Differential effects of D1 and D2 dopamine receptor agonists on substantia nigra pars reticulata neurons

Pharmacology Section, Northeastern University College of Pharmacy and Allied Health Professions, Boston, MA 02115.
Brain Research (Impact Factor: 2.84). 05/1990; 513(1):125-35. DOI: 10.1016/0006-8993(90)91098-2
Source: PubMed


Dopamine was shown in previous studies to exert a dual effect on non-dopaminergic neurons of the substantia nigra pars reticulata: it increases the firing rates of about 50% of cells, and consistently lessens the ability of iontophoretically applied or endogenously released GABA to inhibit their firing. These studies were undertaken to determine (1) whether the two effects could occur independently and, (2) whether different dopamine receptor subtypes might mediate the two responses. Extracellular, single unit activities of pars reticulata neurons were monitored in male rats anesthetized with chloral hydrate. Repeated 30-s iontophoretic pulses of GABA were delivered at an ejection current sufficient to inhibit cell firing by at least 50%, but not totally. After establishing a consistent response to GABA, co-iontophoresis of a test compound was initiated to determine its effects on basal firing rates and responsiveness to GABA. When acetylcholine and glutamate were evaluated in the test paradigm using ejection currents which excited cells by 54.0 +/- 4.9%, neither compound consistently altered the inhibition elicited by GABA. This confirmed that increases in cell firing could occur without concurrent GABA-attenuating effects, and supported the contention that the dual effects of dopamine could be dissociated and perhaps independently mediated. To examine whether the effects of dopamine involve actions at different dopamine receptor subtypes within the nigra, the D1 agonist SKF 38393 and the D2 agonist LY 171555 were substituted in the procedure. Applications of R,S(+/-)-SKF 38393 caused current-dependent increases in firing with a maximal increase at 8 nA of 55 +/- 18% above baseline (n = 14). The excitatory effect appeared to be D1-mediated since R(+)-SKF 38393, but not the inactive S(+)-enantiomer, could elicit the response. Conversely, graded applications of LY 171555 caused only occasional and more modest increases in basal activities, but consistently and markedly attenuated responses to GABA, decreasing GABA's inhibitory potency by 60.9 +/- 4.3% at 10 nA (n = 17). These results provide support for discrete roles of D1 and D2 receptors in substantia nigra pars reticulata, and suggest mechanistically distinct ways by which dendritically released dopamine could act to modify basal ganglia output from this region.

