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Intrapontine microinjections of serotonin in acutely decerebrated cats resulted in the bilateral augmentation of the postural muscle tone of the hindlimbs. Optimal injection sites were located in the dorsomedial part of the rostral pontine reticular formation corresponding to the nucleus reticularis pontis oralis (NRPo). In this study, attempts were made to elucidate the cellular basis for the serotoninergically induced augmentation of postural muscle tone by recording the electromyographic (EMG) activity of hindlimb extensor muscles, the monosynaptic reflex responses evoked by electrical stimulation of group Ia muscle afferent fibres and the membrane potentials of hindlimb alpha-motoneurons (MNs). Serotonin injections resulted not only in the augmentation of the EMG activity of gastrocnemius soleus muscles, but also in the restoration of EMG suppression, which was induced by previous injection of carbachol into the NRPo. Extensor and flexor monosynaptic reflex responses were facilitated by serotonin injections into the NRPo. Such reflex facilitation was not induced by serotonin injections into the mesencephalic or the medullary reticular formation. Intrapontine serotonin injections resulted in membrane depolarization of extensor and flexor MNs with decreases in input resistance and rheobase. Spontaneous depolarizing synaptic potentials (EPSPs) increased in both frequency and amplitude. Peak voltage of Ia monosynaptic EPSPs also increased. Serotonin injections which followed carbachol injections resulted in membrane depolarization of MNs along with an increase in the frequency of spontaneous EPSPs and a decrease in carbachol-induced inhibitory postsynaptic potentials. Following pontine carbachol injections, antidromic and orthodromic responses in MNs were suppressed. Discharges of MNs evoked by intracellular current injections were also suppressed, but were restored following serotonin injections. These results indicate that postsynaptic excitation, presynaptic facilitation and disinhibition (withdrawal of postsynaptic inhibition) simultaneously act on the hindlimb MNs during serotonin-induced postural augmentation and restoration.

The effects of electrically stimulating the Flexor Reflex Afferent (FRA) on the soleus H reflexes were investigated in 34 paraplegic patients having a clinically complete spinal cord lesion. Conditioning stimuli (5-50 mA) were applied to the ipsilateral or contralateral sural nerve. The conditioning-test interval ranged from 20 to 1000 ms. A late ipsilateral flexor reflex (EMG) was found in all patients. A late contralateral extension reflex was sporadically observed in only 3 patients. The excitability curves usually showed two phases of ipsilateral H reflex inhibition and contralateral H reflex facilitation, one between 50 and 130 ms and the other after over 200 ms. These intervals correspond to early and late flexion reflexes. With high intensity stimulation the early and late ipsilateral inhibition fused. An early low threshold ipsilateral facilitation occurred in 9 patients. The contralateral late facilitation was followed by prolonged inhibition in 10 patients. Changes in presynaptic inhibition were assessed by measuring the heteronymous monosynaptic Ia facilitation from quadriceps to soleus. For methodological reasons, it was only possible to investigate the effect of contralateral conditioning volleys which was performed in 5 patients. A significant and regular reduction of the heteronymous Ia facilitation was found in 4 patients. The reduction is taken to indicate that the FRA evokes presynaptic inhibition of Ia transmission to alpha motoneurones. Presynaptic inhibition was also indicated by the enhancement of a vibratory stimulus induced inhibition in 2 subjects. These results are consistent with the hypothesis that the reflex organization in patients with a spinal cord section is similar to that of the acute spinal cat injected with DOPA.

The possible occurrence and role of protein kinase C at the lateral olfactory tract (LOT)-pyramidal cell synapse of the rat olfactory cortex slice has been investigated by determining the effects of both activators (4-beta-phorbol-12,13,diacetate [PDAc] and 1,2-dioctanoyl-sn-glycerol) and inhibitors (5-isoquinolinylsulphonyl)-2-methylpiperazine [H-7], sangivamycin and polymyxin B) of the enzyme on the surface field potential known as the N-wave. PDAc (0.3 to 20 mumol/l) and 1,2-dioctanoyl-sn-glycerol (25 to 250 mumol/l) increased the area and amplitude of the potential. In control slices in which a population spike was recorded, PDAc also triggered the appearance of multiple spikes. In a series of input-output experiments, PDAc (2.5 or 5 mumol/l) increased the area and amplitude of the N-wave relative to that of the action potential but did not significantly affect pyramidal cell excitability. The effects of PDAc on the N-wave were antagonised by all three protein kinase C inhibitors but not by the calmodulin antagonist calmidazolium and were greater in slices perfused with solution containing 10 rather than 1 mmol/l Mg2+ or 1.25 rather than 5 mmol/l Ca2+. The effect of PDAc on the amplitude but not area of the N-wave was blocked by the potassium channel blocker tetraethylammonium (10 mmol/l) but not by 4-aminopyridine (0.25 mmol/l). In a series of conditioning experiments, PDAc (1 to 5 mumol/l) reduced the amplitude of the N-wave evoked by a second stimulus compared to that evoked by the first conditioning pulse.(ABSTRACT TRUNCATED AT 250 WORDS)

Using the whole cell patch clamp recording technique, the reversal potential of currents generated by the application of excitatory amino acids and by stimulation of excitatory synapses has been examined in cultured spinal cord neurones, with the partial substitution of intracellular K+ by TEA+. A previous report (Clements et al. 1986) showed that intracellular injection of TEA into the soma of spinal motoneurones in the cat shifted the reversal of the 1a EPSC to more positive potentials, but the reason for this shift was not clear. The results reported here show that the observed change in the reversal potential for both excitatory amino acid agonists and the excitatory synaptic current, was not due to a change in the relative permeability of the channels to potassium or sodium, but could be explained by a change in driving force for the permeant intracellular ions (K+ and/or Cs+) on their substitution with the impermeant TEA+ ion.

