Bulbospinal control of spinal cord pathways generating locomotor extensor activities in the cat.
Intracellular recording of lumbosacral motoneurones in the decerebrate and partially spinalized cat injected with nialamide and L-dihydroxyphenylalanine (l-DOPA) was used to investigate the interneuronal convergence of two bulbospinal pathways and of the segmental pathways involved with the generation of extensor activities during locomotion. Deiter's nucleus (DN) or the medial longitudinal fasciculus (MLF) was stimulated in alternation with, and in combination with, stimulation of group I afferents from extensor muscles or of contralateral flexor reflex afferents (coFRA). The evoked polysynaptic EPSPs were recorded in extensor motoneurones when long-latency, long-lasting discharges were evoked by the stimulation of coFRA and when the group I autogenetic inhibition in extensors was reversed to polysynaptic excitation. Spatial facilitation was inferred when the amplitude of the EPSPs evoked by the combined stimuli was notably larger than the algebraic sum of the EPSPs evoked by individual stimulation. Both DN (16 motoneurones) and MLF inputs (8 motoneurones) showed spatial facilitation when preceded by coFRA stimuli and both could reset the rhythm of fictive stepping by triggering a precocious extensor phase. MLF showed spatial facilitation with extensor group I inputs in 69% of trials but DN failed to show spatial facilitation in any cells. These results indicate that DN and MLF project to the coFRA pathways of the extensor half-centre for locomotion and MLF, but not DN, converge on segmental interneurones of the extensor group I pathways. The implications of such convergence patterns on the functional organization of the extensor half-centre are discussed. (+info)
Parallel nociceptive reflex pathways with negative and positive feedback functions to foot extensors in the cat.
1. Nociceptive reflex pathways to foot extensors were investigated with particular attention given to those not following a flexor reflex (FRA) or withdrawal pattern. 2. In anaemically decapitated, high spinal paralysed cats nociceptive afferents of the foot pad were activated by noxious radiant heat (48-60 degrees C), while for comparison non-nociceptive afferents were activated by weak mechanical stimulation of the skin or graded electrical nerve stimulation. The reflex action of the afferents on hindlimb motoneurones, innervating plantaris and intrinsic foot extensors (tibial nerve), was investigated by intracellular recording, by monosynaptic reflex testing and by recording of neurograms during fictive locomotion. A possible descending control of the nociceptive and non-nociceptive pathways was tested by application of opioidergic and monoaminergic compounds. 3. Beside the typical FRA pattern evoked in the majority of hindlimb motoneurone pools by nociceptive afferents from different skin areas of the foot, the results revealed parallel excitatory and inhibitory nociceptive reflex pathways from the central pad and partly from the toe pads to foot extensors. The excitatory pathways, which did not follow the FRA pattern, were predominantly to plantaris and intrinsic foot extensors. They were distinctly less depressed by opioids and monoaminergic compounds than FRA pathways. 4. While the nociceptive FRA pathways have a general nocifensive withdrawal function, the nociceptive excitatory non-FRA pathway to the foot extensors causes a movement of the affected area towards the stimulus or at least a resistance against the stimulus, i.e. it mediates a positive feedback. (+info)
Variation in activity of monoamine metabolizing enzymes in rat liver during pregnancy.
1. Catechol-0-methyltransferase (COMT) and monoamine oxidase (MAO) activities in rat liver were measured during pregnancy, parturition and postpartum. Compared with activity in non-pregnant controls, both enzymes showed a significant decrease in activity which was most pronounced at day 18. 2. The metabolism of intravenously infused [3H]-adrenaline to [3H]-metanephrine and to [3H]-acidic metabolites was also significantly depressed during pregnancy but had returned to control values by the 21st day. 3. The effects of reserpine and/or nialamide on hepatic COMT and MAO were studied in control and 20-day-pregnant rats. Their action on COMT activity differed in the two groups. MAO was inhibited to a similar extent in these groups whether the drugs were given separately or in combination. 4. It seems possible that the changes in endocrine function which occur during pregnancy are responsible for the observed alterations in enzyme activity. (+info)
The effects of nialamide on adrenergic functions.
