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At least 19 recordsLinked to original sources

PubMed2004

Peering into the dendritic machinery of striatal medium spiny neurons.

Striatal medium spiny neurons are principal players in the basal ganglia macrocircuits implicated in an astonishing array of psychomotor disorders, including Parkinson's disease, schizophrenia, Huntington's disease, and drug abuse. Using an elegant combination of 2-photon laser scanning microscopy and 2-photon uncaging of glutamate, Carter and Sabatini (this issue of Neuron) provide our first glimpse into the dendrites and spines of striatal medium spiny neurons. The results offer new insights into the workings of these clinically important yet mysterious neurons.

Action Potentials↗

PubMed2004

State-dependent calcium signaling in dendritic spines of striatal medium spiny neurons.

Striatal medium spiny neurons (MSNs) in vivo undergo large membrane depolarizations known as state transitions. Calcium (Ca) entry into MSNs triggers diverse downstream cellular processes. However, little is known about Ca signals in MSN dendrites and spines and how state transitions influence these signals. Here, we develop a novel approach, combining 2-photon Ca imaging and 2-photon glutamate uncaging, to examine how voltage-sensitive Ca channels (VSCCs) and ionotropic glutamate receptors contribute to Ca signals in MSNs. We find that upstate transitions switch the VSCCs available in dendrites and spines, decreasing T-type while enhancing L-type channels. Moreover, these transitions change the dominant synaptic Ca source from Ca-permeable AMPA receptors to NMDA receptors. Finally, pairing bAPs with synaptic inputs generates additional synaptic Ca signals due to enhanced Ca influx through NMDA receptors. By altering the sources, amplitude, and kinetics of spine Ca signals, state transitions may gate synaptic plasticity and gene expression in MSNs.

Animals↗

PubMed1994

Quantal properties of H-type glutamatergic synaptic input to the striatal medium spiny neurons.

The striatal medium spiny neuron receives two distinct glutamatergic synaptic inputs, S-type and H-type inputs, which have very different amplitudes. We report here that peak amplitudes of unitary H-type excitatory postsynaptic currents (EPSCs) could be reduced by decreasing external Ca2+, unlike S-type EPSCs. This suggests that H-type EPSCs are multiquantal, and supports the idea that the cellular origin of H-type EPSCs is distinct from that of the S-type EPSCs.

Animals↗

PubMed2001

Metabotropic glutamate receptor 5 mediates the potentiation of N-methyl-D-aspartate responses in medium spiny striatal neurons.

Medium spiny neurons were recorded from striatal slices obtained from mice lacking the group I metabotropic glutamate receptor (mGluR) subtype 1 or subtype 5. In wild-type animals, N-methyl-D-aspartate (NMDA)-induced membrane depolarization/inward currents were potentiated in the presence of both the group I mGluR agonist 3,5-dihydroxyphenylglycine (3,5-DHPG) and the mGluR5 selective agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG). Likewise, in mGluR1 knockout mice, both 3,5-DHPG and CHPG were able to potentiate NMDA responses. Conversely, in neurons recorded from mGluR5-deficient mice, the enhancement of NMDA responses by both 3,5-DHPG and CHPG was absent. Pharmacological analysis performed from rat slices confirmed the data obtained with mice. In the presence of the competitive mGluR1 antagonist LY367385, the NMDA responses were potentiated in the presence of CHPG, whereas the CHPG-induced enhancement was not observed in slices treated with the non-competitive mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine. As in wild-type mice, in neither of the mGluR1- and mGluR5-deficient mice did (2S,1'R,2'R,3'R)-2-(2,3-dicarboxylcyclopropyl)-glycine (1 microM), nor L-serine-O-phosphate (30 microM) (agonists for group II and III mGluRs, respectively) affect the NMDA-evoked responses. In striatal medium spiny neurons, NMDA responses are potentiated by endogenous acetylcholine via M1-like muscarinic receptors. Since the enhancement of NMDA responses by 3,5-DHPG and by M1-like muscarinic agonists was shown to share common post-receptor mechanisms, we verified whether the muscarinic potentiation of NMDA responses was affected in these group I mGluR-deficient mice. Both in mGluR1 and mGluR5 knockout animals, in the presence of either muscarine or the M1-like muscarinic receptor agonist McN-A-343, the positive modulation of the NMDA-induced membrane depolarization persisted.These results confirm the permissive role of group I mGluRs on NMDA responses in striatal neurons and reveal that this functional interplay occurs exclusively through the mGluR5 subtype. The NMDA-mGluR5 interaction might play an important modulatory role in the final excitatory drive from corticostriatal afferents and suggests that drugs acting at mGluR5 might prove useful for the treatment of movement disorders involving the striatum.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗

