Na+/K+ ATPase α1 and α3 isoforms are differentially expressed in α- and γ-motoneurons.

The Na(+)/K(+) ATPase (NKA) is an essential membrane protein underlying the membrane potential in excitable cells. Transmembrane ion transport is performed by the catalytic α subunits (α1-4). The predominant subunits in neurons are α1 and α3, which have different affinities for Na(+) and K(+), impacting on transport kinetics. The exchange rate of Na(+)/K(+) markedly influences the activity of the neurons expressing them. We have investigated the distribution and function of the main isoforms of the α subunit expressed in the mouse spinal cord. NKAα1 immunoreactivity (IR) displayed restricted labeling, mainly confined to large ventral horn neurons and ependymal cells. NKAα3 IR was more widespread in the spinal cord, again being observed in large ventral horn neurons, but also in smaller interneurons throughout the dorsal and ventral horns. Within the ventral horn, the α1 and α3 isoforms were mutually exclusive, with the α3 isoform in smaller neurons displaying markers of γ-motoneurons and α1 in α-motoneurons. The α3 isoform was also observed within muscle spindle afferent neurons in dorsal root ganglia with a higher proportion at cervical versus lumbar regions. We confirmed the differential expression of α subunits in motoneurons electrophysiologically in neonatal slices of mouse spinal cord. γ-Motoneurons were excited by bath application of low concentrations of ouabain that selectively inhibit NKAα3 while α-motoneurons were insensitive to these low concentrations. The selective expression of NKAα3 in γ-motoneurons and muscle spindle afferents, which may affect excitability of these neurons, has implications in motor control and disease states associated with NKAα3 dysfunction.

Gamma-frequency neuronal activity is diminished in adults with attention-deficit/hyperactivity disorder: a pharmaco-MEG study.

Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder affecting approximately 4-7% of children and persisting in 2-5% of adults. The core symptoms include pervasive inattention and inappropriate levels of hyperactivity-impulsivity. High-frequency gamma activity has been implicated in the temporal binding of stimulus properties across cortical areas, and is known to be crucial for complex information processing and attentional processes in particular. Thus, we evaluated the amplitude of gamma-frequency neural responses in adults with and those without ADHD, and tested whether stimulant medications, the most common treatment for ADHD, modulate gamma activity in affected adults. Participants underwent two sessions (~75 min apart) of auditory stimulation using stimuli known to elicit 40 Hz gamma-band responses as magnetoencephalography data were acquired. Between sessions, the ADHD group (who were in maintenance therapy) were administered their daily stimulant medication and both groups were told to relax. The primary results indicated that gamma activity was weaker in the ADHD group during session one (pre-drug), but not session two (post-drug), and that gamma activity significantly increased following stimulant administration in adults with ADHD. These results suggest that ADHD is associated with reduced cortical gamma activity and that stimulants may ameliorate this abnormality.

Effects on the fusimotor-muscle spindle system induced by intramuscular injections of hypertonic saline.

Intramuscular injection of hypertonic saline (HS) is a procedure widely adopted to experimentally induce deep muscle pain in humans. This study was undertaken to test whether intramuscular injections of HS (5%) influence the activity of primary and secondary muscle spindle afferents (MSAs) from homonymous as well as heteronymous muscles. The experiments were performed on six cats anaesthetised with alpha-chloralose. Usually responses of two to nine MSAs from gastrocnemius medialis (GM) and/or gastrocnemius lateralis (GL) muscles were recorded simultaneously, while HS was injected either into the receptor-bearing muscle (homonymous responses) or into a close (GM/GL) or remote synergistic muscle (posterior biceps, PB, heteronymous responses). The mean rate of discharge and the depth of modulation of the MSA responses to sinusoidal stretching of the receptor-bearing muscle were calculated. Out of the 42 afferents tested (7 from GM and 35 from GL), 38 (90%) exhibited statistically significant responses to injections of HS into homonymous and/or heteronymous muscles. With injections into the homonymous muscle, the average maximal increase in mean rate of discharge was 74% and the average decrease in depth of modulation was --18%. The mean duration of the effects was 2.1 min. The corresponding values for heteronymous injections into a close synergist were 87%, -17% and 2.1 min (GM or GL), and for injections into PB 52%, -11%, and 1.8 min. The majority of the responses (72%) were compatible with reflex action on static fusimotor neurones, whereas 20% of the responses could be attributed to mixed static and dynamic fusimotor action. The remaining 8% of the responses were attributed to inhibition of fusimotor activity. There were no statistically significant differences between the responses following injections into homonymous or heteronymous muscles. Injections of Tyrode's solution did not induce any significant alterations in MSA responses, implying that they were not induced by direct and/or injury effects of the injections. HS-related changes in MSA activity were completely abolished after the nerves to corresponding muscles were cut, confirming the reflex nature of the effects. Thus, intramuscular injections of HS induce reflex changes in MSA activity from both homonymous and heteronymous muscles, most likely via fusimotor reflexes. Predominantly static fusimotor neurones were activated. The possible role of the fusimotor-muscle spindle system in altered motor control during experimentally induced muscle pain is discussed.