Nialamide potentiated the pressor effects of noradrenaline in the pithed cat. In cats treated with reserpine and then pithed, it prevented the restoration of the pressor effects of tyramine by slow intravenous infusions of noradrenaline. Nialamide produced a gradual decline in the pressor effects of repeated injections of tyramine whilst the effects of tyramine on the nictitating membrane were potentiated. The development of tachyphylaxis to tyramine in the isolated guinea-pig heart was associated with a 40% reduction in the myocardial concentration of noradrenaline. The onset of tachyphylaxis to tyramine was more rapid when nialamide was either included in the perfusion fluid or administered in vivo. Prior treatment with nialamide increased threefold the myocardial concentration of noradrenaline; however, the development of tachyphylaxis to tyramine was associated with a proportionate fall in the myocardial concentration of noradrenaline. In five out of nine experiments the acute administration of nialamide increased the output of noradrenaline per stimulus from the isolated cross-perfused spleen of the cat when the stimulus frequency was 30 shocks/sec, but not when the frequency was 10 shocks/sec. When nialamide (20 mg/kg) was given subcutaneously to cats 20 hr before their spleens were isolated and perfused, there was a rapid fall-off in the contractions of the spleen in response to periods of nerve stimulation. The outputs of noradrenaline per stimulus were decreased at both frequencies of stimulation. Nialamide decreased the concentrations of noradrenaline in the myocardium and spleen of the cat. The hypothesis is proposed that nialamide diminishes the availability of transmitter, as a consequence of a decreased re-entry of noradrenaline into a storage site present in nerve endings, and that such a decrease in the availability of noradrenaline in hyperactive nerve pathways may account for the antihypertensive effects of monoamine oxidase inhibitors in man. (+info)
Preproenkephalin knockout mice show no depression-related phenotype.
Clinical, preclinical, and pharmacological studies have suggested that decreased enkephalin tone is associated with depression-like symptoms and increase in enkephalin signaling could have a therapeutic value in the treatment of depression. In this study we demonstrate that, surprisingly, animals lacking enkephalin (preproenkephalin, Penk1(-/-)) showed no depression-related phenotype in the Porsolt forced swimming or tail suspension tests. Moreover, Penk1(-/-) mice had a lower frequency of depression-related behavior in stress-induced hypoactivity and ultrasonic vocalization models of depression, similar to animals treated with antidepressant drugs, although this effect was specific to the genetic background. In addition, there was no significant difference in the efficacy of antidepressant reference compounds in wild-type and knockout animals. Nialamide and amitriptyline were even slightly more effective in animals with genetic deletion of Penk1, whereas the minimal effective dose of imipramine and fluoxetine was the same in the two genotypes. The dual peptidase inhibitor RB-101 was also effective in Penk1(-/-) as well as in Penk1(-/-)/Pdyn(-/-) animals, although its efficacy was somewhat reduced compared with wild-type animals. This result was also surprising because the antidepressant effects of RB-101 were thought to be due to the elevation of enkephalin levels. (+info)
Development and validation of a hydrophilic interaction liquid chromatography-tandem mass spectrometry method for determination of isoniazid in human plasma.
The effects of monoamine oxidase inhibitors on the ejaculatory response induced by 5-methoxy-N,N-dimethyltryptamine in the rat.
The ejaculatory response and other components of the 5-hydroxytryptamine (5-HT) behavioural syndrome induced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) (3 mg kg-1, i.p.) were studied following single and repeated treatment of rats with eight different monoamine oxidase (MAO) inhibitors. Single and repeated treatment with the 5-HT agonist 5-MeODMT, and with low doses of the potent releaser of 5-HT, p-chloroamphetamine (PCA) were also included in the study. Repeated but not single treatment with 5-MeODMT reduced strongly but reversibly the ejaculatory response and the behavioural responses. Repeated but not single treatment with the nonselective and irreversible MAO inhibitors nialamide and pargyline reduced markedly the ejaculatory response but only slightly the 5-HT behavioural responses. Repeated treatment with the irreversible MAO-B inhibitor (-)-deprenyl, with the irreversible MAO-A inhibitor, clorgyline, with the reversible MAO-A inhibitor moclobemide, and with low doses of PCA did not affect either of the responses. Repeated but not single combined treatment with clorgyline plus PCA caused an almost complete blockade of all the four responses. The selective and reversible MAO-A inhibitors (as well as 5-HT releasers) amiflamine, alpha-ethyltryptamine, and alpha-methyltryptamine reduced markedly the ejaculatory response after both single and repeated treatments. The behavioural responses were blocked only after repeated treatment. It is concluded that single and repeated treatments of rats with different MAO inhibitors do not produce a common alteration in 5-HT2 receptor functions. Repeated treatment with 5-MeODMT caused a blockade of 75-95% of the ejaculatory response and 5-HT behavioural responses. A similar strong blockade was only produced by the combined effect of MAO-A inhibition and 5-HT release. (+info)