[Central presynaptic receptors].
Experiments on two different inhibitory presynaptic receptor systems are presented. 1. Superfused and electrically stimulated brain slices are a widely used experimental model to study the release of noradrenaline and its modulation by inhibitory alpha-2 adrenoceptors. By using a minisuperfusion chamber we succeeded in studying the simplest case of autoinhibition, i.e. the release of transmitter induced by a single pulse and two consecutive pulses, respectively. When electrical stimulation is performed using a single pulse, no autoinhibition is possible, whereas following stimulation with two pulses the transmitter released by the first pulse will inhibit the effect of the second pulse. By systemically varying the time interval between the two pulses the minimal time requirement for development of autoinhibition was determined to be 100 ms. Short pulse trains of high frequency such as 4 pulses within 30 ms circumvent autoinhibition and cause inhibition-free release by each applied pulse. The release of transmitter evoked in this way is not only free from autoinhibition but, in addition, easily measurable, which makes this method of stimulation very suitable for analyses at presynaptic receptors. By using this approach it became possible, for the first time, to determine dissociation constants of antagonists and agonists at the central presynaptic alpha-2 adrenoceptor without the distortion introduced by autoinhibition occurring during release. 2. There is a substantial body of evidence for a role of medullary serotonergic nerve cells in the regulation of blood pressure and heart rate. It is hypothesized that the serotonergic neurons project to the thoracic spinal cord exerting a tonic excitatory influence on presynaptic sympathetic neurons of the intermediolateral cell column. Experiments were performed in pentobarbital anaesthetized rats to reduce this excitatory tone by activating inhibitory autoreceptors which are located on the perikarya and dendrites on the serotonergic cells and which have been shown to belong to the 5-HT1A subtype. Local stereotactic injection of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) caused a decrease in mean arterial blood pressure (MAP) and heart rate (HR). The effects were blocked by pretreatment of the animals with the 5-HT1A antagonist spiroxatrine. Moreover, neurochemical lesioning of serotonergic neurons by intracisternal injection of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) abolished the effects of 8-OH-DPAT. Bilateral intraspinal injection of 5,7-DHT, which interrupts the medullo-spinal serotonergic pathway, markedly attenuated the effects of local intramedullary injection of 8-OH-DPAT.(ABSTRACT TRUNCATED AT 400 WORDS)
Singer
E A
EA
Pharmakologisches Institut, Universität Wien.
Valenta
B
B
Kotai
E
E
Drobny
H
H
Weisz
E
E
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000502:physiology; D002490:Central Nervous System / Q000187:drug effects / Q000502:physiology*; D004102:Dihydroxytryptamines / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D018492:Dopamine Antagonists; D006339:Heart Rate / Q000187:drug effects; D009474:Neurons / Q000502:physiology; D018377:Neurotransmitter Agents / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000502:physiology*; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology; D013141:Spiro Compounds / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
D000959:Antihypertensive Agents; D004102:Dihydroxytryptamines; D004146:Dioxanes; D018492:Dopamine Antagonists; D018377:Neurotransmitter Agents; D011942:Receptors, Adrenergic, alpha; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013141:Spiro Compounds; D013764:Tetrahydronaphthalenes; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C018387:spiroxatrine; D009638:Norepinephrine