Effect of cocaine on the contractile response to noradrenaline in the epididymal and prostatic regions of the vas deferens

In the prostatic half of the rat vas deferens, the response to noradrenaline under the cocaine effect revealed a phasic and a tonic components, whereas in the epididymal portion of the vas deferens there only occurred the tonic component. Cocaine increased the maximal tonic contractile response to noradrenaline in the epididymal portion and the maximal phasic response--in the prostatic one. Mechanisms of direct postsynaptic action of cocaine are discussed.     

The effect of cocaine, reserpine, and 6-hydroxydopamine on the response of the perfused central artery of the rabbit ear to sympathomimetic amines.

The perfused central artery of the rabbit ear was less sensitive to extraluminal than to intraluminal noradrenaline, but the reverse was true for metaraminol, methoxamine, metanephrine, and isoproterenol. No difference was noted between the extraluminal and intraluminal potency of phenylephrine. Cocaine potentiated the effect of extraluminal and intraluminal noradrenaline, but decreased that of intraluminal phenylephrine. Irrespective of the route of administration, the constrictor potencies of the sympathomimetic amines were not affected by cocaine. Arteries of reserpine-treated rabbits were supersensitive to extraluminally and intraluminally applied noradrenaline and phenylephrine, but they were not supersensitive to metaraminol. 6-Hydroxydopamine effectively destroyed adrenergic nerve endings of the central ear artery and increased its responses to both extraluminal and intraluminal noradrenaline and phenylephrine. However, only the constrictor potencies of intraluminally applied metaraminol and methoxamine were enhanced by 6-hydroxydopamine. The apparent discrepancies between the results obtained by various procedures that eliminate or impair the nerve uptake process suggest that the difference in the constrictor potency of extraluminal and intraluminal sympathomimetic amines is probably unrelated to their uptake by nerves located in the adventitio-medial junction of the artery.     

The role of calcium in monoamine-induced depression of cerebral cortical neurones

The calcium antagonists, lanthanum, verapamil and manganese, have been shown to antagonize the depressant actions of ionto-phoretically applied monoamines (noradrenaline, 5-hydroxytryptamine, dopamine and histamine), but not of γ-aminobutyric acid, on cerebral cortical neurones. Cocaine and ethanol, which also affect membrane calcium fluxes, have a similar antagonistic action. These findings suggest that calcium ions are essential for, and perhaps mediate, the characteristic depressant actions of the monoamines on cerebral cortical neurones.     

Potentiation by cocaine of relaxations of the guinea-pig colon caused by noradrenaline and by stimulation of adrenergic nerves.

The distal colon of the guinea-pig is relaxed by noradrenaline, by isoprenaline and by the stimulation of fibres running with the colonic nerves or intramurally. The relaxations in response to stimulation of the colonic nerves have a guanethidine-sensitive (adrenergic) and a guanethidine-insensitive (non-adrenergic) component. Cocaine causes a three-fold sensitization of the muscle to noradrenaline but no sensitization to isoprenaline. Cocaine increases the duration, but does not affect the amplitude, of the relaxation observed when adrenergic nerves are stimulated, and affects neither duration nor amplitude of the non-adrenergic response. The adrenergic nerve terminals lie in Auerbach's plexus, not in the longitudinal muscle. It is concluded that the sensitization to noradrenaline and the increases in durations of responses to adrenergic nerve stimulation are due to inhibition of catecholamine uptake into adrenergic nerves by cocaine. It appears that, even where the neuromuscular separation is large as it is in the colon, the concentration of exogenous noradrenaline at the receptors can be decreased by neuronal uptake, and the uptake mechanism can modify responses to nerve stimulation in vitro.     

