Dopamine presynaptic agonist activity

Other drug effects that decrease DA activity also support this position. Thus, when DA synthesis is blocked by a-methyl- p-tyrosine (AMPT), the dose necessary for an antipsychotic effect is reduced (i.e., the dose-response curve is shifted to the left by the interaction between dopamine and AMPT). A drug such as reserpine that can deplete DA stores also has relatively mild antipsychotic properties. Also, aripiprazole, which has D 2 presynaptic agonist properties, decreases the production of DA, as well as blocking D2 postsynaptic receptors. 

In contrast, SK F 82526 is about ten times as potent as dopamine, and has about 1.6 times the maximal effect of dopamine as a renal vasodilator in anesthetized dogs. It causes a slight tachycardia, and at higher doses moderately decreases blood pressure. SK F 87516 is about three times as potent as, and shows about 80% of the maximal effect of dopamine as a renal vasodilator. However, it produces negligible blood pressure effects and exhibits a potent and profound bradycardiac effect suggesting that it may have presynaptic dopamine agonist activ-... 

A very intriguing observation noted above was the possibility of presynaptic dopamine agonist activity with SK F 87516 and SK F 85174. The inhibitions of the constrictor response and the 3H -norepinephrine release induced by brief intermittent periarterial sympathetic nerve stimulation of the perfused rabbit ear artery is a convenient in vitro assay for presynaptic dopamine agonist activity (30). In this preparation, both SK F 85174 and SK F 87516 inhibited both stimulation responses with an EC50 of about 100 riM. Another measure of D-2 activity is inhibition of specific spiroperidol binding (20). Comparison of these data (Table I) showed that SK F 85174 is thirty times as potent as dopamine, and thus is a potent D-2 agonist. However, the activity in adenylate cyclase stimulation indicates that this compound may be best described as a D-l/D-2 agonist (19, 20). 

Fig. 3. Locomotor hyperactivity to drugs activating forebrain dopamine systems (schematic illustration of response). A. Moderate doses of amphetamine induce progressive dose-dependent increases in counts recorded in automated activity chambers. B. At higher dose, amphetamine induces stereotypy which competes with the expression of locomotion resulting in a suppression of activity counts at peak dose. C. Competing stereotypy yields an inverse U function in the dose response curve (total activity over 2 h test). D. The dopamine receptor agonist apomorphine also increases activity at moderate doses which is blocked by competing stereotypy at high dose, but this drug also inhibits activity at the lowest doses, believed to be due to selective action at presynaptic autoreceptors (see text).

Eighteen chronic schizophrenic patients receiving subcutaneous doses of apomorphine (a dopamine receptor agonist) and of placebo, in separate trials, showed significant improvement in psychotic symptoms after apomorphine. The results were interpreted in terms of the activation of presynaptic dopamine receptors by apomorphine, with a subsequent decrease in dopamine-mediated neural transmission. " The neuropsychotropic activity and toxicity of the oxidation products of apomorphine have been described. ... 

Activation of neostriatal tyrosine hydroxylase was observed when cyclic AMP was added to high speed supernatants from rat neostriatum (133). Intraventricular injection of dibutyryl cyclic AMP stimulated tyrosine hydroxylation in the neostriatum (134). However, it is still questionable if under physiological conditions this cyclic AMP involvement in the feedback control of tyrosine hydroxylase activity is mediated by presynaptic dopamine receptors or by presynaptic allo-receptors. In addition, if a dopamine sensitive adenylate cyclase is involved in the regulation of neostriatal tyrosine hydroxylase activity it is relevant to know if this adenylate cyclase is linked to a D-1 and/or a D-2 receptor. At this point in time experimental data are not in favour of the presence of a D-l receptor linked to an adeiylate cyclase on the varicosities of dopaminergic neurons in the neostriatum. E.g. concentrations of dopamine agonists stimulating cyclic AMP formation inhibit tyrosine... 

Dopamine agonists exert their effect by activating dopamine receptors and bypassing the presynaptic synthesis of... 

Studies in rodent models suggested a DA D2 autoreceptor mechanism of action for 85. In electrophysiological studies in anesthetized rats, compound 85 was able to completely block firing of substantia nigra DA neurons, an effect believed to involve activation of presynaptic DA D2 autoreceptors. Inhibition of brain dopamine synthesis in rats as measured by decreases in GBL induced DOPA levels, as well as decreases in striatal DA levels in in vivo microdialysis studies, were also consistent with a DA autoreceptor mechanism of action. Similar results were measured in in vivo microdialysis studies carried out in a squirrel monkey, suggesting that the compound was also acting as a DA partial agonist. Reductions in the DA levels of the caudate putamen of a monkey were observed after ip administration of 85. 

Amphetamine and related substances show symphaticomimetic and CNS stimulant activity. Amphetamines are indirect monoamine agonists and interact with the membrane transporters involved in neurotransmitter reuptake and vesicular storage systems. Therefore, they stimulate the release of norepinephrine, dopamine, and serotonin from presynaptic terminals in the CNS and at the peripheral level (De La Torre et al., 2004). Methamphetamine and the methylenedioxy derivatives (MDA, MDMA, MDEA, MBDB) can inhibit the activity of enzymes of dopamine or serotonin biosynthesis (De La Torre et al., 2004). 

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