A simple in vivo method for studying spinal reflexes and neuromuscular transmission in anaesthetized mice is described. The technique utilizes electromyographic recording from muscles of both hind limbs following stimulation of the sciatic nerve in one limb. Drug effects on the neuromuscular junction, on monosynaptic reflex transmission and on crossed polysynaptic reflexes can be assessed. In addition a method for distinguishing between drugs which affect neuromuscular transmission and those which affect nerve conduction is described using their different effects on reexcitation of motoneurons. Details of data collection and analysis using a laboratory microcomputer are presented. The effects of a variety of representative compounds which have been shown to affect central and peripheral neurotransmission in other systems have been evaluated. The actions of these drugs in this system are compared with those obtained using spinal animals and more sophisticated recording techniques. The results compare favourably with those obtained using more complex methods and the technique offers a simple and inexpensive way of evaluating drug action at these synapses.

Intravenous baclofen (1-6.25 mg kg-1) substantially reduced the monosynaptic excitation of neurones in the intermediate nucleus of the cat spinal cord by impulses in group I extensor muscle primary afferent fibres, but had little or no effect on excitation by stimulating fibres of the ipsilateral dorsolateral funiculus or the contralateral red nucleus. Relatively low concentrations of baclofen thus appear not to influence the release of excitatory transmitter from the terminals of rubrospinal, corticospinal and long descending propriospinal fibres, in contrast to the reduction of the release of primary afferent transmitters.

1. Botulinum toxin type A was injected into gastrocnemius muscles of cats and 2 days later its action on the monosynaptic gastrocnemius reflex and on the recurrent inhibition was investigated. 2. In early local botulism, no significant change in the monosynaptic gastrocnemius reflex was observed. 3. The inhibition by antidromic stimulation of the monosynaptic gastrocnemius reflex was significantly reduced. 4. During the early phases of local botulism an action of botulinum toxin on parts of the soma membrane of the alpha-motoneuron is suggested.

Tetanus toxin was injected at various doses (0.1-10,000 mouse MLD/kg) into the gastrocnemius muscle of the left hind leg of the cat. The relative excitability of the monosynaptic reflex (MSR) was increased in the very early period of the intoxication decreased in the later period, during which the MSR of the gastrocnemius was either partially or totally depressed at doses as low as 10 mouse MLD/kg.

The effects of a series of purine nucleosides, including the novel marine natural product 1-methylisoguanosine, have been examined on muscle relaxation in conscious animals and on spinal reflexes and neuromuscular transmission in mice anaesthetized with sodium pentobarbitone. 1-Methylisoguanosine (5--15 mumol kg--1) and 2-chloroadenosine (1--5 mumol kg--1), both of which cause muscle relaxation in conscious animals, depressed both mono- and polysynaptic spinal reflexes but did not affect neuromuscular transmission. At much higher doses (300 mumol kg--1) both compounds did depress neuromuscular transmission. Adenosine and 1-methyladenosine did not produce muscle relaxation in conscious animals and only slightly depressed polysynaptic reflexes at the highest doses tested (300 mumol kg--1). Theophylline 50 mumol kg--1 enhanced polysynaptic reflexes and antagonized the depression of these reflexes by 1-methylisoguanosine. Neither adenosine nor 1-methylisoguanosine affected the development of tension by isolated diaphragm muscles in vitro. It is concluded that the muscle relaxant purine nucleosides 2-chloroadenosine and 1-methylisoguanosine produce their effects primarily by depressing activity in the central nervous system. Transmission at the neuromuscular junction is not affected at doses in the range of those producing muscle relaxation.

The action of delta-aminovaleric acid (AVA) on the muscle relaxant properties of baclofen, a GABAB receptor agonist, was investigated in two experimental models: (1) the pathologically increased muscle tone of the gastrocnemius muscle in spastic mutant Han-Wistar rats and (2) the Hoffmann (H)-reflex recorded from plantar foot muscles after electrical stimulation of the tibial nerve in barbiturate (60 mg/kg) anaesthetized rats. In both paradigms coadministration of AVA (500 nmol/5 microliter) antagonized the muscle relaxant action of intrathecally applied baclofen (0.2-2 nmol), but failed to affect the muscle relaxant effects of intrathecally injected muscimol (2-20 nmol). In contrast, coadministration of bicuculline (1 nmol) did block the muscle relaxant action of muscimol, but failed to alter the effects of baclofen. When administered alone, bicuculline (1 nmol), or AVA (500 nmol-2 mumol) were without intrinsic action in both paradigms. In an additional series of experiments we investigated the action of AVA on a supraspinal effect of baclofen. Coadministration of AVA (12.5 nmol/0.5 microliter) in the ventromedial thalamic nucleus antagonized the catalepsy induced by baclofen (ED50 10 pmol/0.5 microliter), as indicated by an increase in ED50 of baclofen by a factor of 4.835 and a parallel shift of the probit-log dosage regression line to the right. The parallel shift seems to be consistent with a competitive mechanism of action of AVA. This study presents evidence that AVA antagonizes central pharmacological actions of baclofen at both spinal and supraspinal sites without affecting the actions of a GABAA agonist, muscimol.