J.W. Phillis

Activation of a noradrenergic pathway from the brain stem to rat cerebral cortex.

Abstract 1. 1. Stimulation of the nucleus locus coeruleus (LC) inhibits the extracellularly recorded electrical activity of corticospinal and other unidentified neurones in the rat cerebral cortex. 2. 2. With 3–4 pulse trains of stimulation, the inhibitions had mean latencies of 32 ± 1.5 msec and 54 ± 2.3 msec (mean ± S.E.M.) for identified and unidentified neurones, respectively. 3. 3. The duration of LC evoked inhibition was 148 ± 4.6 msec and 148 ± 3.7 msec for the two groups of nerve cells. 4. 4. Iontophoretically applied noradrenaline depressed the spontaneous firing of all LC-inhibited cells on which it was tested. 5. 5. The LC-evoked inhibition was reversibly antagonized by MJ 1999 (Sotalol, a β-adrenergic blocker) and was absent in 6-OHDA-treated animals. 6. 6. Phenylephrine and salbutamol had depressant effects on cerebral cortical neurones. 7. 7. The findings show that the LC projection inhibits cerebral cortical neurones and implicate noradrenaline as the transmitter released by these fibres.

Effects of α- and β-adrenergic blocking agents on the biogenic amine stimulated (Na+K+) ATPase of rat cerebral cortical synaptosomal membrane

Abstract 1. 1. Adrenergic agonists (adrenaline, noradrenaline, isoproterenol and phenylephrine) stimulate the activity of (Na + K + ) ATPase (EC 3.6.1.3) in rat cerebral cortical synaptosomal fractions. 2. 2. The potencies of the agonists on the stimulation of the enzyme arranged in descending order are adrenaline ⩾ noradrenaline > isoproterenol > phenylephrine. 3. 3. The response to noradrenaline can be antagonized by both α- and β-adrenergic blockers. 4. 4. We conclude that the stimulation of cerebral (Na + K + ) ATPase by biogenic amines could be a receptor-mediated process. 5. 5. The results also indicate that it is possible that both α- and β-receptors activate a common mechanism.

Receptor-mediated noradrenaline stimulation of (Na+-K+) ATPase in rat brain cortical homogenates.

Abstract 1. 1. The stimulation by biogenic amines of (Na+-K+) ATPase in a rat brain cortical homogenate has been examined. 2. 2. It was found that amine stimulation of (Na+-K+) ATPase activity possibly involves a “catecholic receptor”. 3. 3. The binding affinity of the amines to the “receptor” as measured by the concentration of amine required to produce a 50% stimulation of the enzyme was; noradrenaline (3.1 × 10−7 M), adrenaline (3.1 × 10−6 M) and isoprenaline (6.7 × 10−6 M). Phenylephrine was ineffective. 4. 4. The α- and β-adrenergic blockers, phentolamine and propranolol stimulated enzyme activity at 10−5 and 10−6 M, however, they both inhibited (Na+-K+) ATPase activity at a 10−3M concentration. 5. 5. Both phentolamine and propranolol (10−5M) abolished the enzyme stimulation by 10−6M noradrenaline. This blocking effect of the antagonists could be reversed by increasing the noradrenaline concentration to 10−5M suggesting that noradrenaline may have a higher binding affinity to the “catecholic receptor” than do the adrenergic antagonists. 6. 6. Isoprenaline (10−5M) did not reverse the blocking effect of either phentolamine or propranolol (10−5M). However, increasing the isoprenaline concentration to 10−4M reversed the effect of the blockers, suggesting that isoprenaline may have a lower affinity to the “receptor” than noradrenaline. 7. 7. In conclusion, it appears that noradrenaline stimulation of (Na+-K+) ATPase in rat brain homogenate may be mediated by a “catecholic receptor” whose activation can be antagonized by the α-and β-blockers, phentolamine and propranolol.

The actions of adenosine and various nucleosides and nucleotides on the isolated toad spinal cord

1. 1. The effects of nucleosides and nucleotides of several purines and pyrimidines have been ascertained on the a.c. and d.c. recorded dorsal and ventral root responses of isolated, hemisected, perfused toad spinal cords. 2. 2. On preparations subjected to repetitive dorsal root stimulation, adenosine and adenosine 5′-monophosphate, 5′-diphosphate and 5′-triphosphate (2 × 10−4−10−2 M) hyperpolarized both dorsal and ventral roots. Dorsal root-evoked dorsal and ventral root potentials were reduced in duration but not amplitude. These effects were antagonized by theophylline and caffeine. 3. 3. Adenosine 5′-triphosphate and, to a lesser extent, adenosine 5′-diphosphate, at concentrations of 10−3 M or higher frequently depolarized one or both roots. This effect was potentiated by caffeine and theophylline. 4. 4. Guanosine 5′-monophosphate, 5′-diphosphate and 5′-triphosphate (10−3−10−2 M) hyperpolarized both roots and reduced both the amplitude and duration of dorsal and ventral root potentials evoked by dorsal root stimulation. These effects were only weakly antagonized by caffeine and theophylline. Depolarizations of the roots were sometimes observed with guanosine and its 5′-di- and triphosphates. 5. 5. Adenosine 3′,5′-cyclic monophosphate and guanosine 3′,5′-cyclic monophosphate had no effect at concentrations of up to 10−2 M on the responses and polarization levels of the dorsal and ventral roots. 6. 6. Inosine 5′-monophosphate at high concentrations (10−3−10−2 M) had a weak hyperpolarizing action on the ventral root potential. Cytidine, thymidine, uridine and xanthosine and their 5′-monophosphates had no effect at concentrations of up to 10−2 M. The 5′-triphosphates of these substances all depolarized dorsal and ventral roots. 7. 7. After perfusion with magnesium-containing solutions, adenine nucleotides and uridine 5′-triphosphate depolarized the dorsal roots but had no consistent effect on ventral root polarization levels. 8. 8. The sodium and dicalcium salts of adenosine 5′-triphosphate had equipotent depolarizing actions. The excitant actions of the nucleotides are therefore unlikely to be due to calcium chelation. 9. 9. In conclusion, it appears that adenosine and the adenine nucleotides can have depressant and hyperpolarizing actions on dorsal root terminals and motoneurons of repetitively stimulated preparations. It is suggested that these effects result from a reduction in the release of excitatory transmitter. The 5′-polyphosphates of all the purines and pyrimidines tested can have an excitatory action, the nature of which is currently uncertain.