Mandibular-position sensation during sedation by administration of nitrous-oxide (N2O) gas.

Our aim was to confirm the influence of N2O gas on mandibular-position sensation. The subjects in this study were eight healthy adults. Each subject was asked to hold the reference stick for five seconds between the central tooth in his or her upper and lower jaws. Then, the reference stick was replaced by the test sticks with different thickness, each of which the subjects were again asked to hold at the same position for five seconds. The subjects were instructed to determine, based on judgement of the interincisal distance, whether the thickness of each test stick was larger or smaller than the reference stick. A series of trials was administered to each subject using all eight sizes of test sticks. We compared the ability of the subjects to discriminate mandibular position both before and after the application of a vibrating stimulus to the masticatory muscles, and before and during the administration of N2O gas. Discrimination ability was significantly decreased after the application of the vibrating stimulus. However, during the administration of N2O gas, no significant difference in discrimination ability was observed between before and after the vibrating stimulus. The results of this study indicated that N2O gas had an inhibitory effect on gamma-motor neuron activity, which is presumed to be mediated to some extent through the higher central nervous system. This is the case because the gamma-motor neurons are generally activated by vibrating stimuli applied to the muscle causing decreased discrimination ability of mandibular position. Thus, we conclude that mandibular-position sensation was influenced by N2O gas during the administration of N2O gas.

Modulation of responses of feline gamma-motoneurones by noradrenaline, tizanidine and clonidine.

1. Effects of noradrenaline (NA) and the alpha2 agonists tizanidine and clonidine were tested on extracellularly recorded responses of gamma-motoneurones in deeply anaesthetized cats. Two types of responses were used; firstly, short latency phasic responses evoked by electrical stimulation of group II afferents in a muscle nerve and, secondly, tonic background discharges. 2. Responses evoked by group II muscle afferents were depressed when NA and tizanidine were applied ionophoretically close to a gamma-motoneurone and when clonidine was applied systemically. The number of spike potentials evoked by stimulation of these afferents decreased and their latencies increased. Responses evoked by flexor or extensor afferents in gamma-motoneurones innervating flexors or extensors were similarly depressed. 3. Tonic discharges were inconsistently and/or insignificantly affected by locally applied NA and tizanidine but were depressed by systemically applied clonidine. 4. Control tests indicate specific effects of NA and tizanidine application since similarly ionophoresed H+ ions did not change responses of gamma-motoneurones to stimulation of group II afferents, or only weakly enhanced their background discharges. Furthermore, serotonin ejected from a solution with a similar pH facilitated rather than depressed responses of gamma-motoneurones. 5. The results indicate that some antispastic effects of clonidine and tizanidine may be due to the depression of group II-evoked responses of gamma-motoneurones, resulting in weaker responses of muscle spindles to muscle stretches.

Increased intramuscular concentration of bradykinin increases the static fusimotor drive to muscle spindles in neck muscles of the cat.

