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The effects of benzodiazepines on spinal homosynaptic depression.

Clonazepam (0.5 mg/kg, i.v.) changed the characteristic pattern of the exponential decline of the monosynaptic responses, the early tetanic rundown, evoked by trains of 10 stimuli (2, 5 or 10 Hz) applied to either the biceps-semitendinosus or triceps surae nerve, and recorded from the ventral root in spinal cats. In the case of the biceps-semitendinosus, clonazepam did not affect the first monosynaptic response or the last five monosynaptic responses forming the plateau, while the second monosynaptic response was markedly depressed, especially at the higher frequencies tested. The triceps surae reacted differently to the administration of clonazepam, in that the first response was increased and the amount of depression of the second response was lessened, with no change of the plateau. All the effects of clonazepam were reversed by the benzodiazepine antagonist, ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylate (Ro15-1788; 5 mg/kg, i.v.), which alone had no effect of its own on any parameters, suggesting that the effects of clonazepam were mediated by central benzodiazepine receptors. Diazepam (1.0 mg/kg, i.v.), caused the same changes in the homosynaptic depression of the biceps-semitendinosus pathway as did clonazepam, but increased the plateau instead of the second response in that of the triceps surae pathway.

Animals↗

Inputs from regularly and irregularly discharging vestibular nerve afferents to secondary neurons in squirrel monkey vestibular nuclei. III. Correlation with vestibulospinal and vestibuloocular output pathways.

1. A previous study measured the relative contributions made by regularly and irregularly discharging afferents to the monosynaptic vestibular nerve (Vi) input of individual secondary neurons located in and around the superior vestibular nucleus of barbiturate-anesthetized squirrel monkeys. Here, the analysis is extended to more caudal regions of the vestibular nuclei, which are a major source of both vestibuloocular and vestibulospinal pathways. As in the previous study, antidromic stimulation techniques are used to classify secondary neurons as oculomotor or spinal projecting. In addition, spinal-projecting neurons are distinguished by their descending pathways, their termination levels in the spinal cord, and their collateral projections to the IIIrd nucleus. 2. Monosynaptic excitatory postsynaptic potentials (EPSPs) were recorded intracellularly from secondary neurons as shocks of increasing strength were applied to Vi. Shocks were normalized in terms of the threshold (T) required to evoke field potentials in the vestibular nuclei. As shown previously, the relative contribution of irregular afferents to the total monosynaptic Vi input of each secondary neuron can be expressed as a %I index, the ratio (x100) of the relative sizes of the EPSPs evoked by shocks of 4 x T and 16 x T. 3. Antidromic stimulation was used to type secondary neurons as 1) medial vestibulospinal tract (MVST) cells projecting to spinal segments C1 or C6; 2) lateral vestibulospinal tract (LVST) cells projecting to C1, C6; or L1; 3) vestibulooculo-collic (VOC) cells projecting both to the IIIrd nucleus and by way of the MVST to C1 or C6; and 4) vestibuloocular (VOR) neurons projecting to the IIIrd nucleus but not to the spinal cord. Most of the neurons were located in the lateral vestibular nucleus (LV), including its dorsal (dLV) and ventral (vLV) divisions, and adjacent parts of the medial (MV) and descending nuclei (DV). Cells receiving quite different proportions of their direct inputs from regular and irregular afferents were intermingled in all regions explored. 4. LVST neurons are restricted to LV and DV and show a somatotopic organization. Those destined for the cervical and thoracic cord come from vLV, from a transition zone between vLV and DV, and to a lesser extent from dLV. Lumbar-projecting neurons are located more dorsally in dLV and more caudally in DV. MVST neurons reside in MV and in the vLV-DV transition zone.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

Effects of chronic spinalization on ankle extensor motoneurons. I. Composite monosynaptic Ia EPSPs in four motoneuron pools.

