Altered striatal function in a mutant mouse lacking D1A dopamine receptors.

Abstract

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...

Contributions of Dopamine D1, D2, and D3 Receptor Subtypes to the Disruptive Effects of Cocaine on Prepulse Inhibition in Mice

“…A colony of D1R mutant mice (Drago et al, 1994) was originally established at OHSU from breeding stock of B6.129S4-Drd1a tm1Jcd male mice obtained from The Jackson Laboratory (Bar Harbor, ME). The heterozygous (HET) mice had been backcrossed for a minimum of five generations onto the inbred C57BL/6J line before importation and were then backcrossed for two additional generations in Portland (OHSU, Vollum Institute) to produce incipient congenic (N7) mice.…”

“…N7 C57BL/6J D1R HET breeding pairs were used to generate the mice for behavioral studies. Because the D1R KO mice were growthretarded (Drago et al, 1994), pups were not weaned from their mothers until 4 weeks of age and were then provided with moistened chow until approximately 8 weeks of age to maximize growth. The D1R mice were genotyped by PCR using a protocol and primer sequences provided by The Jackson Laboratory.…”

Quantitative Changes in Gαolf Protein Levels, but not D1 Receptor, Alter Specifically Acute Responses to Psychostimulants

“…They were produced by Drago and coll. (Laboratory of mammalian genes and development, NIH, Bethesda; Drago et al (1994)) and backcrossed in our laboratory for up to five generations with C57BL/6J mice (purchased from Charles River France, L'Arbresle, France) to obtain heterozygous mice (Drd1a + /À mice) and their control littermates (Drd1a + / + mice). Similarly, mice with a disrupted Gnal gene were produced by Belluscio et coll.…”

“…Complete impairment of D1R signaling, resulting from homozygous null mutations of genes encoding for D1R or Gaolf proteins, Drd1a and Gnal genes respectively, has major consequences on behavioral responses to psychostimulants in mice Herve et al, 2001;Xu et al, 2000;Zhuang et al, 2000). In the present study, we examined the consequences of quantitative variations in D1R or Gaolf protein levels using heterozygous knockout mice which express reduced amounts of the corresponding protein in the striatum, as compared to wild-type mice Drago et al, 1994). We investigated biochemical and behavioral effects of acute and chronic administration of psychostimulants in Drd1a and Gnal heterozygous mice (Drd1a + /À and Gnal + /À mice, respectively).…”

Conditional inactivation of the dopamine receptor 5 gene: Flanking the Drd5 gene with loxP sites

“…The D5 receptor gene (Drd5) codes for a 475 amino acid protein and is located on chromosome HSA4/MMU5 (Weinshank et al, 1991). Genetic inactivation for the D1-like receptor genes has been reported but no conditional allele (Drago et al, 1994;Sibley, 1999;Xu et al, 1994). Here we present a conditional Drd5 allele utilizing the phage P1 Cre/ loxP system.…”