Spontaneous saccades under different visual conditions in the pigeon.

Spontaneous saccades of both eyes were recorded in head-restrained pigeons placed in 6 different visual conditions (darkness and biocular, uniocular, frontal or lateral viewing). Most saccades (95%) were biocular and directed forward (around the beak axis) and backward (around the horizontal line). In the dark, the proportions of forward and backward saccades were different, they became symmetrical when the visual input involved either the left eye, the lateral fields or both eyes. This spatial reorganization could be mediated by one 'dominant' eye through the lateral and foveal vision. Although some biocular saccades were strictly convergent, divergent or conjugate, most of them showed a higher independence since they had different directions and amplitudes for each eye.

Specific respiratory patterns distinguish among human basic emotions.

Prototypical respiratory-facial-postural actions ('emotional effector patterns') related to six basic emotions had been extracted from an ensemble of physiological reactions present in subjects reliving intense emotional situations (Bloch & Santibañez, 1972). Subjects reproducing these actions could evoke the corresponding subjective experience, which suggested their use as an experimental model for generating controlled emotional states. The aim of the present study was to quantify the respiratory parameters which characterize the emotions of joy-laughter, sadness-crying, fear-anxiety, anger, erotic love and tenderness. Respiratory movements and facial/postural expressions were recorded from 36 young actors who had learned in previous workshops to express these emotions by reproducing the corresponding prototypical actions. A qualitative analysis of the recordings showed that as the emotional reproduction went along, both breathing and expression evolved from an initial 'robot-like' phase to a more natural stage in which spontaneous vocalizations and gestures appeared. This suggested a partial activation of the emotional network. The quantitative analysis of the respiratory movements for the fundamental cycles showed that for anger, erotic love and tenderness significant changes in amplitude, rate and duration of the 'expiratory pause' were the major elements of differentiation, while for sadness, joy and fear inspiratory over expiratory time ratios were the elements of differentiation. These last three emotions were further characterized by small amplitude/high rate saccadic respiratory movements superposed to different phases of the fundamental cycles. It is concluded that quantitatively well differentiated sets of respiratory changes characterize each of six basic emotions. The bottom-up experimental model for generating such emotions based on the joint activation of the respiratory-facial-postural systems and its relation to corresponding 'real-life' emotions is discussed.

Interocular transfer of depth discrimination in intact and in DSO-sectioned pigeons.

Interocular transfer (IOT) of a depth discrimination task was studied in intact pigeons and with a section of the supraoptic decussation (DSO). Animals were trained to respond to the nearer of two small light emitting diodes placed at different depths in the left and right compartments of a black tunnel. The near stimulus (at 10.5 cm from the eyes) and the far one (at 21 cm) could only be seen one at a time. Though the task was difficult to learn monocularly, intact as well as lesioned animals had good transfer scores with the untrained eye. Success in transfer may be related to the presentation of the discriminanda which assured that their images impinged upon the retinal 'red field'. DSO-transection did not affect IOT possibly because differential oculomotor adjustments needed for focusing near or far targets provide central bilateral and/or binocular information which is not conveyed by the DSO.

Aminoglycosides and 3,4-diaminopyridine on neuromuscular block caused by botulinum type A toxin.

Impulse-evoked transmitter release was greatly reduced at frog neuromuscular junctions 3-20 days after botulinum type A toxin (BoTx) poisoning. The reduction in transmitter release was accompanied by an increased variability in the latency between the presynaptic spike and the release of transmitter. The aminoglycoside antibiotics amikacin, gentamycin, and bekanamycin, when applied at concentrations within their therapeutic levels, markedly enhanced the blockade of transmitter release in BoTx-poisoned junctions. 3,4-diaminopyridine strongly antagonized the effects of BoTx at early stages of poisoning, and the combined presynaptic effects of BoTx and aminoglycoside antibiotics provided that transmitter release was not completely blocked by the toxin. The antagonism was apparent at all frequencies of stimulation. Since the aminoglycoside antibiotics enhanced the neuromuscular block caused by BoTx, these drugs should be avoided in patients suspected of poisoning by this toxin.

Effects of toxin II from the sea anemone Anemonia sulcata on contractile and electrical responses of frog skeletal muscle fibres.

