A neuropharmacological study of central dopamine receptors

Abstract

The experiments in this thesis describe the actions of some novel dopamine agonists and antagonists on the neuronal activity of extrace 11u1ar1y recorded cells in the substantia nigra zona compacta in vivo and in vitro.

The dopamine agonists, apomorphine, piribedil, S-36O8, RU24213 and RU24926 all potently inhibited the neuronal activity of the substantia nigra neurones, when given intravenously. Piribedil and S-3608 were short acting agonists , whereas RU24213 and RU24926 were long a c t i n g , both with a two phase recovery. A second dose of either RU24213 and RU24926 or apomorphine produced a tachyphy1 actic effect, which reduced the inhibitory agonist responses.

The dibenzoyl ester of ADTN, synthesised as a soluble prodrug of ADTN, failed to have any dopaminergic agonist activity on the substantia nigra cells, when given intravenously, at extremely high doses.

In addition, when tested on the hyperactivity induced by dopamine agonists, directly injected I n t o the nucleus accumbens, S-36O8 and RU24213 did not induce any locomotor activity. While RU24926 produced a weak and short stimulation of locomotor activity compared with ADTN.

A newly proposed dopamine antagonist, zetidoline, given intravenously, antagonised the inhibitory effect of apomorphine whereas the dopamine antagonist, sulpiride, at very large doses, failed to antagonise apomorphine inhibitions. Applied iontophoretically, sulpiride and zetidoline antagonised the responses to iontophoretically applied dopamine and noradrenaline, but zetidoline did not affect the responses to the neurotransmitters, glutamate, GABA and glycine. On cerebellar neurones, sulpiride failed to antagonise the responses to dopamine and noradrenaline. Zetidoline applied iontophoretically was directly depressant on cerebellar neurones.

In the in vitro nigral brain slice, zetidoline was a competitive antagonist of the inhibitory actions of dopamine with a pAg of 7.0 2.

In contrast to its potent and selective activity in inhibiting dopamine
responses on substantia nigra neurones, zetidoline, in the ADTN-induced locomotor test for dopaminergic activity, was weakly active as an antagonist. Sulpiride, however, was a potent antagonist in this test .

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