The aim of the present study was to investigate if increased intramuscular concentrations of bradykinin (BK) in one muscle influence the activity in primary and secondary muscle spindle afferents (MSAs) originating from both ipsi- and contralateral muscles, via fusimotor reflexes. The ipsilateral trapezius (TR) and the splenius (SP) muscles were subjected to sinusoidal stretches and 2-3 MSAs were simultaneously recorded from these muscles. Responses of 29 MSAs (15 SP and 14 TR) were registered in five adult cats anaesthetised with alpha-chloralose. Intramuscular injections of 0.5 ml BK (6-86 micrograms/ml) were administered to both the ipsi- and contralateral SP and TR muscles. Similar doses of BK (5-10 micrograms) have been shown to induce muscle pain when injected into the temporal muscle in man. The responsiveness of the MSAs to the injections of BK was 86% and 87.5% from the contralateral TR and SP muscles, respectively. The effects were predominantly static onto the MSAs. The duration of the effects was on average 3.5-4 min, however some effects lasted for more than 15 min. The effects were always abolished after cutting the nerve to the injected muscle. The large majority of the spindle afferents were unresponsive to i.m. Tyrode injections (23 of 29). For the afferents that were responsive to injection of Tyrode, the effects were always considerably smaller and with shorter duration than those evoked by BK injections. Thus, increased intramuscular concentrations of BK may excite primary and secondary MSAs from ipsi- and contralateral muscles, via fusimotor reflexes evoked most probably by activity in chemosensitive muscle afferents. The results are discussed in relation to a recent hypothesis on pathophysiological mechanisms behind genesis, spread and perpetuation of muscle tension and pain in chronic musculoskeletal pain syndromes.

Regulation of soleus muscle spindle sensitivity in decerebrate and spinal cats during postural and locomotor activities.

1. In order to study fusimotor control in reduced preparations, soleus muscle spindle afferents were recorded in premammillary decerebrate cats (n = 15) during crossed extensor reflexes and, after spinalization, during locomotion produced by either clonidine or L-beta-3,4-dihydroxyphenylalanine (L-DOPA). The soleus muscle was oscillated sinusoidally (0.25 mm, 4 Hz) and the afferent mean firing rate and modulation were calculated. An increase in firing rate was assumed to arise from activity in dynamic gamma-motoneurones (dynamic gamma-drive) when associated with an increase in modulation to stretching, and in static gamma-motoneurones (static gamma-drive) when modulation decreased. 2. At rest in all preparations the firing rate and modulation in primary muscle spindle afferents were generally much higher than after de-efferentation (ventral root section), suggesting a predominant dynamic gamma-drive. Clonidine decreased and even eliminated this presumed resting gamma-drive in many afferents, both in the decerebrate (7 of 8) and the spinal (6 of 18) state. This effect on gamma-drive may account, at least in part, for its suppressive effect on spasticity in humans. 3. When locomotion commenced in clonidine-treated spinal cats, primary afferents generally fired with much higher mean rates (+121%) and lower sensitivities (-32%), suggesting a large increase in static gamma-drive (possibly accompanied by a small decrease in dynamic gamma-drive). These high rates were usually maintained tonically throughout the step cycle. However, a third of the afferents were silenced during locomotor contractions, and de-efferentation had no significant effect on their firing rates. Thus, for some spindles alpha-activity can occur without significant gamma-drive. 4. During locomotion in L-DOPA-treated spinal cats the inferred static gamma-drive only occurred phasically, coactivated with the EMG, though it could precede the EMG by 100-500 ms. In the flexion phase both the afferent rate and modulation were lower than before locomotion, suggesting a lack of effective gamma-drive. 5. Crossed extensor reflexes in decerebrate cats also produced a substantial increase in primary afferent firing rate (+187%) and decrease in sensitivity (-37%), again suggesting increased static gamma-drive (n = 18). This gamma-drive was largely independent of EMG activity and often occurred without alpha-activity. The mean firing rate of secondary muscle spindle afferents increased significantly during locomotion (with L-DOPA) and crossed extensor reflexes, again indicating increased static gamma-drive. Clonidine reduced or eliminated the gamma-drive in seven of eight afferents during crossed extensor reflexes. 6. In conclusion, although there are some common features, such as a predominant static gamma-drive in all walking preparations, the pattern of static and dynamic gamma-drive is not closely linked to alpha-activity under the conditions studied. As well as gamma-drive without alpha-activity, we have shown for the first time that alpha-motoneurones can be activated without significant gamma-drive to many spindles during behavioural tasks.

