRNA distribution in the brain has been found previously to be more ubiquitous. Xenopus oocytes injected with GLYT2 cRNA transport glycine with a Km of 17 microM, and the uptake of glycine is resistant to inhibition by sarcosine. The experimental data suggests GLYT2 might play a major role in the termination of the inhibitory effect of glycine in the brain stem and spinal cord of vertebrates. On the other hand, the main function of GLYT1 may be in the modulation of excitatory nerve terminals. Two types of GLYT1 cDNA, GLYT1a and GLYT1b, were cloned from the mouse brain library. They differ only at their amino-terminal sequences, and GLYT1b contains two additional potential phosphorylation sites for proline-dependent kinase. Cloning of the gene encoding the GLYT1 revealed that the two variants resulted from a differential splicing.

Presynaptic glutamate receptors depress inhibitory postsynaptic transmission in lobster neuromuscular synapse.

1. We examined the functional role of GTP-coupled glutamate receptor (GluB-R) in the presynaptic membrane of lobster neuromuscular synapse. 2. Injection of guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S), a hydrolysis-resistant analogue of GTP, into the excitatory axon mimicked the presynaptic glutamate response and effectively suppressed excitatory postsynaptic potentials or excitatory postsynaptic currents (EPSCs). 3. Statistical analysis revealed that the coefficient of variation (standard deviation divided by the mean of EPSC amplitude) was increased after injection of GTP gamma S into the excitatory axon, indicating a presynaptic inhibition of transmitter release. 4. The effect of glutamate on inhibitory postsynaptic potentials (IPSPs) or inhibitory postsynaptic currents (IPSCs) was studied when the postsynaptic glutamate receptors were blocked by the Joro spider toxin (JSTX). Glutamate depressed IPSPs or IPSCs in the JSTX-treated preparation. Furthermore, repetitive stimulation of the excitatory nerve produced effective inhibition of IPSCs. 5. Quisqualate and kainate suppressed IPSCs in a similar way to glutamate. In contrast, N-methyl-D-aspartate, ibotenic acid, trans-D,L-1-amino-1,3-cyclopentanedicarboxyloc acid, and 2-amino-4-phosphonobutanate had no effect on GluB-R. 6. Our results indicate that GluB-R, which exists in both excitatory and inhibitory nerve terminals, regulates transmitter release by a presynaptic inhibitory mechanism.

Reciprocal axo-axonal synapses between the common inhibitor and excitor motoneurons in crustacean limb muscles

Nerve terminals of the common inhibitor motoneuron in a crab (Eriphia spiniforns) limb closer muscle and in a crayfish (Procambarus clarkii) limb accessory flexor muscle make neuromuscular synapses with the muscle membrane (postsynaptic inhibition) as well as axo-axonal synapses with the terminals of the excitatory axon (presynaptic inhibition). That transmission is from the inhibitor to the excitor terminals at these axo-axonal synapses is indicated by the occurrence on the inhibitor membrane of presynaptic dense bars denoting sites of transmitter release. Axo-axonal synapses with the opposite polarity, in which transmission is from an excitatory onto an inhibitory terminal, were occasionally seen either adjacent to or separate from the inhibitory axo-axonal synapse. Nerve terminals of the specific inhibitor in the crayfish opener muscle were seen to make numerous axo-axonal output synapses upon excitatory nerve terminals but excitor nerve terminals were not seen to make output synapses onto inhibitor terminals. Thus reciprocal axo-axonal synapses appear to be a feature of the common inhibitor but not of the specific inhibitor. The excitor-to-inhibitor component of these reciprocal synapses may serve to limit transmitter output in the common inhibitor axon by activating glutamateB receptors which facilitate efflux of K+ and hyperpolarization of the membrane.

The actions of the κ1 opioid agonist U-50,488 on presynaptic nerve terminals of the chick ciliary ganglion

The actions of the κ 1 opioid receptor agonist U-50,488 ( trans-(±)-3,4-dichloro- N-methyl- N-[2-(1-pyrrolidinyl) cyclohexyr]-benzene-acetamide methane sulfonate) on the membrane properties of presynaptic calyciform nerve terminals of the chick ciliary ganglion were examined using intracellular recordings obtained from intact ganglion preparations maintained in vitro. U-50,488 produced a concentrationdependent (30–1000 μM) hyperpolarization with an apparent increase in input resistance. This hyperpolarization resulted from inhibition of the Na +-K + inward rectifier, since it was blocked by 3 mM Cs + and was not observed when terminals were depolarized beyond resting potential where inward rectification was voltage inactivated. A depolarizing effect on membrane potential with a further rise in input resistance was commonly observed at the highest perfused U-50,488 concentration (1 mM). The depolarizing event appears to result from a decrease in membrane potassium conductance, as the reversal potential for the response was estimated to be between −70 and −90 mV and the potassium channel blocker Ba 2+ (1mM) abolished the response. The κ 1 opioid receptor agonist also blocked spontaneously occurring miniature hyperpolarizations in the terminals, which are considered to be due to a Ca 2+-dependent K + conductance. Most of the responses to U-50,488 were abolished in the presence of the κ 1 receptor antagonist norbinaltorphimine. In conclusion, the excitability of presynaptic nerve terminals in the chick ciliary ganglion can be modulated by the inhibition of at least three separate ion conductances following activation of κ 1 opioid receptor sites in the nerve terminal region.