PubMed2006

Endocannabinoid-mediated short-term suppression of excitatory synaptic transmission to medium spiny neurons in the striatum.

Medium spiny neurons in the dorsal striatum receive glutamatergic excitatory synaptic inputs from the cerebral cortex. These synapses undergo long-term depression that requires release of endocannabinoids from medium spiny neurons and activation of cannabinoid CB1 receptors. However, it remains unclear how cortico-striatal synapses exhibit endocannabinoid-mediated short-term suppression, which has been found in various brain regions including the hippocampus and cerebellum. Endocannabinoids are released from postsynaptic neurons by strong depolarization and resultant Ca2+ elevation or activation of postsynaptic Gq/11-coupled receptors such as group I metabotropic glutamate receptors (mGluRs) and M1/M3 muscarinic acetylcholine receptors. Moreover, endocannabioids are effectively released when weak depolarization is combined with Gq/11-coupled receptor activation. We found that muscarinic activation induced transient suppression of excitatory synaptic transmission to medium spiny neurons, which was independent of retrograde endocannabinoid signaling but was mediated directly by presynaptic muscarinic receptors. Neither postsynaptic depolarization alone nor depolarization and muscarinic activation caused suppression of cortico-striatal synapses. In contrast, activation of group I mGluRs readily suppressed cortico-striatal excitatory synaptic transmission. Furthermore, postsynaptic depolarization induced clear suppression when combined with group I mGluR activation. These results indicate that group I mGluRs but not muscarinic receptors contribute to endocannabinoid-mediated short-term suppression of cortico-striatal excitatory synaptic transmission.

Animals↗

PubMed2005

Cholinergic suppression of KCNQ channel currents enhances excitability of striatal medium spiny neurons.

In response to glutamatergic synaptic drive, striatal medium spiny neurons in vivo transition to a depolarized "up state" near spike threshold. In the up state, medium spiny neurons either depolarize enough to spike or remain below spike threshold and are silent before returning to the hyperpolarized "down state." Previous work has suggested that subthreshold K+ channel currents were responsible for this dichotomous behavior, but the channels giving rise to the current and the factors determining its engagement have been a mystery. To move toward resolution of these questions, perforated-patch recordings from medium spiny neurons in tissue slices were performed. K+ channels with pharmacological and kinetic features of KCNQ channels potently regulated spiking at up-state potentials. Single-cell reverse transcriptase-PCR confirmed the expression of KCNQ2, KCNQ3, and KCNQ5 mRNAs in medium spiny neurons. KCNQ channel currents in these cells were potently reduced by M1 muscarinic receptors, because the effects of carbachol were blocked by M1 receptor antagonists and lost in neurons lacking M1 receptors. Reversal of the modulation was blocked by a phosphoinositol 4-kinase inhibitor, indicating a requirement for phosphotidylinositol 4,5-bisphosphate resynthesis for recovery. Inhibition of protein kinase C reduced the efficacy of the muscarinic modulation. Finally, acceleration of cholinergic interneuron spiking with 4-aminopyridine mimicked the effects of exogenous agonist application. Together, these results show that KCNQ channels are potent regulators of the excitability of medium spiny neurons at up-state potentials, and they are modulated by intrastriatal cholinergic interneurons, providing a mechanistic explanation for variability in spiking during up states seen in vivo.