Impulse initiation in the mammalian muscle spindle during combined fusimotor stimulation and succinyl choline infusion.

1. This is a report of observations on the responses of the primary and secondary endings of soleus muscle spindles of the anesthetized cat to the combined effects of the depolarizing neuromuscular blocker succinyl choline (SCh), given intravenously, and fusimotor stimulation. The findings were interpreted in terms of a dual pacemaker model for activity generated in the bag1 intrafusal fiber interacting with activity coming from bag2 and chain fibers. 2. In preliminary experiments it was found, using whole ventral root stimulation at fusimotor strength, that spindle responses to fusimotor stimulation were not blocked by SCh, whereas extrafusal junctions blocked rapidly. In the presence of SCh, fusimotor responses of spindle secondary endings were, on average, slightly larger than their control values before SCh was given, whereas fusimotor responses of primary endings were slightly smaller. 3. A study of the responses of spindle primary endings to stimulation of single dynamic (gamma D) and static (gamma S) axons in the presence of SCh revealed a fundamental difference in behavior. None of the responses to stimulation of gamma D axons (9 gamma D axons with 8 primary endings) showed significant summation with the responses to SCh. By contrast, the 20 gamma S axons studied showed varying degrees of summation with the responses to SCh. The responses of secondary endings to gamma S stimulation in the presence of SCh resembled those of primary endings and gamma S stimulation. 4. To explain these differences it is proposed that the primary ending has two separate sites of impulse initiation, one close to terminals on the bag1 intrafusal fiber (innervated by gamma D axons) and a second close to terminals on the bag2 and chain fibers (innervated by gamma S axons). It is proposed that the maintained increase in spindle firing observed during SCh infusion is the result of a bag2 contracture. The response to gamma S stimulation, contracting bag2 and chain fibers, adds to the SCh response. The degree of summation varies depending on whether the gamma S activates bag2 fibers, chain fibers, or both. The bag1 contracture, together with the effects of gamma D stimulation, acts through a separate pacemaker and therefore does not sum with the steady increase in spindle firing in the presence of SCh. There may be pacemaker switching between the bag1 generator and the bag2 and chain generator. 5. If the model is representative of most spindles containing the three kinds of intrafusal fibers, and the contractions of bag2 and chain fibers generate activity through a common impulse generator, then this bears on the question of the functional independence of the bag2 and chain fiber systems.

Time-dependent fusimotor effects on the discharge of cat primary muscle spindle afferents induced by a long-lasting succinylcholine infusion.

The responses of 46 Ia afferents from the tibial anterior muscle of the cat to repetitive ramp-and-hold stretches were investigated under a succinylcholine (SCh) infusion of 120 micrograms.kg-1.min-1 lasting 15 to 25 min. It was possible to distinguish four consecutive phases of the effect of the SCh on the responsiveness of the Ia afferents. The first three of these four phases have already been described. We analysed in more detail the changes from Phase III to the end of Phase IV. Static fusimotor effects were dominant in the discharge patterns obtained during Phase III; dynamic fusimotor effects prevail at the end of Phase IV. Our observations were quantified by comparing the mean values of initial activity, final static value, dynamic response and slow receptor adaptation read from the discharge patterns obtained during Phase III with the mean values of the same parameters obtained from discharge patterns from the end of Phase IV: the two mean values were significantly different for each of the four measurements. This change from Phase III to the end of Phase IV is highly specific for each spindle. To demonstrate this spindle specificity, discharge patterns were selected from among those produced by each Ia afferent in Phase III and at the end of Phase IV. Each of these discharge patterns was assigned to one of six categories. Category I displays purely dynamic fusimotor effects and Category VI purely static fusimotor effects. Categories II, IV and V display combinations of static and dynamic fusimotor effects with an increasing admixture of static fusimotor effects. The spindle-specific change from Phase III to the end of Phase IV is defined in terms of the specific degree of change from a higher-number to a lower-number category in the case of each of the 46 Ia afferents. In the discussion a combination of activity by the two nuclear bag fibres of a spindle is deduced from the specific discharge pattern of each category. The conclusion from these considerations is that results obtained from the administration of SCh have to be interpreted with great caution in making any statement about the existence of a dynamic bag1 fibre in a spindle.