Antagonism of 5-Hydroxytryptamine by Methiothepin shown in Micro-electrophoretic Studies of Neurones in the Lateral Geniculate Nucleus

THERE has been little success in the search for a specific antagonist of the actions of 5-hydroxytryptamine (5-HT) on central neurones, although several compounds reduce the effects of both tryptamine derivatives and catecholamines in the central nervous system^1,2. The recent report that lysergic acid diethylamide blocked the excitant action of 5-HT, but not that of noradrenaline, on medullary reticular neurones³ has not been confirmed⁴. Moreover, an earlier investigation of olfactory bulb neurones indicated that lysergic acid diethylamide blocked the action of noradrenaline more readily than that of 5-HT⁵.     

Noradrenergic enhancement of Ca2+ responses of basal dendrites in layer 5 pyramidal neurons of the prefrontal cortex

Although the excitatory effects of noradrenaline have been thoroughly studied in the central nervous system, there is relatively little known about the adrenergic effects on Ca2+ dynamics of dendrites. In the present study, we imaged basal dendrites of layer 5 pyramidal neurons in the prefrontal cortex using two-photon microscopy. In our experiments noradrenaline, applied in the bath, enhanced excitability of layer 5 pyramidal neurons. The number of evoked action potentials following current injection to the soma increased by 44.7% on average. In the basal dendrites and spines the evoked Ca2+ responses were also markedly enhanced. Noradrenaline-induced effects could be blocked by the beta-adrenergic blocker propranolol. Our data, that activation of the noradrenergic system increases excitability of layer 5 pyramidal neurons via beta-adrenergic receptors and enhances Ca2+ signaling in basal dendrites, suggest a cellular site of action for noradrenaline to improve the integrative capabilities of dendrites.     

The responses of acetylcholine, γ-aminobutyric acid (GABA), dopamine,octopamine and other putative transmitters on Limulus polyphemus central neurons

1. Intracellular recordings have been made from neurons in the nerve cord of the horse-shoe crab, Limulus polyphemus. The resting potentials range between −30 and −60 mV, while the action potentials range from 2–4 mV up to 60 mV.2. All the cells tested were inhibited by GABA and excited by cholinergic agonists. The action of GABA was reversibly antagonised by picrotoxin while the acetylcholine response was reversibly antagonised by pentolinium and hexamethonium.3. Cells also responded to dopamine, noradrenaline, octopamine, glutamic acid, histamine and 5-hydrosytryptamine (5-HT); certain cells being inhibited by one or more of these compounds while other cells were excited. The actions of dopamine and noradrenaline were always the same, with noradrenaline being about 100 times less potent than dopamine. The action of dopamine was antagonised by metoclopramide and the action of histamine was antagonised by mepyramine.4. The pharmacology of these neurons is compared to insect and crustacean central neurons.     

Role of neurotransmitters in coordination of male sexual behavior

The review considers the published data and the results obtained by the author on the role of monoamines (serotonin, dopamine, and noradrenaline) in the control of male sexual behavior. In the above respect, the central mechanisms of action of the neurotransmitters are discussed.     

Noradrenaline modulates transmission at a central synapse by a presynaptic mechanism

The lateral division of the central amygdala (CeAL) is the target of ascending fibers from the pain-responsive and stress-responsive nuclei in the brainstem. We show that single fiber inputs from the nociceptive pontine parabrachial nucleus onto CeAL neurons form suprathreshold glutamatergic synapses with multiple release sites. Noradrenaline, acting at presynaptic alpha2 receptors, potently inhibits this synapse. This inhibition results from a decrease in the number of active release sites with no change in release probability. Introduction of a presynaptic scavenger of Gbetagamma subunits blocked the effects of noradrenaline, and botulinum toxin A reduced its effects, showing a direct action of betagamma subunits on the release machinery. These data illustrate a mechanism of presynaptic modulation where the output of a large multiple-release-site synapse is potently regulated by endogenously released noradrenaline and suggests that the CeA may be a target for the central nociceptive actions of noradrenaline.     