4-Aminopyridine↗

PubMed1997

Brain-derived neurotrophic factor regulates maturation of the DARPP-32 phenotype in striatal medium spiny neurons: studies in vivo and in vitro.

The medium spiny neuron is the predominant striatal neuronal subtype. The striatum, a participant in motor and cognitive functions, is a site of pathophysiology in prevalent neuropsychiatric diseases and is the target of many currently utilized pharmacologic agents. DARPP-32, a dopamine and cyclic AMP-regulated phosphoprotein, is a widely-used marker of mature striatal medium-sized neurons, but the molecules regulating DARPP-32 transcription have not been identified. We show that a null mutation in the mouse brain-derived neurotrophic factor gene leads to decreased DARPP-32 immunoreactivity in striatal medium spiny neurons at birth and postnatal day 10. Striatal DARPP-32 messenger RNA and protein are decreased relative to wild-type littermate controls. In densely plated (1 x 10(6) cells/cm2) primary cultures derived from the ganglionic eminences, addition of brain-derived neurotrophic factor (100 ng/ml) to defined media results in a greater than 3-fold increase in the number of DARPP-32-immunopositive cells after 12 h and greater than 4-fold (P<0.005) after 24 h. The increase in DARPP-32-immunopositivity is abolished by the addition of 2 microg/ml actinomycin D without a significant effect on cell viability. These data suggest that brain-derived neurotrophic factor directly or indirectly regulates DARPP-32 transcription in medium spiny neurons. This is the first demonstration of transcriptional regulation of DARPP-32, and the first evidence of a forebrain abnormality in a newborn neurotrophin "knockout" mouse.

Animals↗

PubMed1993

Dendritic domains of medium spiny neurons in the primate striatum: relationships to striosomal borders.

Medium spiny neurons are the projection neurons of the striatum. They receive the majority of striatal afferents, and they make up the vast majority of all neurons in the striatum. These densely spiny cells thus constitute a major substrate for input-output processing in the striatum. In the experiments described here we analyzed the dendritic fields of spiny neurons in the squirrel monkey striatum and plotted their orientations with respect to the borders between striosomes and matrix. Medium-sized spiny neurons in the caudate nucleus were filled intracellularly in a fixed-slice preparation with the fluorescent dye Lucifer Yellow. Dendritic arbors were reconstructed following immunostaining of the injected neurons with antiserum to Lucifer Yellow and counterstaining for striosome/matrix compartments. A majority of the medium spiny neurons studied had dendritic arborizations that remained within their compartment of origin. Thus the striosome/matrix subdivision not only partitions neurotransmitter molecules and extrinsic striatal connections into two domains in the primate caudate nucleus, but also constrains the dendritic arbors of many projection neurons there. Other medium spiny neurons, however, in both striosomes and matrix, had dendrites that crossed from one compartment into the other. About a quarter of the spiny neurons reconstructed had at least one such crossing dendrite. These results suggest that compartmentalization of afferent and efferent processing by projection neurons in the primate striatum is not absolute. For a subpopulation of spiny neurons in striosomes and matrix, inputs to one compartment could have a direct influence on output cells of the other.

Animals↗

PubMed1998

Physiological and molecular properties of AMPA/Kainate receptors expressed by striatal medium spiny neurons.

