Mechanisms of action of pramipexole: Effects on receptors

Pramipexole, a tetrahydrobenzothiazole compound, has selective affinity for dopamine receptors of the D2 subfamily, with a 7-10-fold greater affinity for D-3 than for D-2 receptor subtypes; affinity for the D-4 receptor subty pe is 17-fold less than for D-3 receptors. The available experimental evide nce suggests that, in intact normofunctional dopaminergic systems, pramipex ole exerts its primary effects on presynaptic dopamine autoreceptors, proba bly of both D-2 and D-3 subtypes, as a result of which it suppresses the sy nthesis and synaptic release of dopamine; effects on postsynaptic receptors are elicited only at higher dose levels and with substantially longer late ncies than are needed for presynaptic autoreceptor stimulation. However, in dopaminergic systems in which dopamine release is reduced, as a result of presynaptic neurone degeneration or destruction, or by other means, postsyn aptic dopamine D-2 and D-3 receptors are much more readily stimulated by pr amipexole. These receptor effects of pramipexole may be linked to its estab lished or putative therapeutic effects in conditions related to reduced lev els of dopamine release. Thus, it is proposed that, in Parkinson's disease, pramipexole readjusts the balance between direct and indirect striatopalli dal outflow pathways which, acting together, modulate the inhibition/facili tation of motor activity; this occurs as a result of the stimulation of bot h D-2 and D-3 postsynaptic receptors in dopamine depleted circuits. Pramipe xole has been reported to have beneficial effects against depression, an ac tion which seems likely to reflect pramipexole-induced stimulation of posts ynaptic dopamine D2 receptors; this same effect in frontal cortical regions may reduce the negative symptoms of schizophrenia. Pramipexole may also ex ert therapeutic effects in certain states of dopaminergic dysfunction which do not involve reduced levels of dopamine. The suppression of dopamine rel ease in mesolimbic regions, resulting from the stimulation by pramipexole o f presynaptic dopamine D2 autoreceptors, may lead to positive therapeutic e ffects in schizophrenia and anxiety disorders. Pramipexole may find some cl inical role as an adjunct to treatment programmes aimed at reducing cocaine abuse. Further elucidation of the effects which pramipexole is able to eli cit at the level of dopamine receptors in different brain regions will not only provide valuable insights into the role of dopaminergic mechanisms in a range of neuropsychiatric dysfunctions, but will lead to the further refi nement of effective therapies for such conditions.