Within the basal ganglia, acetylcholine and dopamine play a central role in the extrapyramidal control of motor function. The physiologic effects of these neurotransmitters are mediated by a diversity of receptor subtypes, several of Which have now been cloned. Muscarinic acetylcholine receptors are encoded by five genes (ml-mS), and of the two known dopamine receptor subtypes (Dl and D2) the D2 receptor gene has been characterized. To gain insight into the physiological roles of each of these receptor subtypes, we prepared oligodeoxynucleotide probes to localize receptor subtype mRNAs within tlie rat striatum and substantia nigra by in situ hybridization histochemistry. Within the striatum, three muscarinic (ml, m2, m4) receptor mRNAs and the D2 receptor mRNA were detected.The ml mRNA was expressed in most neurons (>80%); the m2 mRNA, in neurons which were both very large and rare; and the m4 and D2 mRNAs, in 40-50% of the neurons, one-third of which express both mRNAs. Within the substantia nigra, pars compacta, only the m5 and D2 mRNAs were detected, and most neurons expressed both mRNAs. These data provide anatomical evidence for the identity of the receptor subtypes which mediate the diverse effects of muscarinic and dopaminergic drugs on basal ganglia function.The maintenance of a balance between cholinergic and dopaminergic tone within the basal ganglia has long been appreciated as being central to the clinical management of many extrapyramidal motor disorders (1-3). For example, muscarinic antagonists and dopamine agonists have both been used in the treatment of Parkinson disease (2, 3).Unfortunately, both types of drugs exert many untoward side effects (2), particularly in later phases of the disease. The recent discovery of a heterogeneity of muscarinic and dopaminergic receptor subtypes has led to the suggestion that these subtypes may mediate distinct aspects of cholinergic and dopaminergic function. On the basis of pharmacologic data, muscarinic receptors have been divided into three subtypes (Ml, M2, and M3) (4) and dopaminergic receptors into two (Dl and D2) (5, 6). Molecular cloning efforts have identified five genetically distinct muscarinic receptor subtypes (ml-m5) (7-10). Functional expression of these genes has indicated a correlation between the genetically and pharmacologically defined subtypes, where the Ml = ml, m4, and m5; the M2 = m2; and the M3 = m3 (11). A dopamine D2 receptor has also recently been cloned (12-15). Because the available pharmacologic tools do not discriminate among all the receptor subtypes, and due to the limited anatomic resolution that receptor autoradiographic procedures allow, we have prepared oligodeoxynucleotide probes to determine which cells within the basal ganglia express each receptor subtype mRNA. ¶ These data should provide a rational basis for the development of subtype-selective drugs for the management of movement disorders. MATERIALS AND METHODSOligodeoxynucleotide Probes. Three 48-base oligodeoxynucleotide probes for each of the five muscar...

Physiological and pharmacological criteria have divided dopamine receptors into D1 and D2 subtypes, and genes encoding these subtypes have recently been cloned. Based on the sequences of the cloned receptors, we prepared oligodeoxynucleotide probes to map the cellular expression of the corresponding mRNAs in rat brain by in situ hybridization histochemistry. These mRNAs showed largely overlapping yet distinct patterns of expression. The highest levels of expression for both mRNAs were observed in the caudate-putamen, nucleus accumbens, and olfactory tubercle. Within the caudate-putamen, 47 ± 6% and 46 ± 5% of the medium-sized neurons (10-15 Im) expressed the D1 and D2 mRNAs, respectively, and only the D2 mRNA was observed in the larger neurons (>20 ,um). The D1 and D2 mRNAs were expressed in most cortical regions, with the highest levels in the prefrontal and entorhinal cortices. Within neocortex, D1 mRNA was observed primarily in layer 6 and D2 mRNA in layers 4-5.Within the amygdala, Di mRNA was observed in the intercalated nuclei, and D2 mRNA in the central nucleus. Within the hypothalamus, D1 mRNA was observed in the suprachiasmatic nucleus and D2 mRNA in many of the dopaminergic cell groups. Within the septum, globus pallidus, superior and inferior colliculi, mammillary bodies, and substantia nigra only D2 mRNA was detected. These data provide insight into the neuroanatomical basis of the differential effects of drugs that act on D1 or D2 receptors. Dopamine is a neurotransmitter that mediates many aspects of cognitive, emotive, motor, and endocrine function. Disturbances in dopaminergic neurotransmission are thought to contribute to the pathogenesis of schizophrenia and Parkinson disease. Drugs that interact with dopamine receptors are used to treat these and other neuropsychiatric and neuroendocrine disorders (1-3). Based on pharmacological and physiological criteria, dopamine receptors have been divided into D1 and D2 subtypes (4). For example, the D1 receptor has high affinity for SCH-23390, has low affinity for substituted benzamides, and is able to stimulate adenylyl cyclase by coupling with the guanine nucleotide-binding protein (G protein), Gs (5,6). Conversely, D2 receptors have low affinity for SCH-23390, have high affinity for substituted benzamides, and inhibit adenylyl cyclase by coupling with the G protein Gi (5,6). By virtue of sequence homology with pharmacologically related receptors, genes encoding D1 and D2 receptor subtypes have been cloned (7-9). These genes are members of a gene superfamily that encodes receptors mediating signal transduction by coupling to G proteins (10).The anatomy of dopaminergic systems in the mammalian central nervous system has been well characterized. For example, dopaminergic cell groups in the mesencephalon form specialized innervations of the cerebral cortex, striatum, and various limbic and hindbrain structures (11)(12)(13)(14)(15)(16)(17)(18). Similarly, dopaminergic neurons in the hypothalamus innervate the pituitary (11-13). Using receptor autorad...

The loss of dopaminergic neurons in the substantia nigra pars compacta leads to the characteristic motor symptoms of Parkinson's disease: bradykinesia, rigidity and resting tremors. Although these symptoms can be improved using currently available dopamine replacement strategies, there is still a need to improve current strategies of treating these symptoms, together with a need to alleviate non-motor symptoms of the disease. Moreover, treatments that provide neuroprotection and/or disease-modifying effects remain an urgent unmet clinical need. This Review describes the most promising biological targets and therapeutic agents that are currently being assessed to address these treatment goals. Progress will rely on understanding genetic mutations or susceptibility factors that lead to Parkinson's disease, better translation between preclinical animal models and clinical research, and improving the design of future clinical trials.

The muscarinic receptor agonist activities of NDMC are unique among antipsychotics, and provide a possible molecular basis for the superior clinical effects of clozapine pharmacotherapy.

Receptors for dopamine have been classified into two functional types, D1 and D2. They belong to the family of receptors acting through G (or guanine nucleotide-binding) proteins. D2 receptors inhibit adenylyl cyclase, but D1 receptors stimulate adenylyl cyclase and activate cyclic AMP-dependent protein kinases. Dopamine D1 and D2 receptors are targets of drug therapy in many psychomotor disorders, including Parkinson's disease and schizophrenia, and may also have a role in drug addiction and alcoholism. D1 receptors regulate neuron growth and differentiation, influence behaviour and modify dopamine D2 receptor-mediated events. We report here the cloning of the D1 receptor gene, which resides on an intronless region on the long arm of chromosome 5, near two other members of the G-linked receptor family. The expressed protein, encoded by 446 amino acids, binds drugs with affinities identical to the native human D1 receptor. The presence of a D1 receptor gene restriction fragment length polymorphism will be helpful for future disease linkage studies.