Regulation

Most studies concerned with the regulation of CNS dopamine receptors in vivo have examined the effects of long-term treatment with receptor agonists, antagonists, or denervation induced by 6-hydroxydopamine, a selective neurotoxin for catecholaminergic neurons, on striatal D2-like dopamine receptors.

Studies examining chronic agonist exposure have yielded mixed results. Repeated treatment with amphetamine, which increases synaptic levels of dopa-mine, both increased and had no effect on the density ofD2-like receptors in the striatum, probably depending on dose and timing. Treatment with systemic l-DOPA, which also increases synaptic levels of dopamine, has been reported to decrease the density of D2-like receptors in the striatum.

Treatment with D1-like or D2-like antagonists has been shown to increase the density of D1-like and D2-like receptors, respectively, without changing the affinity of these receptors for dopamine. Similarly, denervation following 6-hydroxydopamine administration also leads to an increased dopamine D2-like, but not D1-like, receptor density as well as an enhanced behavioral responsiveness to dopamine. Thus, it appears that dopamine D2-like receptors upregulate in response to reduced levels of dopamine. It is not clear, however, if the molecular mechanism responsible for lesion-induced upregulation of dopa-mine receptors is the same as that underlying the upregulation observed after long-term antagonist treatment. The fact that D1-like receptors upregulate after long-term antagonist treatment, but not after denervation, suggests that the mechanisms must be different, at least for D1-like receptors. In the case of long-term antagonist treatment, it is also possible that the intrinsic properties of the antagonist may play a role in the upregulation of dopamine receptors.

The pathway of protein synthesis, from the initial stage of gene transcription to mRNA splicing, translation, protein processing, and insertion into the membrane, provides a number of potential points of control for the regulation of dopamine receptor number. The rate of receptor removal from the membrane and the recycling or degradation rates are also factors that contribute to the number of receptors available for binding.

It should be noted that the molecular mechanisms underlying dopamine receptor trafficking (another mechanism regulating dopamine receptor expression) are only beginning to be studied.

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