The striatum and cerebral cortex express different muscarinic receptor mRNAs

The existence of four distinct muscarinic acetylcholine receptor genes (m1-mr) has recently been demonstrated. cDNAs for three of these receptors have been cloned from brain (m1, m3, m4) and one from heart (m2). To gain some understanding of the physiological role of the brain muscarinic receptors, we mapped the distribution of their mRNAs in rat brain by in situ hybridization. These mRNAs are barely detectable in the hindbrain and cerebellum. Within forebrain, each mRNA has a strikingly different pattern of distribution. The highest levels of m1 mRNA are in the cerebral cortex and hippocampus followed by the striatum. m3 mRNA is also prominent in the cerebral cortex, but has very low levels in the striatum. Conversely, the levels of m4 mRNA are highest in the striatum. Since the cognitive effects of muscarinic drugs have been localized to the cerebral cortex and hippocampus, and their psychomotor effects to the striatum, these data suggest that the muscarinic receptors which subserve these responses may be different gene products. Finally, we show that these muscarinic receptors can be distinguished pharmacologically, suggesting that it may be possible to develop drugs for the selective treatment of the psychomotor vs cognitive difficulties of Parkinson's and Alzheimer's disease, respectively.