Parallel suppression of extensor muscle tone and respiration by stimulation of pontine dorsal tegmentum in decerebrate cat

This paper describes the pontine brainstem area responsible for the suppression of postural muscle tone as well as of respiration in acute precollicular-postmammillary decerebrate (mesencephalic) cats. Stimulation of the dorsal part of the pontine tegmentum (DTF) along the midline (P4-P7, H-5 to H-6) decreased the bilateral tone of the hindlimb extensor muscles and the diaphragmatic activity. Tonic discharges of the extensor muscles were suppressed by DTF stimulation and the suppression of muscle activity continued for more than 5 min after termination of the stimulation. In contrast, the suppression of the diaphragmatic activity, which resulted in apnea in some of the animals tested, resumed in spite of the continuation of the stimulation. However, the rebound augmentation of the diaphragmatic activity appeared immediately after the termination of the stimulation. The existence of such a rebound phenomenon suggested that the suppressive effects on the diaphragmatic activity persisted during the entire period of the stimulation. The recovery of respiratory movements during the stimulation led us to suggest that the strong respiratory drives emerge to overcome the exerted DTF-elicited suppressive effects on respiration. In the paralyzed and vagotomized animal, the DTF-elicited suppressive effects on phrenic neural discharges were minimal when the end-tidal pCO2 was set at a higher level than during spontaneous breathing.     

Effects of unilateral and bilateral labyrinthectomy on rat postural muscle properties: the soleus

The aim of our study was to determine whether the suppression of the vestibular inputs could have effects on the soleus muscle properties similar to the modifications observed after an episode of microgravity. The inner ear lesion was performed by surgical labyrinthectomy. Twenty-nine male Wistar rats were used for this study and were divided into three experimental groups: control (CONT, n=7), unilateral labyrinthectomized (UL, n=14) and bilateral labyrinthectomized (BL, n=8). Mechanical, histochemical and electrophoretic parameters were determined 17 days after the operation. Furthermore, electromyographic (EMG) activity of the soleus muscle was examined at 1 h, 1 day and 17 days. Our results showed that UL and BL groups did not present any sign of muscle atrophy when compared to CONT group. However, the contractile and phenotypical characteristics of UL and BL soleus muscles revealed that the muscle evolved from slow toward a slower type. This transition was correlated with a more tonic EMG activity pattern. To conclude, our data demonstrated that soleus muscle transformations observed after microgravity (muscle atrophy, slow-to-fast transition, phasic EMG activity) were not directly the consequence of a vestibular silence.     

Evidence for GABAergic projections from the tegmental nuclei of Gudden to the mammillary body in the rat

Immunochemical studies have demonstrated the presence of large numbers of cells immunoreactive for glutamic acid decarboxylase (GAD) within the dorsal and ventral tegmental nuclei of gudden. Following injections of Fluoro-Gold into the medial mammillary nucleus, a substantial proportion of the retrogradely labeled neurons within the ventral tegmental nucleus displayed GAD-like immunoreactivity. Conversely, electrolytic or excitotoxic lesions of the ventral tegmental nucleus produced a large decrease in the number of fibers and terminals immunoreactive for GAD within the medial mammillary nucleus. In contrast, electrolytic lesions of the dorsal tegmental nucleus were found to produced a large decrease in GAD-like immunoreactivity which was restricted to the lateral mammillary nucleus. Control lesions placed caudal to the dorsal tegmental nucleus were without effect. These findings suggest that the dorsal and ventral nuclei send a substantial, topographically organized, GABAergic input to the mammillary body.     

Electromyographic assessment of neonatal muscle tone

A new psychiatric research method for measuring infant muscle tone using quantified electromyography is described. Muscle tone was assessed electromyographically from the arms and legs of 44 neonates; 18 offspring of drug abusing women, 26 control infants. Infants from the drug group had higher muscle tone than control infants. There was also a tendency for smaller infants and females to have higher muscle tone. Electromyographic assessments of tone were correlated with examiners' clinical assessments, but tended to be more sensitive to tone in specific muscle groups.     

