Objective. To investigate the role of the dopamine receptor genes, DRD1, DRD3, and DRD5 in the pathogenesis of migraine. Background. Migraine is a chronic debilitating disorder affecting approximately 12% of the white population. The disease shows strong familial aggregation and presumably has a genetic basis, but at present, the type and number of genes involved is unclear. The study of candidate genes can prove useful in the identification of genes involved in complex diseases such as migraine, especially if the contribution of the gene to phenotypic expression is minor. Genes coding for proteins involved in dopamine metabolism have been implicated in a number of neurologic conditions and may play a contributory role in migraine. Hence, genes that code for enzymes and receptors modulating dopaminergic activity are good candidates for investigation of the molecular genetic basis of migraine. Methods. We tested 275 migraineurs and 275 age- and sex-matched individuals free of migraine. Genotypic results were determined by restriction endonuclease digestion of polymerase chain reaction products to detect DRD1 and DRD3 alleles and by Genescan analysis after polymerase chain reaction using fluorescently labelled oligonucleotide primers for the DRD5 marker. Results. Results of chi-square statistical analyses indicated that the allele distribution for migraine cases compared to controls was not significantly different for any of the three tested gene markers (Ç2 = 0.1, P = .74 for DRD1; Ç2 = 1.8, P = .18 for DRD3; and Ç2 = 20.3, P = .08 for DRD5). Conclusions. These findings offer no evidence for allelic association between the tested dopamine receptor gene polymorphisms and the more prevalent forms of migraine and, therefore, do not support a role for these genes in the pathogenesis of the disorder. While environmental influences play a role in migraine, family studies strongly suggest that defective genes influence an individual's susceptibility to the disorder. It has been suggested that a common genetic background may be responsible for the two most common clinical subtypes of familial migraine, migraine with aura (MWA) and migraine without aura (MWOA).1-3 While the mode of transmission of migraine is widely believed to be multifactorial, a role for a major susceptibility gene cannot be excluded.4 At present, the pathophysiological mechanisms underlying migraine are largely speculative, but clinical trials involving treatment with dopamine receptor antagonists for migraine provide strong evidence for the involvement of dopamine.5,6 Not only can the symptoms of a migraine attack be induced in migraineurs by the administration of dopamine receptor agonists, but dopamine receptor antagonists can be used effectively in headache treatment during the acute phase of an attack.5-7 Using transmission disequilibrium tests in 82 small families and unrelated case-control subjects, we recently found a marker in the dopamine ²-hydroxylase (D²H ) gene that may be associated with migraine.7 The gene product, D²H, catalyzes the conversion of dopamine to norepinephrine and, therefore, links the dopaminergic and noradrenergic neurotransmission systems. Serum levels of this enzyme may serve as an index of peripheral sympathetic activity. Lower levels of serum D²H activity have been measured in patients with MWA, MWOA, and tension-type headache.7 All headache groups had similar levels of D²H activity, and in each that activity was significantly lower than in the control group. In addition, two independent studies have reported an allelic association of the dopamine receptor gene, DRD2, with MWA and MWOA.8,9 While Peroutka et al found a positive association between MWA and DRD2 NcoI alleles using a case-control design, a study by Del Zompo et al investigated the involvement of the DRD2, DRD3, and DRD4 genes and MWOA in a family-based association study.8,9 The latter group reported a significant difference in allelic transmi