Of the five known dopamine receptors, DlA and D2 represent the major subtypes expressed in the striatum of the adult brain. Within the striatum, these two subtypes are differentially distributed in the two main neuronal populations that provide direct and indirect pathways between the striatum and the output nuclei ofthe basal ganglia. Movement The pivotal role played by dopamine receptors in the pathophysiology and treatment ofParkinson disease (1) and schizophrenia (2) and in the mode of action of addictive drugs such as amphetamine and cocaine (3, 4) is well established. Of the five known dopamine receptor subtypes (5), the DlA and D2 receptors account for the vast majority of dopamine receptors (6) expressed in the striatum. The DlA (also known as D, in the primate system) and D2 receptor subtypes are expressed mainly by spiny projection neurons, which account for 90-95% of the striatal neuron population (7). These striatal neurons may be subdivided into two major types on the basis of their axonal projections. One type provides a direct projection to the output nuclei of the basal ganglia: the substantia nigra and entopeduncular nucleus (the internal segment of the globus pallidus in primates). The other type provides projections to the globus pallidus (the external segment of the primate globus pallidus). As this latter type is connected indirectly to the output nuclei of the basal ganglia through connections with the subthalamic nucleus, the two output pathways are referred to as the direct and indirect output systems. Striatal neurons giving rise to the direct pathway express high levels of the DlA dopamine receptor subtype and the neuropeptides substance P and dynorphin, whereas neurons giving rise to the indirect pathway express high levels of the D2 dopamine receptor and the peptide enkephalin (7). The levels of peptide expression in these neurons provide an assay oftheir activity (7), as neuropeptide levels correlated with fuing rates in target neurons (1).Current models suggest that imbalanced activity in the direct and indirect pathways is responsible for clinical movement disorders (8). A number of studies have demonstrated that dopamine oppositely effects these two output pathways through their differential expression ofthe DlA and D2 receptors (7). For example, depletion of striatal dopamine with lesions of the nigrostriatal dopamine pathway in animal models of Parkinson disease results in reduced expression of substance P in direct output neurons and increased enkephalin expression in indirect striatal output neurons. Moreover, these changes may be selectively reversed with selective dopamine receptor agonist treatments, so that D1 agonist treatment normalizes substance P levels whereas D2 agonist treatment normalizes enkephalin levels (9). While these studies have demonstrated the differential role of DlA and D2 receptors in striatal function, important questions concerning the interaction between these neuronal pathways remain. To provide an experimental animal model to address the...

Dopamine is an important transmitter in the CNS and PNS, critically regulating numerous neuropsychiatric and physiological functions. These actions of dopamine are mediated by five distinct receptor subtypes. Of these receptors, probably the least understood in terms of physiological functions is the D5 receptor subtype. To better understand the role of the D5 dopamine receptor (DAR) in normal physiology and behavior, we have now used gene-targeting technology to create mice that lack this receptor subtype. We find that the D5 receptor-deficient mice are viable and fertile and appear to develop normally. No compensatory alterations in other dopamine receptor subtypes were observed. We find, however, that the mutant mice develop hypertension and exhibit significantly elevated blood pressure (BP) by 3 months of age. This hypertension appears to be caused by increased sympathetic tone, primarily attributable to a CNS defect. Our data further suggest that this defect involves an oxytocin-dependent sensitization of V1 vasopressin and non-NMDA glutamatergic receptor-mediated pathways, potentially within the medulla, leading to increased sympathetic outflow. These results indicate that D5 dopamine receptors modulate neuronal pathways regulating blood pressure responses and may provide new insights into mechanisms for some forms of essential hypertension in humans, a disease that afflicts up to 25% of the aged adult population in industrialized societies.

To study behavioral functions of the D5 subtype, mice were generated with null mutations in the D5 gene. This 1st behavioral characterization of D5 null mutant mice (D5-/-) indicated normal general health, sensory abilities, and neurological reflexes. Under basal conditions, D5-/- mice were generally normal on locomotor activity, the rotarod test, acoustic startle response, prepulse inhibition, elevated plus-maze, light <--> dark exploration, Morris water maze, and cued and contextual fear conditioning. In the Porsolt forced swim test for antidepressant activity, male D5-/- mice showed lower levels of immobility. D5-/- mice showed some evidence of reduced responses to the hyperactivity-inducing effects of the D1/D5 receptor agonist SKF 81297. The ability of SKF 81297 to disrupt acoustic startle and prepulse inhibition appeared to be attenuated in D5-/- mice. These results suggest that the D5 receptor is not essential for many dopamine-mediated behaviors but may contribute to the pharmacological activation of dopaminergic pathways relevant to exploratory locomotion, startle, and prepulse inhibition.

Accumulated evidence suggests that dopamine and dopamine D1 agonists can activate phospholipase C in both brain and peripheral tissue. The receptor that mediates the hydrolysis of phosphoinositides has not been identified. The cloned dopamine D1A receptor that is generally thought to be linked to adenylyl cyclase, has also been proposed to couple to phospholipase C. However, a number of studies have suggested that this signaling pathway is mediated via a distinct D1-like dopamine receptor. We tested whether the D1A site plays a role in stimulating phosphoinositide hydrolysis by using the dopamine D1A-deficient mutant mice as a test model. Results show that although D1 dopamine receptor-mediated product on of cAMP is completely absent in membranes of D1A-deficient mice, D1 receptor-mediated accumulation of inositol phosphate is identical in tissues of mutant and wild-type animals. Furthermore, the coupling of [3H]SCH23390 binding sites in striatal or frontal cortex membranes to G alpha s is markedly reduced, although coupling of [3H]SCH23390 binding sites to G alpha q was unaltered in tissue taken from D1A mutant mice compared with control animals. These results clearly demonstrate that dopaminergic stimulation of inositol phosphate formation is mediated by a D1 dopamine receptor subtype that is distinct from the D1A receptor that activates adenylyl cyclase.