Units in tegmental nuclei responding to stimulation of gastric vagal and greater splanchnic fibers in the cat

The response of neurons in the ventral and dorsal tegmental nuclei during electrical stimulation of the gastric vagal fibers which serve the proximal stomach and the left greater splanchnic fibers were evaluated in chloralose-anesthetized cats. The mean latency of 181 gastric vagally evoked unitary responses recorded in the tegmental nuclei was 352.2 ms, whereas the latency of the left greater splanchnic-evoked tegmental response was significantly less (63.2 ms). The unitary responses to the gastric vagal and greater splanchnic fibers stimulation were bilaterally distributed in the ventral and dorsal tegmental nuclei. Convergence of the gastric vagal input from the proximal stomach and the left greater splanchnic input was observed in 151 units (83 percent). Stimulation of the greater splanchnic nerve usually resulted in a short latency excitation followed by an inhibitory effect on gastric vagally evoked responses. The results suggested that some convergent splanchnic inhibition of gastric vagally evoked responses was mediated via an interneuron. Projections from the nucleus tractus solitarius and the parabrachial nucleus to the tegmental nuclei were also identified electrophysiologically by direct microstimulation of the two former areas. The significant number of gastric vagal and splanchnic evoked unitary responses recorded in the ventral and dorsal tegmental nuclei suggested that they may serve as an important pontine site for processing of visceral information between the nucleus tractus solitarius and forebrain sites.     

Substance P-like immunoreactive fibres in the ventromedial mesencephalic tegmentum of rat

The distribution and morphology of the substance P-like immunoreactive (SP-IR) fibres and terminals in the rat ventromedial mesencephalic tegmentum (VMT) were studied using qualitative and quantitative immunohistochemical methods at light and electron microscopic levels. All five component nuclei of the VMT were examined and the size, number and density of immunoreactive terminals determined. The SP-IR fibres were distributed heterogeneously within the VMT. Under the electron microscope, SP-IR axon terminals contained both clear and dense-cored vesicles and made both symmetrical and asymmetrical synapses. The ultrastructure of the SP-IR terminals appeared to differ between nuclei. Small, clear vesicle terminals made symmetrical synaptic junctions with small calibre dendrites in the paranigral nucleus while large, clear and dense-cored vesicle terminals made asymmetrical junctions with somata and large calibre dendrites in the interfascicular nucleus. Quantitative differences between the VMT nuclei were also seen in the density of SP-IR terminals, the paranigral nucleus contained the highest density and the rostral linear nucleus the lowest. A comparison between the number of SP-IR terminals and the total number of axon terminals in the VMT reveals that the majority of all terminals in the paranigral nucleus were SP-IR, as well as the majority of axosomatic synapses in the interfascicular nucleus. These regional differences in the SP-IR innervation suggest that substance P and related peptides may perform several specific functions within the VMT and therefore have a more variable influence on this region than was previously thought.     

Rostral brainstem contributes to medullary inhibition of muscle tone

It has long been known that stimulation of the medial medulla in the decerebrate animal produces bilateral inhibition of muscle tone. In the present study we have found that transection of the brainstem at the pontomedullary junction attenuates this inhibition. An interaction between medullary and rostral brainstem systems is responsible for the medullary inhibition phenomenon. A similar interaction may produce the inhibition of muscle tone seen in REM sleep.     

Mesolimbic dopaminergic system is involved in diurnal blood pressure regulation

Parkinson's disease (PD) patients with autonomic failure show no nocturnal decrease in blood pressure (BP). At present, it is not clear if this symptom is attributable to the disturbance of the dopaminergic (DA) system that is responsible for PD. In the present study, we determined that the mesolimbic DA system is involved in diurnal profiles of the mean BP (MBP) by destroying the A10 DA system in rats with 6-hydroxydopamine. In control rats, a clear dip in the MBP and heart rate (HR) occurs during the light, that is, resting period, analogous to the nocturnal dip in normal humans. This normal daytime decrease in MBP and HR was disturbed by inducing a lesion of the ventral tegmental area (VTA) DA neurons, although the rhythms of wake-sleep duration and behavioral activity remained relatively intact. On the basis of this evidence, the absence of a nocturnal dip in BP in PD patients is attributed to impairment of the mesolimbic DA system.     