The effect of etorphine on dopamine and noradrenaline concentrations in different central nervous system structures in the rat

The effect of etorphine on dopamine and noradrenaline concentrations in different central nervous system structures in the rat. Acta Physiol. Pol., 1977, 28 (6): 529-540. Intramuscular administration of etorphine in immobilizing doses (0.008 mg/kg) was followed by a rise in dopamine concentration in the examined motor structures of the central nervous system (striopallidum, pons, cerebellum, lumbosacral intumescence of the spinal cord). Only in the motor centres of the frontal cortex dropamine concentration was decreased. At the time etorphine decreased the concentration of noradrenaline in striopallidum and raised it in the other examined structures of the central nervous system. A correlation was found between the concentrations of both substances, especially in the frontal motor centres and striopallidum. Post etorphine accumulation of dopamine in the striopallidum (for 6.369 to 11.322 mcg/g of fresh tissue) with simultaneous inhibition of motor activity of the animals suggests that etorphine inhibits the release of dopamine from the presynaptic elements in the motor centres of the central nervous system in rats. This leads to a decreased dopamine action on its receptors. Some post etorphine behavioral changes (rigidity, spastic flexion, muscle tremor) support this hypothesis.     

Brain monoamines and circadian rhythm of spontaneous motor activity of rats]

The effect of three drugs, parachlorophenylalanine, nialamide and disulfiram, drugs known by their action on the two sleep phases, slow wave sleep and I-REM-sleep, have been studied and tested by their effect on the motor circadian rhythm : PCPA and disulfiram reduce the amplitude of the rhythm by two opposed mechanisms : PCPA increases the motor activity, especially the day-time activity, disulfiram reduces the motor activity, especially the night-time activity. The former reduces the serotonine content, the latter the noradrenaline content of the central nervous system. Nialamide (5 or 10 mg/1000 g) is without any action of the rhythm. Both doses increase very much the motor activity ; but the central excitatory state undergoes the normal circadian rhythm. This monoaminoxydase inhibitor is without any action on the circadian rhythm.     

DEGENERATION OF CENTRAL AND PERIPHERAL NORADRENALINE NEURONS PRODUCED BY 6-HYDROXY-DOPA

—The effects of systemically administered 2,4,5-trihydroxyphenylalanine (6-OH-DOPA) on endogenous noradrenaline, [³H]amine uptake and fluorescence morphology has been investigated in mouse brain, heart and iris. 6-OH-DOPA in a dose of 100 mg/kg intraperitoneally caused practically no changes in these parameters. Pretreatment with a potent monoamine oxidase inhibitor (nialamide) led to a pronounced long-lasting 6-OH-DOPA induced reduction in endogenous noradrenaline, [ ³ H]amine uptake and nerve density of noradrenaline nerve terminals both in the central and peripheral nervous system. Histochemically accumulations of noradrenaline were observed in non-terminal axons. These results strongly support the view that 6-OH-DOPA can produce degeneration of both central and peripheral noradrenaline neurons. The degeneration is mediated by decarboxylation of 6-OH-DOPA to 6-OH-DA, since the effects could be abolished by decarboxylase inhibition. The effect of 6-OH-DOPA was selective on noradrenaline neurons in the brain, since neither 5-hydroxytryptamine nor dopamine neurons were affected, opening up new possibilities for studies on central noradrenaline transmitter mechanisms. In the brain there were pronounced accumulations of noradrenaline in the ascending noradrenaline axons making 6-OH-DOPA a powerful tool in the mapping of central noradrenaline pathways.     

Resistance and capacitance functions of gastric vessels under the action of noradrenaline

In acute experiments on cats, the gastric vascular bed being perfused under constant blood flow, the actions of gastric vessels was investigated using newly elaborated approach to their humoral isolation. Increased doses of noradrenaline elicited the dose-dependent constrictive response of gastric arterial vessels. Perfusion pressure increase in the gastric vascular bed under action of the minimal dose of noradrenaline was more pronounced, than in the intestinal vessels. The capacity of the gastric vascular bed under action of the drug changed in different manner, mostly increased, but could be decreased as well. In contrast to the small intestine the gastric vessels are characterized by more pronounced action of noradrenaline on blood depoting processes.     