1. We examined the effects of 6-wk chronic spinalization at the L1-L2 level on composite monosynaptic Ia excitatory postsynaptic potentials (EPSPs) recorded in medial gastrocnemius (MG), lateral gastrocnemius (LG), soleus (SOL), and plantaris (PL) motoneurons. Amplitudes, rise times, and half-widths of composite monosynaptic Ia EPSPs evoked by low-strength electrical stimulation of peripheral nerves were measured in barbiturate-anesthetized cats and compared between unlesioned and chronic spinal preparations. 2. The mean amplitude of homonymous composite Ia EPSPs evoked by 1.2 times threshold (1.2T) stimulation and recorded in all four ankle extensor motoneuron pools increased 26% in chronic spinal animals compared with unlesioned controls. There was also an increased incidence of large-amplitude, short-rise time EPSPs. When the same data were separated according to individual motoneuron species, homonymous EPSP amplitudes in MG motoneurons were found to be unchanged. EPSPs recorded in LG motoneurons and evoked by stimulation of the combined LG and SOL nerve were increased by 46%. Mean EPSP amplitudes recorded in both SOL and PL motoneurons were larger after spinalization but statistical significance was only achieved when values from SOL and PL were combined to produce a larger sample size. 3. In LG motoneurons from chronic spinal animals, all EPSPs evoked by 1.2T stimulation of the LGS nerve were > or = 0.5 mV in amplitude. In unlesioned preparations, one fourth of the LG cells had EPSPs that were < or = 0.2 mV. 4. The mean amplitude of heteronymous EPSPs evoked by 2T stimulation of LGS and MG nerves and recorded in MG and LG motoneurons, respectively, doubled in size after chronic spinalization. Because homonymous EPSP amplitudes were unchanged in MG motoneurons, synaptic mechanisms and not passive membrane properties are likely responsible for increased heteronymous EPSP amplitudes in MG. 5. The mean 10-90% rise time of homonymous composite Ia EPSPs in pooled data from all motoneurons decreased 21% in 6-wk chronic spinal animals. Unlike EPSP amplitude, significant rise time decreases were found in all four motoneuron pools. Compared with the other motoneuron species, the mean homonymous rise time recorded in MG motoneurons was shortest and decreased the least in chronic spinal animals. Rise times of heteronymous Ia EPSPs in MG and LG motoneurons also decreased. The maximum rate of rise of homonymous EPSPs increased in all four motoneuron species. 6. The mean half-widths of Ia composite EPSPs decreased in 6-wk spinalized preparations in all motoneuron species.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

Ultrastructural circuitry of cardiorespiratory reflexes: there is a monosynaptic path between the nucleus of the solitary tract and vagal preganglionic motoneurons controlling atrioventricular conduction in the cat.

We have tested the hypothesis: (1) that presumptive negative dromotropic vagal preganglionic neurons in the ventrolateral nucleus ambiguus (NA-VL) can be selectively labelled from the heart, by injecting one of two fluorescent tracers into the two intracardiac ganglia which independently control sino-atrial (SA) rate or atrioventricular (AV) conduction; i.e., the SA and AV ganglia, respectively. The NA-VL was examined for the presence of single and/or double labelled cells. Over 91% of vagal preganglionic neurons in the NA-VL projecting to either intracardiac ganglion did not project to the second ganglion. Consequently, we also tested the hypothesis: (2) that there is a monosynaptic connection between neurons of the medial, and/or dorsolateral nucleus of the solitary tract (NTS), rostral to obex, and negative dromotropic neurons in the NA-VL. An anterograde tracer was injected into the NTS, and a retrograde tracer into the AV ganglion. The anterograde marker was found in both myelinated and unmyelinated axons in the NA-VL, as well as in nerve terminals. Axo-somatic and axo-dendritic synapses were detected between terminals labelled from the NTS, and retrogradely labelled negative dromotropic neurons in the NA-VL. This is the first ultrastructural demonstration of a monosynaptic pathway between neurons in the NTS and functionally associated (negative dromotropic) cardioinhibitory neurons. The data are consistent with the hypothesis that the neuroanatomical circuitry mediating the vagal baroreflex control of AV conduction may be composed of as few as four neurons in series, although interneurons may also be interposed within the NTS.

