Reduction of Dopamine Synthesis Inhibition by Dopamine Autoreceptor Activation in Striatal Synaptosomes with In Vivo Reserpine Administration

Abstract

In an attempt to clarify the mechanisms by which dopamine (DA) autoreceptor activation inhibits DA synthesis, the efficacy and potency of the D2 DA agonists bromocriptine, lisuride, and pergolide, and the D1-D2 DA agonist apomorphine were studied in rat striatal synaptosomes, in which the rate of DA synthesis (formation of 14CO2 from L-[1-14C]tyrosine) was increased 103% by treating the animals from which the synaptosomes were obtained with reserpine (5 mg/kg i.p. twice, 24 and 2 h before they were killed), using the striatal total homogenate as the standard synaptosomal preparation. The increase in DA synthesis evoked by reserpine was additive with that produced by treatment of the synaptosomes with dibutyryl cyclic AMP, suggesting that, not a cyclic AMP-dependent, but possibly a Ca(2+)-dependent mechanism was involved. The DA agonists showed a concentration-dependent inhibition of DA synthesis in the control synaptosomes, which was antagonized by the selective D2 DA antagonist (-)-sulpiride. In the synaptosomes with increased rate of DA synthesis obtained from the rats treated with reserpine, the concentration-response curves of DA synthesis inhibition for the other DA agonists were shifted to the right, and the effect of bromocriptine was completely eliminated, whereas bromocriptine antagonized the effect of apomorphine. The increased rate of DA synthesis was not preserved in the striatal P1 + P2 fraction obtained from the reserpine-treated rats, but the effects of the DA agonists were still reduced to the same degree as those in the total homogenate. (-)-Sulpiride did not enhance DA synthesis in synaptosomes from the reserpine-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Slowing Parkinson’s disease progression

“…The result is consistent with stimulation of presynaptic autoreceptors that reduce synthesis 106 and release of dopamine. In patients with early PD, acute administration of a dopamine agonist 104 or levodopa 105 reduces striatal L-( 11 C)dopa PET imaging influx.…”

Differential effects of levodopa on dopaminergic function in early and advanced Parkinson's disease

“…We support this hypothesis on experimental evidence where dopamine autoreceptor dysfunction may occur as a consequence of dopaminergic degeneration or excessive dopamine stimulation, which occurs in advanced PD. Such experimental evidence includes dopaminergic autoreceptor subsensitivity after dopamine depletion, eicher by pharmacological means such as after reserpine administra-tion [32] or by 1 -methyl-4-phenylpyridinium (MPP+) lesioning [S]. Dopamine autoreceptor subsensitivity has also been shown to occur after excessive dopamine stimulation such as after acute or chronic amphetamine administration [33, 341. Another possible explanation for this excitatory effect of levodopa could be a differential response to the drug in another interacting neurotransmitter system in the striatum, eg, the glutamate system [35].…”

Dopamine D2-like receptor agonist bromocriptine protects against ischemia/reperfusion injury in rat kidney

“…It is interesting to note that the protective effects of bromocriptine and other dopamine D 2 -like receptor agonist against cerebral I/R injury have been previously reported [35,36,37]. Multiple mechanisms such as (1) inhibition of dopamine release [38], (2) activation of superoxide dismutase/free radical scavenging [39,40,41,42,43], and (3) activation of antiapoptotic factors [35] are responsible for neuroprotective effects of dopamine D 2 -like receptor agonists. It is likely that similar mechanisms, in addition to the one we have described, may also play a role in the protection of proximal tubules during I/R injury.…”