Dopamine receptors - physiological understanding to therapeutic intervention potential

There are two families of dopamine (DA) receptors, called D-1 and D-2, resp ectively. The D-1 family consists of D-1- and D-5-receptor subtypes and the D-2 family consists of D-2-, D-3-, and D-4-receptor subtypes. The amino ac id sequences of these receptors show that they all belong to a large superf amily of receptors with seven transmembrane domains, which are coupled to t heir intracellular signal transduction systems by G-proteins. The implicati ons of DA receptors in neuropsychiatry and cardiovascular and renal disease s are discussed. Neuropsychiatry indications include Parkinson's disease, s chizophrenia, migraine, drug dependence, mania and depression, and Gilles d e la Tourette syndrome. The underlying dysfunction of dopaminergic. systems and the potential benefits of dopaminergic therapy in these different indi cations are critically examined. With respect to the pharmacological treatm ent of Parkinson's disease, a range of DA agonists are in various stages of preclinical and clinical development. D-2-receptor agonist activity is pre dominant in most effective antiparkinsonian DA agonists. However, in practi ce, it is difficult to treat patients for several years with DA agonists al one; therapeutic benefit is not sustained. Rather, the use of a combination of DA agonists and levodopa is considered preferable. Reports of the effic acy of DA partial agonists await confirmation, and recent clinical investig ations also suggest the potential of D-1 receptor agonists as antiparkinson drugs. Regarding migraine pathogenesis, clinical and pharmacological evide nce suggests that DA is involved in this disorder. Most prodromal and accom panying symptoms may be related to dopaminergic activation. Several drugs a cting on D-1 receptors are effective in migraine treatment. Furthermore, mi graine patients show a higher incidence of dopaminergic symptoms following acute DA agonist administration when compared with normal controls. In card iology, the therapeutic benefits of DA agonists are noted in the treatment of heart failure. Low doses of DA are widely used for its specific dopamine rgic effects on renal function, which are suggested to be beneficial, and f or its alpha- and beta-adrenergicmmedaate responses that occur with higher doses. However, studies have been unable to demonstrate that DA can prevent acute renal failure or reduce mortality. It appears that the significant p rogress that is being made in the molecular understanding of DA receptors w ill continue to have a tremendous impact in the pharmacological treatment o f neuropsychiatric, cardiovascular, and renal diseases. (C) 1999 Elsevier S cience Inc. All rights reserved.