Increase of tyrosine hydroxylase-like immunoreactive neurons in the nucleus accumbens and the olfactory bulb in the rat with the lesion in the ventral tegmental area of the midbrain

A small number of neurons in the nucleus accumbens of the rat showed tyrosine hydroxylase-like immunoreactivity (TH-LI). These TH-LI neurons had medium-sized cell bodies with several spiny dendrites. When a lesion was produced in the ventral tegmental area of the midbrain by injecting 6-hydroxydopamine, TH-LI neurons in the nucleus accumbens, as well as those in the olfactory bulb, were increased in number on the side ipsilateral to the lesion. The results indicated that expression of TH might be enhanced in some neurons deprived of dopaminergic afferent fibers.     

Sodium oxybate treatment in narcolepsy and its effect on muscle tone

AimsTo estimate the effect of the compound sodium oxybate (SO) on chin muscle tone in sleep, a re-analysis of the results of the international multicenter study SXB-15 was performed, applying a validated semi-automatic analysis of muscle tone. This analysis distinguishes short (<0.5 s) and long (>0.5 s) muscle activity indices per hour (SMI, LMI) in 116 patients with narcolepsy-cataplexy. While stable stimulant medication was permitted, tricyclics and SSRIs were withdrawn. Polysomnographies were performed at baseline (V5), four weeks after titration of SO to 4.5 g, 6 g, or 9 g or placebo (V6) and after another four weeks on stable SO dose (V7).ResultsSMI and LMI decreased significantly during light sleep. LMI remained stable in all SO groups during slow wave sleep (SWS), but decreased significantly during REM sleep. SMI decreased non-significantly, but consistently during SWS and REM in the 9 g group only. A subgroup analysis of patients who stayed on stimulants showed that they had higher SMIs and LMIs in all groups. Patients who had been treated with anticataplectic medication prior to study inclusion had lower LMIs in the 9 g group during REM sleep in all visits.ConclusionSO has a differential effect on muscle tone that is dose and sleep stage dependent. Low dosages increase short muscle activity, possibly enabling the occurrence of parasomnias. High doses are especially efficacious in REM sleep, suggesting that SO could be used to treat REM sleep behavior disorder. Comedication with stimulants and prior medication with anticataplectic medication exerts an influence on muscle tone.     

Dopaminergic innervation of the primary visual cortex in the rat, and some correlations with human cortex

Dopaminergic terminals have been identified in the primary visual cortex with three techniques; immunocytochemistry with an anti-dopamine antiserum, retrograde axonal transport techniques using unconjugated wheat germ agglutinin and HPLC determination of catecholamines and metabolites in microdissected sub-regions of occipital cortex in the rat. The results demonstrate a specific dopaminergic innervation, arising from the ventral tegmental area, which is found mainly in laminae VI and V, but with minor innervation also in lamina I. Dopaminergic innervation to adjacent cortical regions is also described. Neurochemical data from post-mortem human material suggests that a similar innervation exists in man. An analysis of the distribution of dopaminergic fibres in relation to the known connections and possible functions of the deep laminae of visual cortex suggests that dopaminergic axons may participate in the corticofugal control of visual afferent pathways.     

Lesion and electrical stimulation of the ventral tegmental area modify persistent nociceptive behavior in the rat

The ventral tegmental area (VTA) has been traditionally related with the control of motor responses. However, some studies show that this area is also involved in the processing of nociceptive information. It has been reported that this nucleus participates in the dissociative analgesia phenomenon. In the few works where electrical stimulation and lesion of the VTA have been performed, evaluated with persistent or chronic pain related behaviors, contradictory results have been obtained. Thus, a more detailed analysis of the role of the VTA in persistent pain is needed. Two series of experiments were performed: lesions of this nucleus were done with radiofrequency, (bilaterally at two points per side using a temperature range from 50 to 80 degrees C), and the VTA was electrically stimulated (10 min daily over 5 days, 2 ms rectangular pulses at 100 Hz during 1 s every 5 s) using two different schemes:10 min before the induction of the nociceptive stimulus and 90 min after the induction of the nociceptive stimulus. The latter allowed us to distinguish if the VTA electrical stimulation had a distinctive antinociceptive effect when applied before or after the induction of the nociceptive stimulus on a persistent pain related behavioral response in the rat, the self injury behavior (SIB). Our results showed that VTA lesions enhanced the occurrence of SIB; while activation of this same nucleus by electrical stimulation after the nociceptive stimulus, but not before, facilitates the analgesic process, expressed as a 1 day delay in SIB onset. These results indicate that the VTA is a brain structure that plays a key role in the processing and modulation of persistent pain information. Data are discussed in terms of the relationship of the VTA with the affective component of pain.     