An inward rectifier is present in presynaptic nerve terminals in the chick ciliary ganglion

Inwardly rectifying voltage-sensitive channels have been detected in the cell bodies and axons of a number of excitable cells. The question of whether similar channels exist at axon terminals has been a matter of speculation for some time. We now report the first direct evidence for the existence of inward rectifiers in vertebrate presynaptic nerve terminals. Following impalement with intracellular electrodes, the large calyciform nerve terminals innervating chick ciliary ganglion neurons exhibit pronounced inward rectification upon hyperpolarization that increases with increasing current strength. The response is blocked by 2 mM Cs +, but is insensitive to Ba 2+, tetraethylammonium and tetrodotoxin. The inward rectifier exhibits dependence on both Na + and K +, but is unaffected by altering extracellular Ca 2+. Ciliary neurons innervated by these nerve terminals display inward rectification with similar properties. We conclude that the inward rectifier present in these presynaptic nerve terminals resembles the H-current previously described in sensory ganglion neurons and the Q-current found in hippocampal pyramidal neurons. The presence of channels that are activated by hyperpolarization may serve to enhance the excitability of the calyciform nerve terminals, which are capable of relatively high frequencies (> 100 Hz) of discharge.

Muscle cramp: Main theories as to aetiology

Historically relevant hypotheses on the pathophysiology of muscle cramp are reviewed. Psychosomatic, static, vascular, myogenic and neural theories are highlighted from a clinician's point of view. Modern neurophysiological research leaves little doubt that true muscle cramp is caused by explosive hyperactivity of motor nerves. Several mechanisms may be involved including spinal disinhibition, abnormal excitability of motor nerve terminals and spreading of muscle contraction by ephaptic transmission or axon reflexes.

The interactions of ouabain with post-tetanic and facilitatory drug potentiations at cat soleus neuromuscular junctions in vivo

Cat soleus motor nerve terminals, after high frequency conditioning, generate a post-tetanic repetition (PTR) which leads to a post-tetanic (PTP) of the muscle response. This property enables quantitative assessment of enhancement or depression of this nerve terminal excitability in vivo. The present study focuses on ionic mechanisms underlying the PTRs produced in this neuromuscular system either by high frequency stimulation or edrophonium. Ouabain was used as a specific probe for inhibition of Na(+)-K+ ATPase and its known consequences on Na+ and Ca2+ translocation. Ouabain pretreatment doubled the duration over which single stimuli, following either high frequency or edrophonium conditioning produced PTR. Ouabain in the doses used had no effect per se but as a function of dose augmented the frequency dependent responses. This pointed to Na+ loading of nerve terminals via high frequency stimulation plus ouabain inhibition of Na(+)-K+ ATPase. Ouabain potentiation of PTR responses evidently depends on exchange of intra-terminal sodium for external calcium. Thus, calcium entry blockers, Mn2+, and Co2+ suppressed or abolished the potentiations both before and after ouabain. Diphenylhydantoin, a Na+ and Ca2+ blocker, acted similarly. The effects of stimulation frequency, ouabain and the sequence of events leading to PTR in the soleus neuromuscular system appeared in general no different from those derived from the many in vitro microphysiologic studies of this phenomenon. Thus, EPPs were augmented and prolonged. It was concluded that intracellular Ca2+ is critical for regulating the stability of systems in which repetitive firing is both a normal and abnormal function.

Effects of charybdotoxin, a blocker of Ca2+ ‐activated K + channels, on motor nerve terminals

1. The contribution of Ca2+-activated K+ currents (IK,Ca) to the control of electrical excitability of motor nerve terminals and the control of acetylcholine release was assessed by studying the effects of the specific K(Ca) channel blocking toxins charybdotoxin and apamin. Electrical activity of the terminal regions of motor nerves was assessed by extracellular recording from an electrode placed in the perineural sheaths of nerves in the mouse triangularis sterni and frog cutaneous pectoris preparations. Acetylcholine release was monitored by intracellular recording of endplate potentials (e.p.ps). 2. Charybdotoxin (20-300 nM), but not apamin (10 nM-2.5 microM), selectively reduced the amplitude of an IK,Ca unmasked by prior blockade of the delayed rectifier K+ current with 3,4-diaminopyridine (3,4-DAP). 3. In the combined presence of 3,4-DAP and charybdotoxin, large Ca2+-dependent plateau responses developed, but only moderate and transient increases in acetylcholine release occurred. 4. In the absence of 3,4-DAP, charybdotoxin did not alter the electrical activity of, or the transmitter release from motor nerve terminals. 5. A possible role of the charybdotoxin-sensitive IK,Ca in the control of transmitter release is discussed.