The mechanisms by which glutamate shapes the activity of striatal medium spiny neurons are of fundamental importance to our understanding of normative and pathological striatal physiology. Non-N-Methyl-D-aspartate (non-NMDA) glutamate receptor expression and function were studied in medium spiny neurons with a combination of single cell RT-PCR, immunocytochemistry and whole-cell voltage-clamp techniques. Reverse transcription polymerase chain reaction analysis found that GluR2 mRNA appeared to be the most abundant and widely distributed AMPA receptor mRNA. GluR1 was also commonly detected. However, GluR3 mRNA was preferentially expressed by neurons coexpressing substance P and enkephalin and GluR4 mRNA was not detected in identified medium spiny neurons. All neuronal classes appeared to express GluR5 or GluR6 and/or GluR7 mRNA in addition to kainate (KA) subunit mRNA. Immunocytochemical studies confirmed the mRNA distributions and also revealed that GluR1 protein was largely restricted to dendritic spines. Although the mRNA and protein for both alpha-amino-3-hydroxy-5-methyl-ioxyzole-4-proprionic acid (AMPA) and KA class subunits was detected, the physiological response to glutamatergic ligands and the benzothiadizine cyclothiazide was characteristic of AMPA, not KA receptors. The AMPA receptor antagonist GYKI 52466 blocked the response to AMPA and all but a small transient component of the response to KA. The current-voltage relationship of the AMPA-evoked currents was relatively linear but Ca2+ fluorometry revealed that substantial changes in intracellular Ca2+ concentration accompanied exposure to either agonist. These results argue that somatodendritic non-NMDA glutamate receptors in medium spiny neurons are primarily GluR2-containing receptors of the AMPA class but that activation of these receptors as a group nevertheless results in a significant Ca2+ influx.

Animals↗

PubMed2006

Psychoactive drugs and regulation of the cAMP/PKA/DARPP-32 cascade in striatal medium spiny neurons.

Changes in activity of the medium spiny neurons (MSNs) of dorsal and ventral striatum result in alterations of motor performance, ranging from rapid increases or decreases in locomotor activity, to long-term modifications of motor behaviours. In the dorsal striatum, MSNs can be distinguished based on the organization of their connectivity to substantia nigra pars reticulata (SNpr) and internal segment of the globus pallidus (GPi), which, in turn, control thalamocortical neurons. Approximately half of the MSNs project directly to SNpr and GPi, their activation leading to disinhibition of thalamocortical neurons and increased motor activity. The other subpopulation of MSNs connects to SNpr and GPi indirectly and when activated promotes inhibition of thalamocortical neurons, thereby reducing motor activity. The dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) is a modulator of the cAMP signalling pathway, highly expressed in MSNs. This review discusses the regulation of DARPP-32 exerted by psychoactive substances in specific populations of striatal projection neurons and its involvement in short- and long-term motor responses.

Amphetamine↗

PubMed2003

Receptor subtype-specific modulation by dopamine of glutamatergic responses in striatal medium spiny neurons.

The output of GABAergic medium-sized spiny neurons in the dorsal striatum is controlled in part by glutamatergic input from the neocortex and the thalamus, and dopaminergic input from ventral midbrain. We acutely isolated these neurons from juvenile (P14-24) rats to study the consequences of the interaction between glutamate and dopamine for neuronal excitability. Single-cell RT-PCR analysis was used to identify the expression patterns of dopamine receptors. D1 and D2 dopamine receptor mRNA was detected in 11/22 and 3/22 of isolated neurons, respectively. Receptor mRNA co-expression was detected in 1/22 cells tested. Whole-cell voltage clamp recording (V(h)=-70 mV) was combined with local or bath application of dopaminergic and glutamatergic agonists to explore dopamine receptor modulation of glutamatergic excitation. Glutamate-evoked inward currents (5 microM, Mg(2+)-free, 1 microM glycine) were attenuated by dopamine (5 microM) to 83.2+/-3.6% (n=31). NMDA-evoked (20 microM), APV-sensitive currents were attenuated by dopamine to 80.9+/-4.5% (n=24). NMDA-induced responses were also attenuated by the D1 receptor agonist SKF 38393 (1 microM; n=28), while the D2/3 receptor agonist quinpirole (10 microM) had no effect. The currents evoked by application of AMPA (5 microM) displayed a steady rundown. Application of dopamine abolished or significantly reduced the rundown in the cells tested (n=17). A similar effect was observed after the application of SKF 38393 (1 microM), while quinpirole (10 microM) had no significant effect. Our results provide direct evidence for modulation by dopamine of glutamatergic responses of striatal medium spiny neurons, and demonstrate that the effects of this neuromodulator are receptor subtype specific. Disruption of this modulatory effect is likely to contribute to movement disorders associated with Parkinson's disease.