Vulnerabilities of ventral mesencephalic neurons projecting to the nucleus accumbens following infusions of 6-hydroxydopamine into the medial forebrain bundle in the rat

The terminal arbors of dopaminergic projections in the nucleus accumbens (Acb) core degenerate more rapidly, completely and permanently in a variety of neurotoxic circumstances than do those in the medial shell. It is unknown if this always reflects purely losses of the distal parts of axons from the core (as proposed in methamphetamine intoxication), or whether, in some circumstances, the disproportionate loss of core axons may also stem from an intrinsic vulnerability to degeneration of core-projecting neuronal perikarya. Experiments described here addressed this issue in the following manner. Three days after Fluoro-Gold (FG), a retrogradely transported tracer, had been iontophoresed selectively into the core or medial shell of male Sprague-Dawley rats, each received an infusion of saline vehicle containing or lacking 6-hydroxydopamine (6-OHDA) in the ipsilateral medial forebrain bundle (MFB). Twenty-one days later the brains were processed to exhibit ventral mesencephalic neurons containing FG. Application of an unbiased sampling method revealed substantially greater losses of FG labeled neurons relative to controls in rats that had received 6-OHDA lesions and deposition of FG in the Acb core as compared to the medial shell. Of the few core-projecting neurons that remained in the ventral mesencephalon after these lesions, 54% did not co-localize tyrosine hydroxylase immunoreactivity (TH-ir) and, thus, were not expected to degenerate. The capacity to selectively remove core-projecting dopaminergic neurons may be useful in the determination of molecular correlates of vulnerability and resistance to neurotoxicity and to possibly test the role of the core in reinforcement paradigms.     

Stimulation of the rat mesolimbic dopaminergic system produces a pressor response which is mediated by dopamine D-1 and D-2 receptor activation and the release of vasopressin

Treatment with dopamine receptor agonists has been shown to induce centrally mediated effects on cardiovascular regulation. We have investigated the effect on blood pressure and heart rate of stimulating the release of endogenous dopamine in the brain from the mesolimbic/mesocortical (A10) dopaminergic system of conscious Sprague-Dawley rats. Stimulation of the region of origin of the A10 dopaminergic system, the ventral tegmental area (VTA), with local micro-injection of the substance P analogue DiMe-C7, produced a dose-dependent increase in blood pressure and heart rate. The injection of 10 nmol of DiMe-C7 produced a maximum increase in blood pressure of 15–20 mmHg at 10 min following administration and a maximum tachycardia of 70–80 B/min. Intravenous pretreatment with the dopamine D-1 receptor antagonist SCH 23390 (0.1 mg/kg) or the dopamine D-2 receptor antagonist raclopride (0.5 mg/kg) markedly inhibited the pressor response and revealed a bradycardia. Furthermore, the pressor response and tachycardia were completely blocked by pretreatment with the vasopressin V-1 receptor antagonist, Pmp¹,O-Me-Tyr²-[Arg⁸]vasopressin (10 μg/kg). Pretreatment with the ganglion blocker, pentolinium (10 mg/kg), had little effect on the blood pressure response, however it attenuated the tachycardia. Micro-injection of 10 nmol of DiMe-C7 into a region 2 mm dorsal to the VTA had little effect on blood pressure yet produced a marked bradycardia. The administration of DiMe-C7 into the region of origin of the nigrostriatal A9 dopaminergic system, the substantia nigra, produced a slight but significant increase in blood pressure with little effect on heart rate. Intracerebroventricular administration of DiMe-C7 also produced a pressor response with a more pronounced tachycardia. The blood pressure responses produced by intranigral or i.c.v. injection of DiMe-C7 were not inhibited by pretreating the rats with raclopride. These results suggest an involvement of the mesolimbic A10 dopaminergic system in the regulation of blood pressure and heart rate through the activation of dopamine D-1 and D-2 receptors and vasopressin release.     