Effects of L-DOPA on fusimotor control of triceps surae muscle spindles in the cat.

The experiments were performed on lightly alpha-chloralose anaesthetised and spinalized cats. Alterations in fusimotor activity were assessed by recordings from single spindle afferents (90 primary and 12 secondary) from the triceps surae muscle, before and after i.v. administration of L-beta-3,4-dihydroxyphenylalanine (L-DOPA). The effects of L-DOPA on fusimotor reflexes from ipsi- and contralateral hind limb afferents were investigated by using extensions of the intact contralateral hind limb and tonic stretches of the ipsilateral posterior biceps and semitendinosus muscles as reflex stimuli. Prior to injection of L-DOPA, a low reflex responsiveness was found to both the ipsi- and the contralateral stimulation. After administration of L-DOPA, the reflex responsiveness as well as the resting activity of the muscle spindle afferents were increased as a result of enhanced activity in mainly dynamic fusimotor neurones. The results indicate that changes in fusimotor activity elicited after administration of L-DOPA are caused by release of transmission in interneuronal pathways mediating ipsi- and contralateral reflexes to mainly dynamic fusimotor neurones. The possible role of monoaminergic descending control of fusimotor neurones in the regulation of muscle tone, tremor and rigidity is discussed.

Influences on the gamma-muscle spindle system from muscle afferents stimulated by increased intramuscular concentrations of bradykinin and 5-HT.

There is evidence that static muscular contractions induce a release of bradykinin (BK) in the working muscle, and that increased concentration of BK and 5-HT in a muscle increases the discharge rate of a subpopulation of group III and group IV muscular afferents. It is also known that activity in group III and IV muscle afferents may activate gamma-motoneurones to both homonymous and heteronymous muscles. The aim of the present study was to investigate whether increased concentration of BK and 5-HT in one muscle may influence the activity in primary and secondary muscle spindle afferents (MSAs) from the chemically affected muscle and from surrounding muscles, via fusimotor reflexes. The experiments were made on six cats anaesthetised with alpha-chloralose. The triceps surae (GS) and the posterior biceps and semitendinosus (PBSt) muscles were subjected to sinusoidal stretches. Simultaneous recordings of 2-11 MSAs from these muscles were made and the mean rate of firing and the modulation for each MSA were determined. Responses of 47 MSAs (26 PBSt and 21 GS) were recorded. The responsiveness of the MSAs to injections of BK (9-100 mg/ml, 0.5-1.0 ml) and 5-HT (25-150 mg/ml, 0.5-1.0 ml) was 89% and 83%, respectively, for injections into the arterial supply of the ipsilateral GS muscle, and 84% and 40% respectively for injections to the contralateral GS muscle. Of 10 secondarLy MSAs, only one was unresponsive to BK injections, while several MSAs responded to both ipsilateral and contralateral BK injections.(ABSTRACT TRUNCATED AT 250 WORDS)

Fusimotor-induced changes in muscle spindle outflow and responsiveness in muscle fatigue in decerebrate cats.

Changes in discharge rate and responsiveness of muscle spindle afferents from triceps surae muscles were studied during long-lasting fatigue isometric contractions of either medial gastrocnemius or lateral gastrocnemius and soleus muscles in decerebrate cats. The rest of the hind limb was either denervated or its innervation was preserved. In denervated preparations a long-lasting post-contraction increase in discharge rate developed in the majority of primary (15 of 18) and in all (20) secondary afferents. This increase was abolished, while the decrease during muscle contraction was enhanced after application of procaine to the corresponding muscle nerve, to block either the small-diameter afferents from the contracting muscle or the fusimotor axons to the spindle of origin of the afferent recorded. In innervated preparations the long-lasting increase was replaced in the majority of primary endings (14 of 22) by a sharp burst at the end of muscle contraction, while in secondary afferents it was either absent or shorter-lasting than in denervated preparations. Changes in responsiveness to sinusoidal muscle length changes, indicating influences of both static and dynamic fusimotor neurons, were, however, similar in innervated and denervated preparations. The results obtained provide evidence that changes in muscle spindle outflow and responsiveness are elicited by the reflex increase in fusimotor activity developing in response to the fatigue-induced afferent discharges from the contracting muscle. Concomitant afferent inflow of another origin to fusimotor neurons affects the changes in spindle outflow, but not in responsiveness. In this way an appropriate increase in support to skeletomotor activity as well as in information on the fatigued muscle of higher motor centres, initiated by the fatigue itself, could be achieved through the gamma loop.

