Coordinated Expression of Dopamine Receptors in Neostriatal Medium Spiny Neurons

Abstract

In recent years, the distribution of dopamine receptor subtypes among the principal neurons of the neostriatum has been the subject of debate. Conventional anatomical and physiological approaches have yielded starkly different estimates of the extent to which D 1 and D 2 class dopamine receptors are colocalized. One plausible explanation for the discrepancy is that some dopamine receptors are present in physiologically significant numbers, but the mRNA for these receptors is not detectable with conventional techniques. To test this hypothesis, we examined the expression of DA receptors in individual neostriatal neurons by patch-clamp and RT-PCR techniques. Because of the strong correlation between peptide expression and projection site, medium spiny neurons were divided into three groups on the basis of expression of mRNA for enkephalin (ENK) and substance P (SP The signaling pathways activated by dopamine in the neostriatum have been the subject of intense study since it was discovered that the loss of dopamine leads to the psychomotor symptoms of Parkinson's disease (Hornykiewcz, 1973). Subsequently, several other common psychomotor disorders, including schizophrenia and Tourette's syndrome, have been linked to alterations in neostriatal dopaminergic signaling (Nemeroff and Bissette, 1988;Erenberg, 1992). In recent years, significant progress has been made in characterizing the membrane receptors transducing the signals of dopamine in the neostriatum and the brain in general. How these receptors are distributed among the principal neuronal cell types in the neostriatum has been the subject of debate (Surmeier et al., 1993). This controversy stems primarily from discrepancies in the results obtained from functional studies on the one hand and anatomical studies on the other. The most compelling anatomical data are in situ hybridization studies suggesting that D 1a and D 2 mRNA are segregated primarily in the two major efferent neostriatal populations (Gerfen, 1992; LeMoine and Bloch, 1995). In particular, D 1a receptor mRNA is found in substance P-expressing (SP) neurons projecting to the substantia nigra, whereas D 2 receptor mRNA is found in enkephalin-expressing (ENK) neurons projecting exclusively to the globus pallidus. More recent immunocytochemical work supports this conclusion (Hersch et al., 1995), although others have reported significant degrees of receptor protein colocalization .Functional studies, on the other hand, repeatedly have observed responses to D 1 and D 2 class agonists that are difficult to explain if these receptor classes are not colocalized (Uchimura et al., 1986;Akaike et al., 1987;Cepeda et al., 1993; for review, see Surmeier et al., 1993). The most compelling evidence comes from patch-clamp studies of acutely isolated neostriatal neuronswhere synaptic interactions have been removed-showing neuromodulatory effects of both D 1 and D 2 class agonists in the same cell (Surmeier et al., 1992). In this study, it was also shown that neurons projecting axons to the substantia nigra coexp...

Cocaine and Amphetamine Depress Striatal GABAergic Synaptic Transmission through D2 Dopamine Receptors

“…The enhancement of paired pulse facilitation, together with the lack of any postsynaptic action of these compounds on IPSC reversal potential, holding current and membrane conductance, all point to a presynaptic site for this action. Accordingly, although DA receptors are abundantly expressed postsynaptically on striatal neurons (Surmeier et al 1996), their activation is known to modulate membrane conductances operating in voltage ranges far from the values chosen in this study to evoke synaptic events (Ϫ80 mV and Ϫ40 mV) (Schiffmann et al 1995;Surmeier et al 1995;Lin et al 1996;Hernandez-Lopez et al 2000). This observation, therefore, further confirms that the postsynaptic effects of DA receptor activation cannot be responsible for the observed modulation of striatal IPSCs.…”

“…In particular, the increased locomotor activity and stereotypy caused by psychostimulants seem to involve specifically the nucleus striatum (Kelly et al 1975;Amalric and Koob 1993;Berke and Hyman 2000), a structure that receives virtually all the cortical information directed to the basal ganglia (Penney and Young 1983;Albin et al 1989;McGeorge and Faull 1989;Calabresi et al 1996 Kaneko et al 2000). The nucleus striatum also receives profuse dopaminergic innervation from the substantia nigra and has a very high density of D1 and D2 dopamine (DA) receptors but also of D3, D4 and D5 receptors (Mansour and Watson 1995;Surmeier et al 1996;Bordet et al 1997;LaHoste et al 2000). Amphetamine and cocaine cause in the striatum rapid induction of c-fos, a commonly used molecular marker for neuronal activity.…”

Distribution of Dopamine D3 Receptor Expressing Neurons in the Human Forebrain Comparison with D2 Receptor Expressing Neurons

“…Thus, brain areas with relatively high densities of D 3 receptors may be under tonic regulatory influence of the brain dopaminergic system, even if the dopaminergic innervation is sparse. D 2 and D 3 receptors may elicit opposing responses in neurons Lévesque et al 1995;Surmeier et al 1996), and may respond differently to loss of DA or antipsychotic treatment (reviewed in Joyce and Meador-Woodruff 1997). Our data provide initial insight into details of distribution and co-expression of DA D 2 and D 3 receptors in the human brain.…”

Behavioral Sensitization, Alternative Splicing, and D3 Dopamine Receptor-Mediated Inhibitory Function

“…Because D3 receptors exhibit functional as well as physical interactions with both D1 and D2 receptors (Scarselli et al, 2001;Zeng et al, 2006), it is of interest that receptor colocalization studies indicate that D1 and D3 receptors are coexpressed in islands of Calleja, nucleus accumbens, and caudate (Schwartz et al, 1998;Ridray et al, 1998;Surmeier et al, 1996;Le Moine and Bloch, 1996). In human brain, most D3 mRNA-expressing cells also express D2 mRNA (Gurevich and Joyce, 1999), whereas in rodent brain, in contrast, D2 and D3 receptors appear to have predominantly complementary rather than overlapping patterns of expression (Bouthenet et al, 1991).…”