Facilitatory effects of piracetam on excitability of motor nerve terminals and neuromuscular transmission

The possible in vivo facilitatory effects of the pyrrolidine acetamide no-otropic agent piracetam on neuromuscular transmission, were studied based upon reports of enhancement of central cholinergic function. Piracetam was shown to antagonize the lethal effects of the neuromuscular blocking agent hemicholinium-3 (HC-3), in female CF-1 mice when administered in a dose of 100mg/kg (i.p.) simultaneously with HC-3, A 30 mg/kg (i.p.) dose of piracetam was ineffective by itself, although it potentiated the protective effects of choline (25 mg/kg i.p.). The analogs of piracetam, aniracetam, oxiracetam, pramiracetam and dupracetam also significantly antagonized the lethality of HC-3 at doses over a 30–300 mg/kg range. The acute facilitatory properties of piracetam on neuromuscular transmission were examined in more detail in vivo in the soleus nerve muscle preparation of the cat. A 100 mg/kg (i.v.) dose of piracetam, while having no effect on its own, significantly enhanced the ability of a 200 μg/kg (i.v.) dose of edrophonium to produce a potentiation of muscle contraction dependent on repetitive discharges in the soleus motor nerve terminals. In preparations in which the motor nerve terminals of the soleus were in a partially degenerated state as a result of section of the motor axons 48 hr earlier, piracetam acted to restore their sensitivity to edrophonium. Furthermore, in both normal and partially degenerated preparations, piracetam significantly decreased the neuromuscular blocking effects of a 150 μg/kg (i.v.) dose of d-tubocurarine. The mechanism of the neuromuscular facilitatory effects of piracetam on neuromuscular transmission is discussed in terms of an enhanced excitability of motor nerve terminals together with an action to increase the synthesis and/or release of acetylcholine.

Multiple potassium conductances at the mammalian motor nerve terminal.

The possibility that multiple K+ conductances are present in mammalian motor nerve terminals was investigated by measuring the differential effects of tetraethylammonium (TEA) and 4-aminopyridine (4-AP) on transmitter release and on nerve terminal excitability in mouse phrenic nerve-diaphram preparations. Neither 4-AP nor TEA alter the spontaneous frequency of miniature end-plate potentials (fmepp) and therefore evidently do not affect calcium channels directly. Both 4-AP and TEA increased the quantal content of end-plate potentials (epps) evoked by nerve stimulation but the effects were not mutually exclusive; TEA continued to act in the presence of a maximally effective concentration of 4-AP. The increase in transmitter release evoked by focal polarisation of the terminal was not affected by 4-AP, whereas TEA exerted an effect consistent with a reduction in membrane conductance. Similarly, threshold for nerve terminal action potential generation was not affected by 4-AP, but TEA caused a reduction in threshold and alteration of the 'accommodation curve' indicative of a reduction of membrane conductance. Under conditions where one would predict no contribution of calcium K+ conductance, i.e., when release was evoked by Ba2+ in the absence of Ca2+, the different and non-competing effects of TEA and 4-AP were still apparent. It is concluded, therefore, that the motor nerve terminal possesses at least two K+ conductances, not including calcium activated gK, which may be distinguished pharmacologically.

Anion permeability of motor nerve terminals.

Motor nerve terminals in mouse and frog display behavior consistent with an appreciable permeability of the nerve terminal membrane to chloride. In mouse diaphragm, in the presence of 15 mM K+ and 2 mM or 8 mM Ca2+, replacement of Cl- by NO3-, Br- or acetate causes a transient increase in the quantal release of acetylcholine, measured as the frequency of spontaneously occurring miniature end plate potentials (FMEPP); a rapid rise in FMEPP is followed by a slow decline, with a half-time of about 4 min, to an equilibration level close to the control level. After equilibration in a solution in which the Cl- is replaced by another anion, return to Cl- -containing solution causes a transient decrease in FMEPP with a subsequent slow recovery. The data are consistent with transient nerve terminal depolarization or hyperpolarization, reflecting a nerve terminal permeability to anions in the sequence Cl- greater than Br- greater than NO3- greater than acetate. In 5 mM K+, changes in nerve terminal excitability, determined using focal stimulation, are also consistent with alteration of nerve terminal membrane potential as a consequence of anion substitution. The time course of relaxation of FMEPP after a change from Cl- to an anion of lower permeability, or vice versa, is considerably slower than that expected if Cl- permeability of nerve terminals is similar to that of skeletal muscle fibres, and if the nerve terminal behaves as a single compartment. In frog cutaneous pectoris, transient changes in FMEPP produced by substitution of anions in the bathing solution were similar to those produced in mouse diaphragm, but more rapid in time course.