The effects of ethanol on acetylcholine release from the brain of unanaesthetized cats

Abstract 1. 1. Acetylcholine release from the sensorimotor cortex and lateral ventricles of unanaesthetized, freely mobile, cats was determined by perfusion with push-pull cannulae. 2. 2. Ethanol (1·0 or 1·5 g/kg) administered intraperitoneally evoked behavioral changes characteristic of intoxication. Both doses depressed acetylcholine release from the cerebral cortex but only the higher dose significantly depressed release from the lateral ventricle. 3. 3. Recovery from both the behavioral and acetylcholine-release effects of ethanol commenced some 60 min after its administration.

Action of biogenic amines on the isolated toad spinal cord

Abstract 1. The effects of noradrenaline, adrenaline, dopamine and 5-hydroxytryptamine have been tested on isolated hemisected spinal cords in which synaptic transmission or action potential propagation were blocked by perfusion with high Mg2+—or tetrodotoxin—containing solutions respectively. 2. The catecholamines at a concentration of 10−3M consistently depolarized dorsal root terminals, and in most preparations elicited a small depolarization of motoneurons. At lower concentrations their effects were less consistent. The threshold concentration for discernable effects on the dorsal roots was ∼10−4M. 3. Desensitization to its own effects and those of the other catecholamines occurred following catecholamine application. Recovery from desensitization took up to 60 min. 4. Noradrenaline evoked depolarizations of both roots were antagonized by phentolamine (2 × 10−5M) and propranolol (10−4M). There may be both α- and β-receptors on amphibian neurons and axon terminals. 5. 5-Hydroxytryptamine (10−4M) consistently depolarized dorsal root terminals, usually with a small depolarization of the ventral roots. Higher concentrations elicited pronounced depolarizations in both roots. Desensitization to the effects of 5-hydroxytryptamine was observed with repeated applications. Cross-desensitization between the indole-amine and catecholamines was not observed.

The interaction of four putative glutamate antagonists with glutamate and their effects on the toad spinal cord

1. Four putative glutamate antagonists (L-glutamate diethyl ester, L-glutamate dimethyl ester, L-proline and 1-hydroxy-3-amino-pyrrolidone-2) were tested on the isolated hemisected toad spinal cord. 2. 1-hydroxy-3-amino-pyrrolidone-2 (10(-3)-10(-2) M) selectively antagonized the depolarizations evoked in both dorsal and ventral roots by applications of L-glutamate (5 X 10(-4) M). 3 1-hydroxy-3-amino-pyrrolidone-2 also antagonized the depolarizations evoked in both dorsal and ventral roots by stimulation of the adjacent dorsal root. 4. The dimethyl and diethyl esters of L-glutamate and L-proline had their own depolarizing actions on the dorsal and ventral roots, and neither potentiated nor antagonized the effects of L-glutamate. 5. The results with 1-hydroxy-3-amino-pyrrolidone-2 offer further evidence for the involvement of L-glutamate and L-aspartate in synaptic transmission in the amphibian spinal cord.

Antagonism of glutamate and acetylcholine excitation of rat cerebral cortical neurones by diphenylhydantoin

Abstract 1. 1. Iontophoretically applied diphenylhydantoin (DPH) antagonized glutamate and acetylcholine excitation of cerebral cortical neurones of rats anaesthetized with methoxyflurane and nitrous oxide. 2. 2. It is suggested that the antiepileptic action of DPH could involve an antagonism of glutamate and acetylcholine excitation of central neurones. 3. 3. Although the mechanism through which DPH exerts this antagonism is not understood, a local anaesthetic type action may be a possibility.

Adenosine may regulate the vascular supply and thus the growth and spread of neoplastic tissues: A proposal

Abstract 1. 1. The proposal is developed that endogenously released adenosine may regulate the vascular supply to neoplastic tissue. Evidence supporting this suggestion includes findings that agents which potentiate adenosines action enhance tumor growth and the adenosine antagonists reduce the size of primary tumours and the size and number of metastases.

The role of calcium ions in noradrenaline-elicited hyperpolarization of frog skeletal muscle.

Abstract 1. 1. Noradrenaline hyperpolarizes frog sartorius muscle fibres. Ouabain prevents this hyperpolarization, which is likely due to activation of an electrogenic sodium pump. 2. 2. Decreases or increases in the normal calcium content of the perfusion solution can cause a reduction in the magnitude of noradrenaline-elicited hyperpolarization and reduce its sensitivity to ouabain. 3. 3. In the presence of 0 mM Ca 2+ and 5 mM EDTA, noradrenaline failed to hyperpolarize the muscle fibres. 4. 4. The results suggest that calcium ions are essential for noradrenaline-elicited activation of the ouabin-sensitive electrogenic pump. The pump may be inhibited by excessive levels of calcium in the perfusion solution.