The effects of Anemonia sulcata toxin II (ATX-II) were studied on mechanical and electrical activities of frog muscle fibres isolated from semitendinosus or tibialis anterior muscles of Rana temporaria (2.8-7.7 degrees C). In concentrations ranging between 7.7 and 100 microM, ATX-II greatly potentiated the isometric twitch of single muscle fibres in a time-dependent manner. Increase in twitch amplitude by ATX-II was associated with an increase in time to peak tension and time from peak tension to half relaxation. ATX-II caused no change in maximum force production during fused tetanus, but the tension was maintained for several seconds after the cessation of stimulation. Such long tetanic contractions were also obtained in low-Na Ringer solution, but their duration was somewhat shorter. No specific action of ATX-II was detected on relaxation kinetics during a tetanus. The twitch potentiating effect of ATX-II was markedly increased by 3,4-diaminopyridine. Action potentials recorded from single muscle fibres in the presence of ATX-II showed a delayed onset of repolarization with a reduced rate of fall. In addition, ATX-II caused repetitive spontaneous firing of action potentials after the cessation of tetanic stimulation. ATX-II (3.3 - 10 microM) also increased action potential duration by reducing the rate of repolarization in surface fibres of formamide-treated sartorius or cutaneous pectoris muscles (20 degrees C) stimulated indirectly or directly. The potentiation of twitch force and the prolongation of contractions caused by tetanic stimulation can be attributed to the membrane action of ATX-II, which leads to prolongation of action potentials, to repetitive muscle firing and to the appearance of plateau potentials.

Enhancement by Anemonia sulcata toxin II of spontaneous quantal transmitter release from mammalian motor nerve terminals.

The action of Anemonia sulcata toxin II (ATX-II) on spontaneous quantal transmitter release from motor nerve terminals was investigated by recording miniature end-plate potentials (MEPPs) from isolated mouse phrenic nerve--hemidiaphragm nerve--muscle preparations. ATX-II (3.2 microM) when applied for 3-40 min to junctions bathed in a normal ionic medium enhanced about one hundred fold the rate of spontaneous MEPPs. Concomitantly, ATX-II depolarized the muscle fiber. The effect of the toxin on MEPP frequency was markedly reduced when junctions were exposed to Na-deficient solutions or pre-treated with dantrolene sodium (10 microM). ATX-II (0.24-3.2 microM) increased MEPP rate in junctions exposed to a Ca-free medium containing 2 mM EGTA and 2 mM Mg2+ in a dose- and time-dependent manner. Tetrodotoxin (0.2-1 microM) prevented the effects of ATX-II on MEPP frequency and on the resting membrane potential of muscle fibers. Tetrodotoxin also antagonized the acceleration of MEPP induced by ATX-II. The experimental findings suggest that ATX-II acts to increase quantal transmitter output from motor nerve terminals by enhancing Na+ influx through tetrodotoxin-sensitive presynaptic channels, since ATX-II action does not appear to depend upon entry of Ca2+ from the extracellular medium. It is likely that ATX-II, by increasing intraterminal Na+ concentration, may trigger calcium release from internal stores.

Equipotency of anti-curare activity of 4-aminopyridine and 3,4-diaminopyridine in anesthetized rats.

In the curarized preparation, 3,4-diaminopyridine (3,4-DAP) and 4-aminopyridine (4-AP) were equiactive in their ability to antagonize d-tubocurarine caused complete depression of the indirectly elicited twitches of the sciatic nerve-tibialis anterior muscle preparation in anesthetized rats. In the non-curarized preparation, 3,4-DAP showed 2.3 to 4.0 times stronger augmentation of the indirectly elicited twitches than 4-AP, but both the drugs increased equivalently and slightly the maximally elicited twitches of the chronically denervated muscle. The results suggest that the difference of their prejunctional effects is masked by the postjunctional effects of d-tubocurarine in the indirectly elicited twitches.

[Presynaptic effects of aminopyridines on the neuromuscular junction of vertebrates]. / Effets présynaptiques des aminopyridines a la jonction neuromusculaire de vertébrés.