2 Reads
  • Source
    • "Most obviously, somatodendritic DA acting at D2 autoreceptors can inhibit DAergic neuron activity (Lacey et al., 1987; Pucak and Grace, 1994; Falkenburger et al., 2001; Beckstead et al., 2004), with consequent inhibition of both somatodendritic and axonal DA release (Santiago and Westerink 1991a,b). Somatodendritic DA also acts at postsynaptic DA receptors on GABAergic neurons in the SNr (Waszczak, 1990), as well as presynaptic DA receptors to regulate local release of GABA and glutamate (Waszczak and Walters, 1986; Miyazaki and Lacey 1998; Radnikow and Misgeld 1998; Hatzipetros and Yamamoto, 2006). However, factors that regulate somatodendritic DA release remain poorly understood. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Somatodendritic dopamine (DA) release in the substantia nigra pars compacta (SNc) shows a limited dependence on extracellular calcium concentration ([Ca(2+)](o)), suggesting the involvement of intracellular Ca(2+) stores. Here, using immunocytochemistry we demonstrate the presence of the sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase 2 (SERCA2) that sequesters cytosolic Ca(2+) into the endoplasmic reticulum (ER), as well as inositol 1,4,5-triphosphate receptors (IP(3)Rs) and ryanodine receptors (RyRs) in DAergic neurons. Notably, RyRs were clustered at the plasma membrane, poised for activation by Ca(2+) entry. Using fast-scan cyclic voltammetry to monitor evoked extracellular DA concentration ([DA](o)) in midbrain slices, we found that SERCA inhibition by cyclopiazonic acid (CPA) decreased evoked [DA](o) in the SNc, indicating a functional role for ER Ca(2+) stores in somatodendritic DA release. Implicating IP(3)R-dependent stores, an IP(3)R antagonist, 2-APB, also decreased evoked [DA](o). Moreover, DHPG, an agonist of group I metabotropic glutamate receptors (mGluR1s, which couple to IP(3) production), increased somatodendritic DA release, whereas CPCCOEt, an mGluR1 antagonist, suppressed it. Release suppression by mGluR1 blockade was prevented by 2-APB or CPA, indicating facilitation of DA release by endogenous glutamate acting via mGluR1s and IP(3)R-gated Ca(2+) stores. Similarly, activation of RyRs by caffeine increased [Ca(2+)](i) and elevated evoked [DA](o). The increase in DA release was prevented by a RyR blocker, dantrolene, and by CPA. Importantly, the efficacy of dantrolene was enhanced in low [Ca(2+)](o), suggesting a mechanism for maintenance of somatodendritic DA release with limited Ca(2+) entry. Thus, both mGluR1-linked IP(3)R- and RyR-dependent ER Ca(2+) stores facilitate somatodendritic DA release in the SNc.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 06/2009; 29(20):6568-79. DOI:10.1523/JNEUROSCI.0181-09.2009 · 6.34 Impact Factor
  • Source
    • "In vivo electrophysiologic studies reported that dopamine acts to increase the activity (Ruffieux and Schultz 1980) and/or to attenuate the inhibitory effects of GABA (Waszczak and Walters 1983, 1986) on SNr neurons. At least some of these effects may have been mediated by D2LRs (Waszczak 1990). More recent in vivo studies in which the electrophysiologic effects of D1LR-specific ligands were investigated have shown that SNr neurons are inhibited by endogenous dopamine, released by application of amphetamine in anesthetized (Timmerman and Abercrombie 1996) or in awake unrestrained rats (Windels and Kiyatkin 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Studies of the effects of dopamine in the basal ganglia have focused on the striatum, whereas the functions of dopamine released in the internal pallidal segment (GPi) or in the substantia nigra pars reticulata (SNr) have received less attention. Anatomic and biochemical investigations have demonstrated the presence of dopamine D1-like receptors (D1LRs) in GPi and SNr, which are primarily located on axons and axon terminals of the GABAergic striatopallidal and striatonigral afferents. Our experiments assessed the effects of D1LR ligands in GPi and SNr on local gamma-aminobutyric acid (GABA) levels and neuronal activity in these nuclei in rhesus monkeys. Microinjections of the D1LR receptor agonist SKF82958 into GPi and SNr significantly reduced discharge rates in GPi and SNr, whereas injections of the D1LR antagonist SCH23390 increased firing in the majority of GPi neurons. D1LR activation also increased bursting and oscillations in neuronal discharge in the 3- to 15-Hz band in both structures, whereas D1LR blockade had the opposite effects in GPi. Microdialysis measurements of GABA concentrations in GPi and SNr showed that the D1LR agonist increased the level of the transmitter. Both findings are compatible with the hypothesis that D1LR activation leads to GABA release from striatopallidal or striatonigral afferents, which may secondarily reduce firing of basal ganglia output neurons. The antagonist experiments suggest that a dopaminergic "tone" exists in GPi. Our results support the finding that D1LR activation may have powerful effects on GPi and SNr neurons and may mediate some of the effects of dopamine replacement therapies in Parkinson's disease.
    Journal of Neurophysiology 10/2007; 98(3):1489-500. DOI:10.1152/jn.00171.2007 · 2.89 Impact Factor
  • Source
    • "These neurons are also exposed to dopamine released from dendrites of the pars compacta neurons as well as from dopaminergic neurons located inside the pars reticulata (Cheramy et al. 1981; Geffen et al. 1976; Nakanishi et al. 1987; Richards et al. 1997; Rohrbacher et al. 2000). Dopamine release and a high density of dopamine receptors in the SNr (Barone et al. 1987; Beckstead et al. 1988; Richfield et al. 1987) suggest a role for dopamine in regulating basal ganglia output nuclei (Double and Crocker 1995; Floran et al. 2002; Robertson and Robertson 1989; Trevitt et al. 2001; Waszczak 1990; Weick et al. 1990; Wichmann et al. 2001). However, most studies on the action of dopamine in the reticulata have been directed to understand the role of dopamine D 1 receptors present on striatonigral afferents (Barone et al. 1987) that when activated, facilitate GABAergic inhibitory transmission onto SNr neurons (Floran et al. 1990; Radnikow and Misgeld 1998). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The effects of activating dopaminergic D1 and D2 class receptors of the subthalamic projections that innervate the pars reticulata of the subtantia nigra (SNr) were explored in slices of the rat brain using the whole cell patch-clamp technique. Excitatory postsynaptic currents (EPSCs) that could be blocked by 6-cyano-7-nitroquinoxalene-2,3-dione and D-(-)-2-amino-5-phosphonopentanoic acid were evoked onto reticulata GABAergic projection neurons by local field stimulation inside the subthalamic nucleus in the presence of bicuculline. Bath application of (RS)-2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine hydrochloride (SKF-38393), a dopaminergic D1-class receptor agonist, increased evoked EPSCs by approximately 30% whereas the D2-class receptor agonist, trans-(-)-4aR-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo(3,4-g)quinoline (quinpirole), reduced EPSCs by approximately 25%. These apparently opposing actions were blocked by the specific D1- and D2-class receptor antagonists: R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetra-hydro-1H-3-benzazepinehydrochloride (SCH 23390) and S-(-)-5-amino-sulfonyl-N-[(1-ethyl-2-pyrrolidinyl)-methyl]-2-methoxybenzamide (sulpiride), respectively. Both effects were accompanied by changes in the paired-pulse ratio, indicative of a presynaptic site of action. The presynaptic location of dopamine receptors at the subthalamonigral projections was confirmed by mean-variance analysis. The effects of both SKF-38393 and quinpirole could be observed on terminals contacting the same postsynaptic neuron. Sulpiride and SCH 23390 enhanced and reduced the evoked EPSC, respectively, suggesting a constitutive receptor activation probably arising from endogenous dopamine. These data suggest that dopamine presynaptically modulates the subthalamic projection that targets GABAergic neurons of the SNr. Implications of this modulation for basal ganglia function are discussed.
    Journal of Neurophysiology 04/2006; 95(3):1800-11. DOI:10.1152/jn.01074.2005 · 2.89 Impact Factor
Show more