Animals↗

PubMed2002

Brain oscillations, medium spiny neurons, and dopamine.

1. The striatum is part of a multisynaptic loop involved in translating higher order cognitive activity into action. The main striatal computational unit is the medium spiny neuron, which integrates inputs arriving from widely distributed cortical neurons and provides the sole striatal output. 2. The membrane potential of medium spiny neurons' displays shifts between a very negative resting state (down state) and depolarizing plateaus (up states) which are driven by the excitatory cortical inputs. 3. Because striatal spiny neurons fire action potentials only during the up state, these plateau depolarizations are perceived as enabling events that allow information processing through cerebral cortex-basal ganglia circuits. In vivo intracellular recording techniques allow to investigate simultaneously the subthreshold behavior of the medium spiny neuron membrane potential (which is a "reading" of distributed patterns of cortical activity) and medium spiny neuron firing (which is an index of striatal output). 4. Recent studies combining intracellular recordings of striatal neurons with field potential recordings of the cerebral cortex illustrate how the analysis of the input-output transformations performed by medium spiny neurons may help to unveil some aspects of information processing in cerebral cortex-basal ganglia circuits, and to understand the origin of the clinical manifestations of Parkinson's disease and other neurologic and neuropsychiatric disorders that result from alterations in dopamine-dependent information processing in the cerebral cortex-basal ganglia circuits.

Action Potentials↗

PubMed2005

Dendritic degeneration in neostriatal medium spiny neurons in Parkinson disease.

Dysfunction of neostriatal medium spiny neurons (MSNs) is hypothesized to underlie late-stage motor complications of Parkinson disease (PD). The authors demonstrate shortened dendrite length of MSNs that was similar in four regions of neostriatum in late-stage PD. In contrast, MSN dendrite spine degeneration was unevenly distributed with the greatest loss in caudal putamen. The authors propose that these structural changes in MSN may contribute to late-stage motor complications of PD.

Aged↗

PubMed2006

Dopaminergic control of corticostriatal long-term synaptic depression in medium spiny neurons is mediated by cholinergic interneurons.

Long-term depression (LTD) of the synapse formed between cortical pyramidal neurons and striatal medium spiny neurons is central to many theories of motor plasticity and associative learning. The induction of LTD at this synapse is thought to depend upon D(2) dopamine receptors localized in the postsynaptic membrane. If this were true, LTD should be inducible in neurons from only one of the two projection systems of the striatum. Using transgenic mice in which neurons that contribute to these two systems are labeled, we show that this is not the case. Rather, in both cell types, the D(2) receptor dependence of LTD induction reflects the need to lower M(1) muscarinic receptor activity-a goal accomplished by D(2) receptors on cholinergic interneurons. In addition to reconciling discordant tracts of the striatal literature, these findings point to cholinergic interneurons as key mediators of dopamine-dependent striatal plasticity and learning.

Acetylcholine↗

PubMed2004

Effects of muscarinic acetylcholine receptor activation on membrane currents and intracellular messengers in medium spiny neurones of the rat striatum.

