Physiology and disease relevance

Dopamine was considered for a long time to be a precursor ofnoradrenaline, but eventually it was recognized as a neurotransmitter in its own right, fulfilling specific physiological roles including the control of different aspects of voluntary and involuntary motor movements and execution of learned motor programs. The central dopaminergic system also regulates the secretion of prolactin and corticotrophin, and is involved in the mediation of reward, control of mood, and working memory as well as goal-oriented behaviour. It is believed that several physiological effects of dopamine are linked to specific brain regions. Thus, the striatum which possesses the highest density of dopaminergic terminals is thought to control motor programs essential for the execution of complex motor acts. This concept is being continually redefined since current evidence suggests that it is the dorsolateral part of the striatum that is important for these motor functions, whereas the ventral or limbic part of the striatum, including nucleus accumbens and olfactory tubercle, are the sites involved in the mediation of rewarding and motivational process related to emotions and goal-directed behaviour (Di Chiara et al. 1992). The dopaminergic neurons involved in the regulation of neuroendocrine functions (i.e. prolactin secretion) are mainly localized in the hypothalamus. Despite this segregation of physiological functions by brain region, it is generally difficult to ascribe specific physiological functions to the different dopamine receptor subtypes. This is because in most brain regions examined there are mixtures of subtypes. Also drugs with high selectivity for the different subtypes do not yet exist. In the motor parts of the striatum the predominant receptor subtypes are D1 and D2 so control of movement by dopamine may depend on both of these receptor subtypes. The D3 and D4 subtypes are found mainly in limbic and cortical brain regions so are probably involved in functions of dopamine such as reward and control of mood and this has made them important targets for drug design. The anterior pituitary contains only the D2 subtype so the control of prolactin release by dopamine is mediated via this subtype.

The dopaminergic system has been the focus of much research over the past 40 years because several pathological conditions such as Parkinson's disease, schizophrenia, bipolar disorder, manic depression, Tourette's syndrome, and hyperprolactinaemia are believed to be associated with either dopaminergic system dysfunction or side effect profiles of drugs used to treat these disorders. Extensive work has also been performed to analyse the genetic relationship between dopamine receptors and the diseases mentioned above (reviewed in Missale et al. 1998). However, the results that have been produced are equivocal. Thus no linkage of D2 and D4 receptors to bipolar disorder has been found (Missale et al. 1998) and the association between the dopamine D2 receptor gene and susceptibility to alcoholism is controversial (Missale et al. 1998). More recently, some evidence has been reported for the genetic association of dopamine D4 receptor polymorphisms with behavioural disorders such as attention deficit hyperactivity disorder (ADHD) (see review in Todd and O'Malley 2001).

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