Electrical excitability of mouse motor nerve terminals: Effects of excitation of up-stream nodes of ranvier on terminal depolarization

Electrical excitability of mouse motor nerve terminals: Effects of excitation of up-stream nodes of ranvier on terminal depolarization

Evidence for GABA as a neurotransmitter in the leech

In the leech, Hirudo medicinalis, the inhibitory motor neurons to the longitudinal muscles in the body wall, cells 1 and 2, are linked via central inhibitory synapses to the excitatory motor neurons innervating the same muscles. Examination of these synapses showed that the inhibitors are GABAergic according to several electrophysiological and pharmacological criteria. Presynaptic release of neurotransmitter during passage of depolarizing current into the inhibitors, as well as direct application of GABA to the excitor cell bodies, hyperpolarizes the postsynaptic excitor. Moreover, both synaptic and extrasynaptic GABA receptors of the excitors are specifically blocked by the GABA antagonist bicuculline methiodide. The inhibitors, dissected from the ganglion and grown in culture, synthesize GABA when exposed to the GABA precursor glutamate, whereas the excitors do not synthesize detectable levels of GABA under these same conditions. The innervation and neurotransmitter sensitivity of the longitudinal muscles in the body wall of the glossiphoniid leeches Haementeria ghilianii and H. officinalis were examined in order to determine if the inhibitory neurotransmitter at the neuromuscular junction is GABA. Individual muscle fibers are innervated by both inhibitory and excitatory motor neurons in a manner such that the inhibitory and excitatory nerve terminals and neurotransmitter receptors are spatially and electrically separate. Intracellular recordings taken from the muscle fibers reveal a resting potential of about -70 mV. The amplitude of the spontaneous inhibitory junctional potentials (IJPs) falls to zero at a polarization of about -65 mV and reverses in sign at the normal resting potential.(ABSTRACT TRUNCATED AT 250 WORDS)

Modification of motor nerve terminal excitability by alkanols and volatile anaesthetics

A method of local polarization-excitation was used to study changes in motor nerve terminal excitability produced by n-alkanols and volatile anaesthetics in mouse diaphragm preparations. Ethanol and propanol caused an exaggeration of 'accommodation', i.e., the increase in excitation threshold produced by a conditioning depolarization. Butanol, hexanol and octanol had mixed effects, producing a rise in the minimum threshold (threshold after removal of resting accommodation) in addition to an increase in accommodation. Volatile anaesthetics produced effects on excitability at concentrations comparable to minimum alveolar concentration. The action of enflurane was essentially only to increase accommodation while methoxyflurane produced an increase in threshold insensitive to conditioning polarization. Halothane and isoflurane produced intermediate effects. Accommodation curves were little affected by Ba2+ or 4-aminopyridine and were consistent with accommodation being a reflection of inactivation of the Na+ current system. We conclude that volatile anaesthetics, at concentrations comparable to those producing anaesthesia, may substantially modify Na+ channel gating and inactivation.

Modulation of terminal excitability of mesolimbic dopaminergic neurons by d-amphetamine and haloperidol

Electrophysiological techniques were used to study the changes in the terminal excitability of mesolimbic DA and non-DA neurons following the infusion of D-amphetamine (D-AMP) and haloperidol (HAL) into the nucleus accumbens (NAc) of rats. The amount of current needed to evoke antidromic spikes by electrical stimulation of the NAc was used as an index of the excitability of axon terminals of these neurons. The excitability of DA neurons was decreased by D-AMP and increased by HAL. In addition, the effect produced by D-AMP was reversed by HAL. By contrast, these drugs either induced an opposite effect or were ineffective in inducing changes on the excitability of nerve terminals of mesolimbic non-DA neurons. Infusion of the vehicle or saline produced no effect. D-AMP and HAL were still effective in modulating the excitability of mesolimbic DA nerve terminals after the destruction of NAc neurons by ibotenic acid. The results suggest that the effects seen after D-AMP and HAL are mediated primarily by DA autoreceptors. It is likely that the increase in the current needed for evoking antidromic spikes after infusion of D-AMP into the terminal region is the consequence of DA autoreceptor-mediated hyperpolarization of terminal membranes. On the other hand, HAL could exert its actions by blocking autoreceptor-mediated hyperpolarization.