Acetylcholine, acting through muscarinic receptors, modulates the excitability of striatal medium spiny neurones. However, the underlying membrane conductances and intracellular signalling pathways have not been fully determined. Our aim was to characterize excitatory effects mediated by M1 muscarinic acetylcholine receptors in these neurones using whole-cell patch-clamp recordings in brain slices of postnatal rats. Under voltage-clamp, muscarine evoked an inward current associated with an increase in cell membrane resistance. The current, which reversed at -85 mV, was sensitive to the M1 receptor antagonist pirenzepine. Blocking the potassium conductance attenuated the response and the residual current was further reduced by ruthenium red (50 microm) and reversed at +15 mV. Simultaneous recordings from cholinergic interneurones and medium spiny neurones in conjunction with spike-triggered averaging revealed small unitary excitatory postsynaptic currents in four of 39 cell pairs tested. The muscarine-induced inward current was attenuated by a phospholipase C (PLC) inhibitor, U73122, but not by a protein kinase C inhibitor, chelerythrine, or by the intracellular calcium chelator 1,2-bis(2-aminophenoxy) ethane-N,N,N',N'-tetra-acetic acid, suggesting that the current was associated with PLC in a protein kinase C- and Ca2+ -independent manner. The phosphatidylinositol 4-kinase inhibitor wortmannin (10 microm) reduced the recovery of the inward current, indicating that the recovery process was dependent on the removal of diacylglycerol and/or inositol 1,4,5 triphosphate or resynthesis of phospholipid phosphatidylinositol 4,5-bisphophate. Ratiometric measurement of intracellular calcium after cell loading with fura-2 demonstrated a muscarine-induced increase in calcium signal that originated mainly from intracellular stores. Thus, the cholinergic excitatory effect in striatal medium spiny neurones, which is important in motor disorders associated with altered cholinergic transmission in the striatum such as Parkinson's disease, is mediated through M1 receptors and the PLC-dependent pathway.

Action Potentials↗

PubMed1983

A short duration GABAergic inhibition in identified neostriatal medium spiny neurons: in vitro slice study.

Inhibition in the neostriatum was investigated in rat in vitro slice preparation using intracellular recording and labeling technique. The initial response recorded following local stimulation is a monosynaptically activated EPSP. In 17% of the neurons tested, IPSPs were observed following EPSPs evoked by local stimulation. In paired shock experiments reduction of test EPSP amplitude or action potentials occurred over interstimulus intervals (ISIs) of 3-38 msec. In some neurons, a pulse injection of depolarizing current was used to trigger an action potential which was in a paired shock, used to condition a test monosynaptically induced EPSP. Test EPSPs were shunted over ISIs less than 45 msec. Paired shock performed on the slices perfused with the medium containing GABA antagonists (e.g., bicuculline methiodide, picrotoxin, or penicillin-G) resulted invariably in potentiation of test EPSPs. Inhibition in the neostriatum in vitro is demonstrated as reduction in test amplitude in paired shock tests, by the presence of IPSPs and by the shunting of EPSPs conditioned by an action potential triggered by direct depolarization. Neurons exhibiting these forms of inhibition were intracellularly labelled with HRP and identified as medium spiny neurons. These results indicate that striatal GABAergic medium spiny neurons which are known to have an extensive axon collateral plexus play in a role in a short lasting inhibition observed in the striatum.

Animals↗

PubMed2003

Kv1.2-containing K+ channels regulate subthreshold excitability of striatal medium spiny neurons.

