Dopamine receptor subtypes colocalize in rat striatonigral neurons.

Abstract

Dopaminergic neurons of the substantia nigra provide one of the major neuromodulatory Inputs to the neostriatum. Recent in situ hybridization experiments have suggested that postsynaptic dopamine receptors are segregated in striatonigral and striatopallidal neurons. We have tested this hypothesis in acutely isolated, retrogradely labeled striatonigral neurons by examining the neuromodulatory effects of selective dopaminergic agonists on Na currents and by probing single-cell antisense RNA populations with dop receptor cDNAs. In most of the neurons examined (20/31), the application of the Di dopamine receptor agonist SKF 38393 reduced evoked whole-cell Na+ current. The D2 agonists quinpirole and bromocriptine had mixed effects; in most neurons (23/42), whole-cell Na+ currents were reduced, but in others (8/42), currents were increased. In cell-attached patch recordings, bath application of SKF 38393 decreased currents as in wholecell recordings, whereas quinpirole consistently (6/10) enhanced currents-suggesting that D2-like receptors could act through membrane delimited and non-delimited pathways. Changes in evoked current were produced by modulation of peak conductance and modest shifts in the voltage dependence of steady-state inactivation. Antisense RNA probes of dopamine receptor cDNA Southern blots consistently (5/5) revealed the presence of Di, D2, and D3 receptor mRNA in single striatonigral neurons. These rnmdings argue that, contrary to a strict receptor segregation hypothesis, many striatonigral neurons colocalize functional Di, D2, and D3 receptors.The role of the dopaminergic nigrostriatal system in controlling the excitability of neostriatal neurons has been intensely studied since it became clear that the loss of this innervation was responsible for the psychomotor symptoms ofParkinson disease (1). Molecular cloning and hybridization studies (2, 3) have revealed that the postsynaptic actions of dopamine are mediated by a family of five G-protein-coupled receptors (D1-D5). In situ hybridization experiments of Gerfen et al. (4, 5) have suggested that two members of this family-the D1 and D2 receptors-are segregated in the two major efferent populations of the neostriatum that project to the substantia nigra and pallidum. They have inferred from their findings that these pathways can be selectively modulated by D1 and D2 agonists. In its strictest form, this hypothesis requires that striatonigral neurons express only those dopamine receptors with a D1 pharmacological profile (D1 and D5) and that striatopallidal neurons express only those receptors with a D2 profile (D2, D3, and D4).This model of receptor segregation is difficult to reconcile with much of the biochemical and physiological literature addressing the effects of dopamine in the neostriatum (6-12). Gerfen et al.'s hypothesis implicitly argues that the appearance of convergence is a consequence of the failure to separate direct postsynaptic effects from indirect effects mediated by adjacent neurons. Such a separation is virtually imp...

Differential expression of the 61 kDa and 63 kDa calmodulin-dependent phosphodiesterases in the mouse brain

“…The very high levels of 63 kDa CaM-PDE mRNA present in the striatum suggest an important function for this isozyme in this region. The distribution of 63 kDa CaM-PDE in this region closely mimics that of the dopamine receptors; in particular the D, and D, receptors are prominently expressed in the caudate-putamen, nucleus accumbens, and olfactory tubercle (Gerfen et al, 1990;Weiner et al, 1990, 199 1;Surmeier et al, 1992). It therefore seems likely that the 63 kDa CaM-PDE may modulate one or more functions of dopamine in this region.…”

Immortalized murine striatal neuronal cell lines expressing dopamine receptors and cholinergic properties

“…Studies of the synergistic interactions between D, and D, receptors with respect to (Na+ + K+ ) ATPase activity (Bertorello et al, 1990) have suggested that these receptors may be coexpressed in the same cells. Using RT-PCR techniques, Surmeier et al (1992) have described the coexpression of D,, D,, and D, cDNA in single striatal neurons. In situ hybridization studies (Lester et al, 1993) indicate that D, and D, receptor mRNA may be coexpressed in approximately 26% of the neurons of the corpus striatum.…”

Modeling functions of striatal dopamine modulation in learning and planning

“…If firing is evoked from such polarized potentials, dopamine D1 class receptor activation attenuates the firing rate. This reduction in firing rate has been attributed to subthreshold K + channels (Pacheco-Cano et al 1996), to the modulation of Na + channels (Calabresi et al 1987;Surmeier et al 1992;Cepeda et al 1995), and to channels participating in the afterhyperpolarization (Rutherford et al 1988;Hernandez-Lopez et al 1996). In contrast, if firing is evoked from elevated holding potentials, dopamine D1 class receptor activation enhances firing via a G-protein dependent potentiation of an L-type calcium current (Surmeier et al, 1995).…”