Neuroanatomy of dopamine receptor gene expression: Potential substrates for neuropsychiatric illness
In situ hybridization has made it possible to localize precisely the neuroanatomical distributions of the five dopamine-receptor subtypes by determining the expression of messenger RNA (mRNA) molecules that encode each receptor. In rat brain, both D1- and D2-receptor mRNAs are found in all the traditional dopaminoceptive regions. The distributions of D3, D4, and D5mRNA, however, are more restricted, and there are striking differences in the distribution of these receptors in the basal ganglia and limbic forebrain structures. The neuroanatomical distribution of receptors in the human brain is in many respects similar to that seen in the rat, although there are some important differences, including a higher cortical:striatal level of receptor expression for all these receptor mRNAs and expression of the D5receptor in the cortex. The unique pattern of regional distribution of each of the dopamine receptors contributes to the net functional expression of the dopaminergic systems. For example, D2receptors are expressed in both motor and limbic regions, whereas D3and D4receptors are present in limbic structures but are relatively absent from the striatum. This differential distribution may account for the observation that clozapine has effective antipsychotic properties without the motor side effects associated with typical antipsychotic agents. The development of novel compounds with relatively higher D4(or perhaps D3) affinities may help to achieve an antipsychotic response while minimizing the risk of extrapyramidal side effects.
Meador-Woodruff, JH; Caron, MG; Carlsson, A; Piercey, MF; Bedard, PJ; Van Tol, HHM
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