A slowly inactivating, low-threshold K(+) current has been implicated in the regulation of state transitions and repetitive activity in striatal medium spiny neurons. However, the molecular identity of the channels underlying this current and their biophysical properties remain to be clearly determined. Because previous work had suggested this current arose from Kv1 family channels, high-affinity toxins for this family were tested for their ability to block whole cell K(+) currents activated by depolarization of acutely isolated neurons. alpha-Dendrotoxin, which blocks channels containing Kv1.1, Kv1.2, or Kv1.6 subunits, decreased currents evoked by depolarization. Three other Kv1 family toxins that lack a high affinity for Kv1.2 subunits, r-agitoxin-2, dendrotoxin-K, and r-margatoxin, failed to significantly reduce currents, implicating channels with Kv1.2 subunits. RT-PCR results confirmed the expression of Kv1.2 mRNA in identified medium spiny neurons. Currents attributable to Kv1.2 channels activated rapidly, inactivated slowly, and recovered from inactivation slowly. In the subthreshold range (ca. -60 mV), these currents accounted for as much as 50% of the depolarization-activated K(+) current. Moreover, their rapid activation and relatively slow deactivation suggested that they contribute to spike afterpotentials regulating repetitive discharge. This inference was confirmed in current-clamp recordings from medium spiny neurons in the slice preparation where Kv1.2 blockade reduced first-spike latency and increased discharge frequency evoked from hyperpolarized membrane potentials resembling the "down-state" found in vivo. These studies establish a clear functional role for somato-dendritic Kv1.2 channels in the regulation of state transitions and repetitive discharge in striatal medium spiny neurons.

Animals↗

PubMed2002

Direct and indirect actions of dopamine on the membrane potential in medium spiny neurons of the mouse neostriatum.

Many studies have shown dopamine (DA) to have a modulatory effect on neuronal excitability, which cannot be simply classified as excitatory or inhibitory in the neostriatum. To clarify whether the responses to DA (10-30 microM) are excitatory or inhibitory in the mouse medium spiny neurons, we examined the effects of DA agonists on the synchronous potential trajectory from the resting potential to the subthreshold potential. The DA-induced potential changes, which were estimated at the subthreshold potential (approximately -60 mV), were summarized as the combination of three kinds of responses: an initial hyperpolarization lasting approximately 1 min and a slow depolarization and/or hyperpolarization lasting more than 20 min. A D(1)-like receptor agonist, R(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF81297, 1 microM) mainly induced the initial hyperpolarization and slow depolarization. A D(2)-like receptor agonist, trans-(-)-4aR-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g]quinoline hydrochloride (quinpirole, 1 microM), mainly induced the initial hyperpolarization and slow hyperpolarization. D(1)-like receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390, 1 microM) depressed both the initial hyperpolarization and slow depolarization. D(2)-like receptor antagonist sulpiride (1 microM) depressed all the DA-induced responses except for the slow depolarization. TTX (0.5 microM) abolished all the DA-induced responses. Bicuculline (20 microM) and atropine (1 microM) abolished the DA-induced initial hyperpolarization and slow depolarization, respectively. Either DL-2-amino-5-phosphonopentanoic acid (AP5; 100 microM) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 20 microM) blocked both the initial hyperpolarization and slow depolarization. The application of exogenous glutamate (Glu) mimicked the initial hyperpolarization and slow depolarization. These results suggest that the initial hyperpolarization is mainly due to GABA release via the cooperative action of D(1)- and D(2)-like receptors and Glu receptors in GABAergic interneurons, whereas the slow depolarization is mediated by acetylcholine (ACh) release via the cooperative action of mainly D(1)-like receptors and Glu receptors in cholinergic interneurons. The potential oscillation was generated at the subthreshold level in a Ba(2+)-, AP5-, CNQX-, bicuculline-, and atropine-containing medium. The oscillation depressed after the addition of TTX, Co(2+), or DA. In DA agonists, quinpirole rather than SKF81297 had a more depressive effect on the potential oscillation. These results indicate that the slow hyperpolarization is due to the suppression of noninactivating Na(+)-Ca(2+) conductances via mainly D(2)-like receptors in the medium spiny neurons. In conclusion, the DA actions on the medium spiny neurons show a transient inhibition by the activation of D(1)- and D(2)-like receptors in mainly GABAergic interneurons and a tonic excitation and/or inhibition by the activation of mainly D(1)-like receptors in cholinergic interneurons and by the activation of mainly D(2)-like receptors in the medium spiny neurons, respectively.

Anesthetics, Local↗