In this review the effects of aminopyridines and chemically related compounds are documented in an attempt to analyse the mechanism underlying their presynaptic actions at the vertebrate neuromuscular junction. Aminopyridines and related compounds are of particular interest because they greatly increase the amount of acetylcholine released in response to both conducted nerve impulses and electrotonic depolarizations of tetrodotoxin blocked motor nerve terminals. The apparent rank order of potency for increasing quantal transmitter release evoked by nerve impulse at physiological pH was as follows: 3,4-diaminopyridine greater than 4-aminopyridine greater than 4-aminoquinoline greater than 3-aminopyridine greater than 2,6-diaminopyridine greater than 2-aminopyridine greater than 4-nitropyridine greater than 4-aminopyridine N-oxyde greater than 4-hydroxypyridine greater than 2,4-dihydroxypyridine. The fact that both pyridine and aniline were found to be inactive indicate that both a pyridine ring and an amino-substituent are necessary for activity. A common site of action for the drugs here reported should be rationalized on the basis that their protonated molecular forms generate a common electrostatic potential field pattern. This results together with those concerning the dependence of pyridine activity on extracellular pH leads to the conclusion that this family of compounds exert its activity at the internal face of the motor nerve terminal membrane. Aminopyridines in concentrations that increase transmitter release evoked by nerve impulses block potassium conductance in motor nerve terminals and lengthen the presynaptic action potential, this effect leads to an enhanced calcium influx and consequently to an increase in acetylcholine release. The fact that aminopyridines had no consistent effect on transmitter release at junctions depolarized by elevated potassium ions strongly supports the view that these drugs have no direct effect on voltage-dependent calcium channels and that their primary site of action is on voltage-sensitive potassium channels of motor nerve terminals.

Evaluation of 4-aminopyridine and 3,4-diaminopyridine penetrability into cerebrospinal fluid in anesthetized rats.

4-aminopyridine (4-AP) and 3,4-diaminopyridine (3,4-DAP) when injected intracisternally to anesthetized rats induced qualitatively similar central nervous system stimulant and convulsant effects at equimolar concentrations. Overall penetrability into cerebrospinal fluid of 4-AP is significantly higher than that of 3,4-DAP after single i.v. administration as evaluated by a high-performance liquid chromatographic determination. The present results can account for the lower central nervous system toxicity of 3,4-DAP when compared to 4-AP previously described after systemic administration.

Increase in transmitter release from motor nerve terminals induced by some pyridine derivatives.

The effects of 4-nitropyridine (4-NP), 4-aminopyridine-N-oxide (4-AP-N-O), 4-hydroxypyridine (4-HP), 2,6-diaminopyridine (2,6-DAP), 2,4-dihydroxypyridine (2,4-DHP) and pyridine on isolated sciatic nerve-sartorius muscle preparations were studied by means of intracellular and extracellular recording techniques. In junctions treated with (+) tubocurarine, 4-NP, 4-AP-N-O, 4-HP and 2,6-DAP reversibly increased the amplitude and the latency of end-plate potentials (EPPs) and induced repetitive EPPs in response to single nerve impulses. As shown by extracellular focal recordings, the increase in latency of EPPs was due to a prolongation of the minimum synaptic delay, while the appearance of repetitive EPPs was the result of repetitive firing of motor nerve terminals. 4-NP, 4-AP-N-O, 4-HP and 2,6-DAP increased dose-dependently the quantal content of EPPs, while 2,4-DHP and pyridine were found to be inactive. Comparison of the apparent rank order of potency in increasing quantal transmitter release indicates that the relative activity of the different pyridine derivatives studied is unrelated to their pK values. Spontaneous quantal transmitter release in resting junctions was unaffected by 4-NP, 4-AP-N-O, 4-HP and 2,6-DAP when applied at concentrations that enhanced evoked transmitter release. 4-NP differed from the other pyridine derivatives by producing in high concentrations a time-dependent increase in miniature end-plate potential frequency and a depolarization of the muscle fibres. In addition, 4-AP-N-O, 4-HP and 2,6-DAP were found to have no effect on MEPP frequency accelerated by increasing the external K+ concentration. In conclusion the data presented strongly suggest that 4-NP, 4-HP, 4-AP-N-O and 2,6-DAP facilitate evoked transmitter release from motor nerve terminals by a presynaptic action that seems related to an increased calcium influx secondary to the blockade of potassium channels in the nerve terminal.

Increase in transmitter release from motor nerve terminals induced by some pyridine derivatives.