Spinal cholinergic inhibition of the pressor response to skeletal muscle activation

The purpose of this study was to delineate the role of the cholinergic pathway within the spinal cord in the reflex cardiovascular responses to muscle activity. Based on dose–response experiments, we microdialyzed a 0.1 mM solution of the acetylcholinesterase inhibitor neostigmine into the L7 level of the dorsal horn of anesthetized cats to determine its effects on the mean arterial blood pressure (MAP) and heart rate (HR) responses to static muscle contraction or passive stretch. The peak responses to 1-min contractions and stretches were reduced from control levels after 1 h of drug administration. In four experiments, the cardiovascular responses returned to control levels after a 2-h recovery period. Perfusion of the cholinergic receptor antagonist atropine accentuated the peak MAP response to muscle contraction. By contrast, atropine administration had no effect on the peak MAP adjustment to passive muscle stretch. These data support the hypothesis that increased acetylcholine (ACh) concentrations in the spinal cord inhibit the reflex cardiovascular responses to static muscle contraction. Further, the results suggest that the spinal cholinergic system is activated by metabolic changes in skeletal muscle, but likely unaffected by mechanical muscle changes.     

Chromogranin A applied to the nucleus accumbens decreases locomotor activity induced by activation of the mesolimbic dopaminergic system in the rat

The aim of the study was to obtain supporting evidence, using a behavioral paradigm, of the hypothesis that chromogranin A attenuates transmitter release in the CNS. We studied the effects of chromogranin A injected into the nucleus accumbens on locomotor activity triggered by application of picrotoxin into the ventral tegmental area of rats. Injection of picrotoxin into the ventral tegmental area, which is known to disinhibit dopaminergic mesolimbic neurons, caused a significant increase in horizontal activity. Distance covered during locomotion and movement time increased more than twofold, whereas stereotypy time and number, indices of nonlocomotor behavior, were not significantly affected by picrotoxin. Pressure injection of Chromogranin A into the nucleus accumbens prior to injection of picrotoxin into the ventral tegmental area prevented these locomotor effects and had little or no effect on nonlocomotor behavior. Similarly, the picrotoxin-induced activity was prevented by injecting cobalt chloride into the nucleus accumbens. The results show that chromogranin A has an attenuating effect, either directly or indirectly, on dopaminergic neurotransmission in the nucleus accumbens that can be exemplified by inhibiting picrotoxin-induced locomotor activity. Further studies are needed to determine the mechanism of chromogranin A action in the nucleus accumbens.     

Early changes in experimental denervated rat gastrocnemius muscle

Summary Computer-aided image analysis of EM images reveals important morphometric alterations after only 10 days of rat gastrocnemius denervation. The increasing importance of early quantitative changes in human diagnostics is stressed.Supported by FGWO grant no. 3.0004.82     

Effect of extracellular adenosine 5′-triphosphate on principal neurons of the rat ventral tegmental area

Intracellular recordings were made in a midbrain slice preparation of the rat brain containing the ventral tegmental area (VTA). Dopaminergic principal cells were identified by their electrophysiological properties and their hyperpolarizing responses to dopamine. Superfusion with dopamine (100 μM) caused hyperpolarization and a decrease of the apparent input resistance. By contrast, two structural analogues of ATP, 2-methylthio ATP (2-MeSATP; 10 μM) and α,β-methylene ATP (α,β-meATP; 30 μM) had no effect, when added to the superfusion medium. Pressure applied dopamine also hyperpolarized the membrane, while both 2-MeSATP and α,β-meATP were ineffective. Hence, dopaminergic principal neurons of the VTA do not possess somatic P2 purinoceptors present on peripheral and central noradrenergic neurons.