Animals↗

General pharmacology of the anxiolytic compound metaclazepam in comparison to other benzodiazepines.

7-Bromo-5-(2-chlorophenyl)-2,3-dihydro-2-(methoxymethyl)-1H-1,4- benzodiazepine X HCl (metaclazepam, KC-2547, Ka-2547, Talis) is a novel 1,4-benzodiazepine characterized by a high selectivity of its anxiolytic effects. The present experiments were performed to contribute to its general pharmacological profile and to evaluate possible risks especially on the cardiovascular field in comparison to standard benzodiazepines. The experiments were performed in guinea pig isolated ileal and papillary muscle preparations, anesthetized cats and dogs, conscious renal hypertensive (RHR) and pithed rats. At intravenous, intraduodenal and repeated oral administration of metaclazepam in anesthetized cats and dogs and RHR arterial hypotension, if any, occurred only at rather high dosages. Tilting experiments in dogs did not show any risk for postural hypotension due to metaclazepam. In guinea pig papillary muscles and in anesthetized dogs (i.v.), metaclazepam had a moderate negative inotropic effect. A diminution of stroke volume was seen only at high i.v. doses whereas cardiac output was maintained nearly constant by an increase in heart rate. In guinea pig papillary muscles metaclazepam, like diazepam, had only a tendency to prolong the refractory period. Unlike diazepam, i.v. metaclazepam had no relevant depressant effect on respiration in anesthetized cats. No specific interaction of metaclazepam with alpha- or beta-adrenoceptors was found in pithed rats and anesthetized cats. The papaverine-like, unspecific spasmolytic profile in the guinea pig isolated ileum suggests that metaclazepam has no relevant antimuscarinic properties. In anesthetized cats neither metaclazepam nor diazepam showed an effect on neuromuscular transmission; metaclazepam caused a markedly weaker inhibition of the polysynaptic linguomandibular reflex than diazepam and did not influence the monosynaptic patellar reflex. In conclusion, the results with metaclazepam did not indicate side effects limiting its therapeutic use as an anxiolytic. Its potential in producing untoward side effects on the cardiovascular and respiratory systems and its central muscle relaxant properties appear to be considerably weaker than with diazepam or bromazepam. Substantial overdosage may result in hypotension and/or impairment of cardiac contractility.

Animals↗

Compensation of human stance perturbations: selection of the appropriate electromyographic pattern.

Perturbations of stance evoke purposive EMG patterns which are directed to hold the body's centre of gravity over the feet. Dorsiflexing rotation of the feet is followed by a monosynaptic stretch reflex response in the gastrocnemius muscle, succeeded by a late compensatory tibialis anterior activation. Backward translation of the feet elicits only a compensatory polysynaptic EMG response in the gastrocnemius muscle, while an early gastrocnemius response is absent. The amplitude modulation of the gastrocnemius H-reflex has been investigated during the early part of the two modes of perturbation. Only during translational perturbation a progressive decrease in gastrocnemius H-reflex amplitude started within 5 ms after onset of displacement. The degree of the reduction in amplitude in the former perturbation was dependent on the displacement velocity. Only the contact forces (torques) differed between the two modes of perturbations within the first 10 ms after onset of perturbations. It is suggested that signals from pressure receptors within the body are responsible for the early change in H-reflex amplitude during translational perturbations and it is concluded that the simplest spinal reflex is under very rapid and powerful moment-to-moment control by changes in peripheral feedback. In view of a strong reciprocal modulation of monosynaptic and polysynaptic reflex responses, the later purposive EMG responses may be determined by early changes in presynaptic inhibition of group I afferents.

Adult↗

The effect of motor preparation on changes in h reflex amplitude during the response latency of a warned reaction time task.