The effects of 4-nitropyridine (4-NP), 4-aminopyridine-N-oxide (4-AP-N-O), 4-hydroxypyridine (4-HP), 2,6-diaminopyridine (2,6-DAP), 2,4-dihydroxypyridine (2,4-DHP) and pyridine on isolated sciatic nerve-sartorius muscle preparations were studied by means of intracellular and extracellular recording techniques. In junctions treated with (+) tubocurarine, 4-NP, 4-AP-N-O, 4-HP and 2,6-DAP reversibly increased the amplitude and the latency of end-plate potentials (EPPs) and induced repetitive EPPs in response to single nerve impulses. As shown by extracellular focal recordings, the increase in latency of EPPs was due to a prolongation of the minimum synaptic delay, while the appearance of repetitive EPPs was the result of repetitive firing of motor nerve terminals. 4-NP, 4-AP-N-O, 4-HP and 2,6-DAP increased dose-dependently the quantal content of EPPs, while 2,4-DHP and pyridine were found to be inactive. Comparison of the apparent rank order of potency in increasing quantal transmitter release indicates that the relative activity of the different pyridine derivatives studied is unrelated to their pK values. Spontaneous quantal transmitter release in resting junctions was unaffected by 4-NP, 4-AP-N-O, 4-HP and 2,6-DAP when applied at concentrations that enhanced evoked transmitter release. 4-NP differed from the other pyridine derivatives by producing in high concentrations a time-dependent increase in miniature end-plate potential frequency and a depolarization of the muscle fibres. In addition, 4-AP-N-O, 4-HP and 2,6-DAP were found to have no effect on MEPP frequency accelerated by increasing the external K+ concentration. In conclusion the data presented strongly suggest that 4-NP, 4-HP, 4-AP-N-O and 2,6-DAP facilitate evoked transmitter release from motor nerve terminals by a presynaptic action that seems related to an increased calcium influx secondary to the blockade of potassium channels in the nerve terminal.

Effects of 3,4-diaminopyridine on mechanical and electrical responses of frog single muscle fibres.

The effects of 3,4-diaminopyridine (3,4-DAP) were studied on isolated muscle fibres of the frog in concentrations ranging between 0.025 and 5.0 mM. Isometric twitch and tetanus responses were recorded at temperatures between 2.5 and 3.9 degrees. 3,4-DAP caused a concentration-dependent increase in twitch amplitude, maximum effects being obtained at a concentration of 3 mM with a mean increase in tension of 70 +/- 12% of control (n = 7). 3,4-DAP in 3 mM concentration had only a slight increase in initial rate of rise of twitch tension (mean increase 8 +/- 4%) but increased the time to half peak tension by 59 +/- 9% and the time from peak tension to half relaxation by 78 +/- 10%. No significant effect of 3,4-DAP was observed on the initial rate of rise and total amplitude of the isometric tetanus. The twitch potentiating effect of 3,4-DAP developed gradually with the number of times the fibre was stimulated and reached a maximum level after 40-50 stimulations. A gradual increase in the duration of the action potential was also observed. It is suggested that 3,4-DAP, like 4-aminopyridine, potentiates the twitch by means of prolonging the duration of the action potential.

Facilitatory effects of 4-aminopyridine on strontium-mediated evoked and delayed transmitter release from motor nerve terminals.

The effect of 4-aminopyridine (4-AP) on Sr-mediated evoked and delayed transmitter release at the frog neuromuscular junction was examined using conventional electrophysiological techniques. 4-AP (5-50 microM) increased transmitter release evoked in response to conducted nerve impulses or to electrotonic depolarization of tetrodotoxin (TTX)-treated motor nerve terminals. Spontaneous quantal transmitter release was not affected by the drug as judged by the lack of effect on miniature end-plate potentials (MEPPs) frequency. However, 4-AP (10-20 microM) markedly enhanced the frequency of MEPPs appearing during conducted low rate repetitive nerve impulses or single electrotonic depolarization of TTX-blocked nerve terminals. The results suggest that 4-AP increases the influx of Sr2+ into nerve terminals in a way that modifies its sequestration and removal by the subcellular elements of the terminal.

Reversibility of kanamycin-induced neuromuscular and cardiovascular depressions by 4-aminopyridine, in comparison with neostigmine.