The pharmacological properties of CS-722, a newly synthesized centrally acting muscle relaxant.

The pharmacological properties of (R)-4-chloro-2-(2-hydroxy-3-morpholinopropyl)-5-phenyl-4-isoxaz olin-3-one hydrochloride (CS-722), a newly synthesized, centrally acting muscle relaxant, were studied in rats. The drug CS-722 reduced the radio frequency decerebrate rigidity in a dose-dependent manner (25-100 mg/kg, p.o.); it inhibited the increase in discharges from Ia afferent fibers, gamma-motor activity, which was induced by stimulation of the reticular formation. The compound, however, showed no effect on the basal discharge of Ia afferent fibers. The polysynaptic reflex was depressed by CS-722, with less influence on the monosynaptic reflex in intact and spinal preparations and CS-722 did not prolong thiopental-induced sleeping time. In rats anesthetized with halothane, CS-722 did not affect the electroencephalogram (EEG) arousal response, which was elicited by stimulation of the reticular formation. The results of this study suggest that CS-722 can exert a muscle relaxant action, at a dose range at which depression of the ascending reticular activating system was negligible. The results also suggest that depressions of the gamma-motor system and the polysynaptic reflex may contribute to the muscle relaxant action of CS-722.

Ketamine effects on somatosensory cortical single neurons and on behavior in rats.

The neurophysiological effects of ketamine were studied at the single-neuron level in the somatosensory cortex of unanesthetized rats behaving in a treadmill movement paradigm. Chronically implanted 25-microns microwire electrodes were used to record spontaneous discharge, sensory responses, and sensorimotor-correlated activity of single neurons before and after ketamine administration. Extracellular action potentials of up to six single neurons were simultaneously recorded for several days, allowing ketamine effects to be tested repeatedly on the same neurons. Videotaped recordings obtained during each experiment were used to measure both the sensorimotor properties of the neurons and the changes in these measures caused by different doses of ketamine. Behaviorally, ketamine produced restless-hyperactive behavior at subanesthetic doses from 5 to 20 mg/kg (intramuscularly). At higher doses (30-50 mg/kg) the rats became cataleptic and immobile after the initial hyperactive period. Whereas the spontaneous rates of most neurons were reduced or unchanged after subanesthetic doses, a subgroup (27% of the total) exhibited markedly increased firing rates. This excitation was of a tonic nature, persisting for a dose-dependent duration in a manner that was not correlated with any of the behavioral effects of the drug. In further analyses, ketamine suppressed the sensory responses of virtually all of the recorded neurons. In particular, low doses of ketamine suppressed "sensorimotor" firing (mainly proprioceptive responses) of neurons in relation to active limb movement. It also suppressed virtually all neuronal sensory responses to the sudden onset of treadmill movement, although the time-course of this effect varied from neuron to neuron. These results reveal two separable effects of ketamine: (a) a strong inhibition of all somatosensory responsiveness in this area and (b) a tonic excitatory influence expressed heterogeneously on a subgroup of neurons. This coexistence of cortical neuronal excitation and sensory suppression in the same cortical region may explain in part the mechanism of dissociative anesthesia and hallucinatory side effects observed in humans during emergence from ketamine anesthesia.

Description and analysis of the myotonolytic effects of phenytoin in the decerebrate cat: implications for potential utility of phenytoin in spastic disorders.