Monosynaptic Hoffman reflexes (H reflexes) were recorded from the soleus muscle during the response latency of a warned reaction time (RT) task that required plantarflexion of the foot. The task was done under four conditions of predictability of the response signal (RS), created by the factorial combination of foreperiod duration (1 and 4 s) and variability (fixed and variable). RT varied systematically with RS predictability and was facilitated in conditions that favored prediction of the RS. The response latency was divided into two successive phases by the onset of reflex augmentation: a premotor phase of constant reflex amplitude and a succeeding motor phase marked by progressively increasing reflex amplitude. Reflex augmentation during the motor phase was coupled more closely to the imminent movement than to the preceding signal to respond. The duration of the premotor phase was unaffected by RS predictability, but the duration of the motor phase (like RT) was shorter when the RS was more predictable. The maximum H reflex amplitude reached during the motor phase was greater when the RS was more predictable. The tonic level of H reflex amplitude during the premotor phase was greater in conditions that made prediction of the RS difficult. A second experiment showed that this difference was present throughout the foreperiod. These results suggest that conditions that favor prediction of the RS enhance motor preparation. changes in motor preparation (which affect RT) affect the processes underlying reflex amplitudes in the premotor phase and throughout the preceding foreperiod, in conditions that make prediction of the RS difficult, appear to reflect heightened general arousal.

Journal Article↗

Effects of intravenous kainic acid, N-methyl-D-aspartate, and (--)-nuciferine on the cat spinal cord.

Kainic acid (a rigid conformational analogue of glutamate), N-methyl-D-aspartate (the methylated derivative of aspartate), and (--)-nuciferine (an aporphine alkaloid with a depressant effect on glutamate-induced neuronal firing), which, so far, have been examined in microiontophoretic studies, were investigated in spinal cats for their effects on some spinal cord activities after intravenous injections. At low doses, kainic acid (0.3 mg kg-1) enhanced segmental monosynaptic but not polysynaptic ventral root reflexes and increased the excitability of motoneurones, whereas N-methyl-D-aspartate (3 mg kg-1) facilitated polysynaptic but not monosynaptic reflexes. Higher doses of the two amino acids depolarized motoneurones and primary afferent endings, enhanced monosynaptic reflexes and depressed polysynaptic reflexes. (--)-Nuciferine (1--10 mg kg-1) depressed monosynaptic but not polysynaptic ventral root reflexes in a dose-dependent manner and antagonized the effects of kainic acid but not of N-methyl-D-aspartate on the spinal cord. The results are consistent with the hypothetical excitatory transmitter role of glutamate in primary afferents and of aspartate in excitatory spinal cord interneurones; the findings also suggest that (--)-nuciferine may be used as a systemically effective, rather selective blocker of central glutamate receptors.

Animals↗

[Testing the excitability of a spiking human motor neuron during the interspike interval].

Excitability of voluntary activated human triceps surae motor units was tested by monosynaptic excitatory Ia afferent volley evoking weak H-reflex. Firing index was used as a quantitative measure of motoneuron excitability. During transition of a low firing rate of a motoneuron (up to 6 imp/s) to moderate one (6-8 imp/s) the firing index fell; with a further increase in the rate (up to 12 imp/s) it practically did not change. Dependence of the firing index on the rate is based on changes in the motoneuron excitability within the interspike interval. The results indicate that at low firing rates of a motoneuron which are characteristic of its natural activation, the firing rate is one of the factors influencing the excitability of the firing motoneuron and hence its input-output relations.

Action Potentials↗

H-reflex changes following spinal cord injury.

Changes in both central synaptic excitability (CSE) and peripheral sensitivity of muscle spindle stretch receptors have been hypothesized to contribute to hyperactive stretch reflexes of spasticity. To assess CSE, the monosynaptic H-reflex to the triceps surae muscles was tested serially over the first six months after traumatic spinal cord injury (SCI). Six clinically complete SCI patients were compared to age-matched control subjects. As a measure of H-reflex excitability, H/M ratios were calculated by dividing maximum H-reflex by maximum M-response amplitude. Analysis of variance over the testing trials showed significant change in H/M ratios for SCI patients (p less than 0.01). T-tests comparing mean H/M ratios at different time periods after SCI revealed a significant increment after three months (p less than 0.01). H-reflex amplitude also increased significantly over this time period (p less than 0.04), but M-response amplitude did not change significantly. These increases in H/M ratio and H-reflex amplitude suggest that an increase in CSE may contribute to the appearance of hyperreflexia after SCI.