Studies on the mechanism of postetorphine catalepsy. Effects of clotiapine, haloperidol and rompun on postetorphine changes in concentrations of dopamine and noradrenaline in central nervous system of rats

Changes in dopamine (DA) and noradrenaline (NA) concentrations in various central nervous system structures were compared in rats after administration of haloperidol, clotiapine and rompun with changes in these concentrations during etorphine-induced catalepsy. Besides that, these changes were compared with changes in DA and NA concentrations after etorphine administration during full action of haloperidol, clotiapine and rompun. Haloperidol, clotiapine and rompun prolonged the duration of etorphine-induced catalepsy in rats and modified significantly postetorphine changes in DA and NA concentrations in the investigated central nervous system structures. The action of haloperidol, clotiapine and rompun increasing the intensity of postetorphine catalepsy and the previously demonstrated anticataleptic and antietorphine action of agents stimulating the postsynaptic adrenergic structures in the central nervous system in rats may suggest that DA release from presynaptic structures is inhibited after etorphine.     

The effect of cocaine on kinetics of α<Subscript>1</Subscript>-adrenergic contractile response in different portions of the rat vas deferens

The effect of cocaine (10 μM) on the kinetics of contractile response to noradrenaline (NA) was studied in the rat epididymal and prostatic vas deferens. Cocaine caused an acute increase in vas deferens adrenergic sensitivity primarily due to blockage of NA neuronal capture. The presynaptic action prevailed in the epididymal half: the EC 50 value decreased 32-fold with a slight increase of the maximum adrenergic response more evident in the prostatic half. In the presence of cocaine, the prostatic contraction to NA was mediated not by a single pool of α₁-adrenoceptors like in epididymal vas deferens but by two. Its high affinity pool had the same affinity as α₁-adrenoceptors of the epididymal half, the affinity value of the low one was 36-fold less, and the total maximal response of both pools increased 4.5-fold. The differences in cocaine effect on the rat epididymal and prostatic vas deferens contractions to NA appear to be caused by the different sources of Ca²⁺ involved in these responses.     

The roles of monoaminergic neurotransmitters in thermoregulation

Recent studies of the organization of the thermoregulatory system and evaluation of experimental evidence from electrophysiological, neuropharmacological, and neuroanatomical studies suggest that the monoamines noradrenaline and 5-hydroxytryptamine are involved in modulations of thermoregulation rather than in thermoregulation per se: they do not seem to transfer specific thermal information but rather modulate the signals passing from thermosensors to thermoregulatory effectors. Theoretically, the central monoamines could be modulating the input from thermosensors, or the central integration of thermal signals, or the outflow of signals to thermoregulatory effectors. The modulatory action of the monoamines on thermosensitive and thermointegrative hypothalamic neurons is best documented. There, the monoamines 5-hydroxytryptamine and noradrenaline seem to act as antagonists, which enhance or diminish the effects of thermal afferents mediated by other transmitters. Moreover, the antagonistic monoaminergic systems are apparently interconnected and can influence each other at a lower brain stem level. The activity in central monoaminergic systems can also be modified by neurohumoral feedback mechanisms from the periphery. By means of these interrelations the vegetative responses of the organism can be corrected and optimized.     

Possible involvement of serotonin receptors in the facilitatory effect of a hallucinogenic phenethylamine on single facial motoneurons