Antagonistic actions of 4-aminopyridine (4-AP) and neostigmine methylsulfate (NSG) on the neuromuscular and cardiovascular depressions by kanamycin (KM) were studied in urethane anesthetized rats, in comparison with D-tubocurarine (D-Tc). Measured parameters were indirectly elicited twitch of tibialis anterior muscle, mean arterial pressure and heart rate. All parameters were progressively depressed by continual infusions (0.2 ml/min) of KM (70 mg/ml) and D-Tc (10 microgram/ml). 4-AP 2.8 mg/kg s.c. significantly antagonized these depressive actions of both of D-Tc and KM, while NSG 0.1 mg/kg s.c. significantly antagonized only those of D-Tc and more strongly than 4-AP did in cardiovascular depression. 4-AP could antagonize the complete neuromuscular blockade and lethality of KM to the equilevel of conscious rats and those of D-Tc to 2.78 and 1.78 time doses of conscious rats in the complete neuromuscular blocking dose and lethal dose respectively. These results suggest that the antagonistic action of 4-AP results from its facilitation activity in the neurotransmitter release and its augmentative activity in the muscle contractility and also indicate a possibility that 4-AP can be used as a relief agent for the neuromuscular and/or cardiovascular depressions induced by some aminoglycoside antibiotics and nondepolarizing neuromuscular blocking drug in the clinical aspect.

Presynaptic effects of bekanamycin at the frog neuromuscular junction. Reversibility by calcium and aminopyridines.

The effects of bekanamycin (5-320 microM) on evoked and spontaneous transmitter release were examined in frog neuromuscular junctions in vitro by using conventional electrophysiological techniques. Bekanamycin in a concentration-dependent fashion reduced reversibly the quantal content of the end-plate potentials while it had no observable effect on the configuration of the extracellularly recorded presynaptic action potential. The reduction in evoked transmitter release produced by bekanamycin could be antagonized either by increasing the external calcium concentration or by drugs like the aminopyridines which are to greatly enhance transmitter release from motor nerve terminals. Regarding the possible mode of action of bekanamycin on transmitter release our results are consistent with the hypothesis that there is competition between calcium and bekanamycin in the excitation-secretion coupling process and that the site of competition has a higher affinity for bekanamycin than for calcium. Bekanamycin also reduced in a dose-dependent manner the acceleration of miniature end-plate potentials induced by increasing the extracellular K+ concentration while it had no effect on spontaneous miniature end-plate potential frequency in resting junctions. Besides its inhibitory pre-junctional effects bekanamycin in concentrations higher than 40 microM decreased dose-dependently the amplitude of miniature end-plate potentials. However, presynaptic effect predominated and seemed to be quantitatively more important for the neuromuscular block than was a possible postsynaptic action of the antibiotic. It is concluded that bekanamycin exerts potent inhibitory effects on transmitter release probably by interfering with the influx of calcium that occurs during depolarization of motor nerve terminals.

Effects of calcitonin-induced hypocalcemia on the neuromuscular and cardiovascular depressive actions of kanamycin in anesthetized and conscious rats.

It was examined whether calcitonin (CT)-induced hypocalcemia could modify the pharmacological actions of kanamycin sulfate (KM). CT produced a dose dependent and long-lasting hypocalcemia in urethane anesthetized and conscious rats. In anesthetized rats, KM infusion depressed the indirectly elicited contractions of the tibialis anterior muscle (MC), mean arterial pressure (AP), heart rate (HR) and respiratory rate. CT did not influence the stability of the above parameters and slightly modified the neuromuscular depression of KM. In conscious rats, KM infusion produced spontaneous and complete head drop, loss of corneal reflex, respiratory arrest and also depressed AP and HR. Much higher doses of KM were required to induce the same pharmacological actions in conscious than in anesthetized rats. CT dose-dependently potentiated the pharmacological actions of KM. A highly significant linear correlation between the serum total calcium levels and the KM dose inducing spontaneous head drop was observed. These data indicate that, in conscious rats, the actions of KM are dependent on the serum calcium levels. In the same experimental conditions, neither CT-induced hypocalcemia nor anesthesia did modify significantly the pharmacological actions of d-tubocurarine.