Adolescent↗

Specification of synaptic connections mediating the simple stretch reflex.

A variety of mechanisms underlie the specification of synaptic connections during development. In the monosynaptic stretch reflex in vertebrates, sensory neurones innervating muscle spindles are not determined until they make contact with a particular muscle. Instead, the muscle they supply appears to specify the pattern of central connections they establish with motoneurones. Developing thoracic sensory neurones made to project to novel peripheral targets in the forelimb of tadpoles project into the brachial spinal cord, something they never do in normal frogs. Moreover, these foreign sensory neurones make monosynaptic connections with the now functionally appropriate brachial motoneurones. Normal patterns of neuronal activity are not necessary for the formation of specific central connections. Neuromuscular blockade of developing chick embryos with curare during the period of synaptogenesis does not prevent the formation of correct sensory-motor connections. Competitive interactions among the afferent fibres also do not appear to be important in this process. When the number of sensory neurones projecting to the forelimb is drastically reduced during development, each afferent fibre still makes central connections of the same strength and specificity as normal. Together, these results suggest that peripheral targets induce some molecular change in developing sensory neurones such that they can recognize their appropriate synaptic partners in the spinal cord.

Animals↗

Evaluation of the muscle relaxant properties of a novel beta-carboline, ZK 93423 in rats and cats.

The muscle relaxant action of ZK 93423 (6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate ethyl ester), a novel beta-carboline with agonistic properties at the benzodiazepine receptor, was examined by assessing its effect on the tonic electromyogram (EMG) activity of the gastrocnemiussoleus (GS) muscle of genetically spastic rats and on ventral root reflexes, presynaptic inhibition and fusimotor activity in the spinal cord of decerebrate cats. ZK 93423 (0.1-10.0 mg kg-1) depressed the tonic EMG activity in mutant rats in a dose-dependent manner. This effect was reversed by the benzodiazepine antagonist Ro 15-1788 (5.0 mg kg-1). Both ZK 93423 (0.5 mg kg-1) and diazepam (0.3 mg kg-1) enhanced the presynaptic inhibition of the GS muscle and associated dorsal root potentials in decerebrate cats in an almost identical manner. The actions of both drugs were reversed by Ro 15-1788 (5.0 mg kg-1). ZK 93423 (0.5 mg kg-1) and diazepam (0.3 mg kg-1) depressed the activity of both static and dynamic fusimotor neurones, as deduced from changes in the afferent responses of muscle spindle primary endings to low frequency (1 s-1) sinusoidal stretching. The depressant action of diazepam (0.3 mg kg-1) was weaker than that of ZK 93423 (0.5 mg kg-1). The actions of both drugs were reversed by Ro 15-1788 (5.0 mg kg-1). ZK 93423 (0.5 mg kg-1) failed to alter the magnitude of monosynaptic ventral root reflexes evoked by electrical stimulation of a flexor and an extensor nerve, whereas diazepam (0.3 mg kg-1) had a depressant effect on both types of monosynaptic reflexes, which was antagonized by Ro 15-1788 (5.0 mg kg-1). Neither ZK 93423 (0.5 mg kg-1) nor diazepam (0.3 mg kg-1) depressed polysynaptic ventral root reflexes evoked by electrical stimulation of a flexor and a cutaneous nerve. The present results demonstrate that ZK 93423 exerts a potent muscle relaxant action due to a specific interaction with benzodiazepine receptors. However, its profile of actions on spinal motor mechanisms is not identical to that of diazepam.

Animals↗