2,5-Dimethoxy-4-methylamphetamine (DOM, "STP") is a potent hallucinogen, proposed to be a serotonin receptor agonist. Its effects have not previously been tested upon central neurons where serotonin is excitatory and serotonin antagonists are effective. Extracellular single unit recordings were obtained from facial motoneurons in anaesthetized rats, and drugs were applied from five-barrelled micropipettes by iontophoresis. Facial motoneurons were commonly silent. During subthreshold application of glutamate, firing could be induced by dopamine and DOM. As reported by others, serotonin and noradrenaline also excited facial motoneurons under these conditions. Methysergide antagonized responses to serotonin and DOM but not those to noradrenaline; methysergide could not usually discriminate between responses to serotonin and dopamine. Ketanserin reversibly antagonized (but could not discriminate between) responses to serotonin, dopamine, and noradrenaline. Chlorpromazine antagonized responses to dopamine at doses that did not alter serotonin-induced excitation, and responses to DOM were not reduced by doses of chlorpromazine, that had no local anaesthetic effect on action potentials elicited by DOM and serotonin. These results suggest that DOM is an agonist on at least one type of central serotonin receptor. This receptor may also be a ketanserin (5-HT2) binding site.     

DEVELOPMENT OF THE BLOOD-BRAIN BARRIER FOR 6-HYDROXYDOPAMINE

The postnatal development of the blood-brain barrier for the neurotoxic action of 6-hydroxydopamine on central noradrenaline neurons has been investigated by recording the in vitro uptake of [³H]noradrenaline in slices from cerebral cortex, hypothalamus and spinal cord in rats treated with large doses of 6-hydroxydopamine at different ages. The [³H]noradranaline uptake was permanently and markedly reduced in all regions when the animals were treated at birth, certainly related to degeneration of noradrenaline neurons, caused by 6-OH-DA. In the cerebral cortex and hypothalamus an efficient protection against the effects of 6-OH-DA on [³H]noradrenaline uptake developed postnatally, while in the spinal cord this protection was never seen to become complete. The results obtained indicate a rapid formation of a blood-brain barrier for 6-OH-DA in the cerebral cortex between the 7th and 9th day after birth. In the hypothalamus the development of this barrier seemed to have a more gradual time-course, but appeared to be fully developed already at day 5 postnatally. Also in the spinal cord the barrier developed more gradually from birth to the adult age. It was observed, however, that both in the cerebral cortex and in the spinal cord, the blood-brain barrier developed, could not completely protect the central noradrenaline neurons from the neurotoxic actions of large doses of 6-OH-DA administered systemically to adult rats. Furthermore, the results obtained support the view that 6-OH-DA does not seem to apparently affect the outgrowth of remaining NA neurons which have not been destroyed by the 6-OH-DA treatment.     

Comparison of central effects of noradrenaline and dopamine injected into the lateral brain ventricle in rats.

Noradrenaline and dopamine injected into the lateral brain ventricle exerted a significant effect on the behavior of rats. Both amines caused a slight rise in the basic locomotor activity which was significantly increased in the animals with inhibited monoamine oxidase activity. Besides that, they suppressed the behavior of rats in the open-field test, inhibited the conditioned avoidance response, decreased body temperature and increased amphetamine-induced motor hyperactivity. Noradrenaline, in contrast to dopamine, changed the intensity of amphetamine-induced stereotypy and prolonged the action of hypnotics. The central action of both catecholamines (in higher doses especially) seemed to have a biphasic course: in the first phase after administration depression was observed which was more pronounced after noradrenaline administration, in the second phase a stimulating effect b     

Autonomic actions of cocaine

The development of our knowledge of the physiological, pharmacological, and biochemical actions of cocaine has in essence occurred in parallel with the development of our knowledge about the function of the autonomic nervous system. Cocaine is a sympathomimetic compound with potent local anesthetic properties. The principal hypothesis accepted to date to explain the sympathomimetic effects of cocaine is that this drug inhibits neuronal monoamine neurotransmitter reuptake by binding to a transporter or uptake site thereby increasing the effective concentration of neurotransmitter at adrenergic receptor sites. Much of the available evidence for this hypothesis has come from studies utilizing in vitro or in situ techniques. There have been relatively fewer studies examining the impact of cocaine on the autonomic nervous system in the intact animal. In addition, few studies have examined the effects of cocaine on central autonomic function. Past studies concerning the mechanism of action of cocaine are reviewed and recent data addressing the cardiovascular, respiratory, and central autonomic effects of cocaine are discussed.