Phenytoin (DPH) was evaluated for its capacity to reduce several motor manifestations of decerebrate rigidity in the cat. In doses of the order of 40 to 50 mg/kg i.v., DPH diminished the force necessary to collapse the hyperextended limbs; at about half this dose range, the drug reduced gamma-motoneuron discharges; at still lower doses the drug profoundly depressed mechanical and electromyographic responses evoked by stretch from both forelimb and hindlimb extensor muscles. Serum levels of DPH associated with substantial reduction in electrical and mechanical manifestations of the extensor hypertonus were of the same order conventionally encountered when the drug is administered to humans for acute seizure management. The data are supportive of a centrally and peripherally mediated muscle relaxing effect of the drug in states where muscle spindle involvement is a contributing factor, and may help to explain further the utility of DPH in the treatment of spasticity.

Comparative study on the effects of haloxazolam and estazolam, new sleep inducing drugs, on the alpha- and gamma-motor systems.

The pharmacological actions, in vivo, of estazolam and haloxazolam were comparatively studied. Spontaneous discharges of spinal motoneurons in cats were markedly suppressed by estazolam (3 mg/kg, i.d.), but unaffected by similarly administered haloxazolam. The facilitatory effect of stimulation of the posterior hypothalamus on the gamma-activity was suppressed by both haloxazolam and estazolam (3 mg/kg, p.o., for each). The stimulus threshold was raised 1.7 times by haloxazolam and 1.6 times by estazolam. The facilitation of the gamma-activity induced by stimulation of the mesencephalic reticular formation was also depressed by both drugs. The stimulus threshold was raised 6 times by estazolam, but unchanged by haloxazolam. The spinal monosynaptic reflex was unaffected by haloxazolam, while its amplitude was depressed to a half by estazolam (3 mg/kg, p.o., for each). The facilitation of the monosynaptic reflex induced by conditioning stimulation was depressed by both drugs (3 mg/kg, p.o.), but estazolam showed a stronger suppressive action. The seizure-like responses of spinal motoneurons, which were induced by stimulation of the gastrocnemius nerve following strychnine administration, were unaffected by 30 mg/kg of haloxazolam, while they were suppressed by estazolam of the same dose. Thus, the results of all experiments in the present study indicate that estazolam blocks the descending activating functions of both alpha- and gamma-motor systems, whereas the blockade by haloxazolam is limited only to the gamma-system, and also that the suppressive actions of estazolam on both alpha- and gamma-motor systems are stronger than that of haloxazolam.

The effects of baclofen on gamma motoneurones supplying gastrocnemius muscle in the rabbit.

The effect of baclofen on gamma motoneurones supplying gastrocnemius medialis muscle in the rabbit has been investigated. Baclofen was found to decrease the frequency of firing of tonic gamma motoneurones, and in some cells to inhibit the tonic discharge altogether. Baclofen also increased the regularity of tonic gamma motoneurone discharge. The drug was found to raise the threshold for firing of gamma motoneurones in response to electrical stimulation of the sural nerve, indicating a depression of reflex transmission between the sural nerve and the motoneurones. The results are discussed and brief consideration given to the possible consequences of these results for the action of the drug in human spasticity.

The effect of dantrolene sodium on intrafusal muscle fibres in the rat soleus muscle.

1. The action of the skeletal muscle relaxant drug, dantrolene sodium, given intravenously, on the intrafusal fibres of the soleus muscle of the urethane-anaesthetized rat has been investigated. The experiments were made on functionally single spindle afferents and gamma fusimotor fibers isolated in dorsal and ventral roots respectively. 2. Dantrolene sodium was without effect on the discharge of primary and secondary afferents from the passive muscle spindle, nor were the dynamic indices of these endings affected. 3. Intrafusal muscle contraction was measured indirectly by means of the spindle afferent discharge. 4. The intrafusal muscle twitch contraction, as measured by means of the amplitude of the frequencygram, was depressed more slowly to a lesser extent than was the twitch of the extrafusal contraction. 5. Intrafusal contraction resulting from tetanic stimulation of the gamma fibre was depressed by dantrolene sodium to an extent dependent upon the stimulation frequency. At frequencies of 10, 25 and perhaps 50 Hz the depression was complete, that is, no afferent response was evoked; at 200 Hz stimulation, the depression was minimal (or non-existent). 6. For a muscle spindle primary ending under dynamic gamma activation dantrolene sodium caused a reduction of dynamic index whereas for the ending under static activation it caused an increase. 7. The significance of the findings in terms of the clinical use of the drug is considered.