In vivo characterization of two cell types in the rat globus pallidus which have opposite responses to dopamine receptor stimulation: Comparison of electrophysiological properties and responses to apomorphine,dizocilpine, and ketamine anesthesia

Extracellular single-unit recording techniques were used to examine the rat globus pallidus (GP). In both locally anesthetized, paralyzed rats and ketamine-anesthetized rats, we observed two distinct biphasic extracellular waveforms, which we have labeled Type I (negative/positive waveform) and Type II (positive/negative waveform). No significant differences were observed in the firing pattern or number of cells per track between these cell types, although the Type II neurons had a faster mean firing rate in the locally anesthetized animals. A portion of both cell types could be antidromically activated from the subthalamic nucleus, although Type II neurons had significantly slower conduction velocities. The most striking pharmacological difference between the two cell types was that Type I GP neurons were inhibited by systemic administration of the dopamine agonist apomorphine; previous studies have repeatedly shown that Type II. GP cells are excited by this treatment. Pretreatment with a subthreshold dose of apomorphine reduced the responsiveness of Type I cells to a subsequent high dose of apomorphine, as has been shown for Type II cells. However, pretreatment with the NMDA antagonist dizocilpine (MK 801) produced a significant change in the pattern of response to apomorphine for Type II GP neurons only. Relative to observations in locally anesthetized, paralyzed rats, ketamine anesthesia reduced the firing rate of both cell types, but did not significantly alter their direction of response to apomorphine. Thus, this study has confirmed the existence of two GP cell types with distinct extracellular waveforms and different responses to dopamine receptor stimulation. These data may necessitate a reevaluation of general theoretical models of basal ganglia function in order to account for these opposite effects of dopamine receptor stimulation on pallidal output. © 1995 Wiley-Liss, Inc.

1 This article is a US Government work and, as such, is in the public domain in the United States of America.

     

Multiple single-unit recordings in the striatum of freely moving animals: effects of apomorphine and -amphetamine in normal and unilateral 6-hydroxydopamine-lesioned rats

Ensembles of striatal neurons were recorded in freely moving normal and unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats using chronically implanted electrode arrays. Animals received bilateral striatal implants of two 16-microwire arrays 1 week before recordings. Identified striatal neurons were categorized as medium spiny-like and large aspiny-like based on a combination of their activity autocorrelations and firing rates. Baseline firing rates of medium spiny-like neurons in the 6-OHDA-lesioned striata were significantly faster than were firing rates of the same neurons in the intact hemispheres of 6-OHDA-lesioned rats or normal animals. However, firing rates of large aspiny-like neurons were faster in both hemispheres of the 6-OHDA-lesioned rats as compared to normal animals. Interestingly, firing rates of neurons in all groups decreased by fivefold or greater under urethane anesthesia, although the relative firing rates between hemispheres were unchanged. -Amphetamine (5.0 mg/kg, s.c.) increased the firing rates of both types of striatal neurons by twofold or greater in normal rats and in the intact hemispheres of 6-OHDA-lesioned animals. By contrast, this treatment did not alter neuron firing in the 6-OHDA-lesioned striata. Apomorphine (0.05 mg/kg, s.c.) did not affect neuronal firing rates either in normal rat striatum or in the unlesioned hemispheres of 6-OHDA-lesioned animals. However, it did significantly increase the firing rate of the medium spiny-like neurons in 6-OHDA-lesioned striata. These results demonstrate that the dopaminergic innervation of the striatum differentially influences two electrophysiologically distinct sets of striatal neurons in freely moving rats.     

Multiple single-unit recordings in the striatum of freely moving animals: effects of apomorphine and D-amphetamine in normal and unilateral 6-hydroxydopamine-lesioned rats.

Ensembles of striatal neurons were recorded in freely moving normal and unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats using chronically implanted electrode arrays. Animals received bilateral striatal implants of two 16-microwire arrays 1 week before recordings. Identified striatal neurons were categorized as medium spiny-like and large aspiny-like based on a combination of their activity autocorrelations and firing rates. Baseline firing rates of medium spiny-like neurons in the 6-OHDA-lesioned striata were significantly faster than were firing rates of the same neurons in the intact hemispheres of 6-OHDA-lesioned rats or normal animals. However, firing rates of large aspiny-like neurons were faster in both hemispheres of the 6-OHDA-lesioned rats as compared to normal animals. Interestingly, firing rates of neurons in all groups decreased by fivefold or greater under urethane anesthesia, although the relative firing rates between hemispheres were unchanged. d-Amphetamine (5.0 mg/kg, s.c.) increased the firing rates of both types of striatal neurons by twofold or greater in normal rats and in the intact hemispheres of 6-OHDA-lesioned animals. By contrast, this treatment did not alter neuron firing in the 6-OHDA-lesioned striata. Apomorphine (0.05 mg/kg, s.c.) did not affect neuronal firing rates either in normal rat striatum or in the unlesioned hemispheres of 6-OHDA-lesioned animals. However, it did significantly increase the firing rate of the medium spiny-like neurons in 6-OHDA-lesioned striata. These results demonstrate that the dopaminergic innervation of the striatum differentially influences two electrophysiologically distinct sets of striatal neurons in freely moving rats.     

Effect of acute and chronic administration of the selective 5-HT2C receptor antagonist SB-243213 on midbrain dopamine neurons in the rat: an in vivo extracellular single cell study

In this study, we examined the effect of the acute and chronic administration of the selective 5-HT2C receptor antagonist SB-243213 (SB) on the activity of spontaneously active dopamine (DA) cells in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized, albino, male Sprague-Dawley rats. This was accomplished using the technique of in vivo extracellular single cell recording. The acute i.v. administration of SB-243213 (0.025-3.2 mg/kg) did not significantly alter the basal firing rate or pattern of either spontaneously active SNC or VTA DA neurons compared to vehicle-treated controls. The acute i.p. administration of either 1 or 10 mg/kg of SB-243213 did not significantly alter the number of spontaneously active DA cells in the SNC or VTA compared to vehicle-treated controls, whereas the 3 mg/kg dose only significantly decreased the number of spontaneously active VTA DA neurons. Overall, the 1 mg/kg dose of SB-243213 did not significantly alter the firing pattern of either SNC or VTA DA neurons compared to vehicle-treated controls. In contrast, the 3 mg/kg dose significantly altered the firing pattern of SNC DA neurons, whereas the 10 mg/kg dose altered the firing pattern of DA neurons in both the SNC and VTA. The repeated i.p. administration (21 days) of 1, 3, and 10 mg/kg of SB-243213 or 20 mg/kg of clozapine produced a significant decrease in the number of spontaneously active DA cells in the VTA compared to vehicle-treated controls. The decrease in the number of spontaneously active VTA DA cells was not reversed by the i.v. administration of (+)-apomorphine (50 microg/kg). The repeated administration of either 1 or 3 mg/kg of SB-243213 had minimal effects on the firing pattern of either SNC or VTA DA neurons. In contrast, the firing pattern of VTA DA neurons was significantly altered by 10 mg/kg dose of SB-243213. Overall, our results indicate that antagonism of the 5-HT2C receptor alters the activity of midbrain DA neurons in anesthetized rats and suggest that SB-243213 has an atypical antipsychotic profile following chronic administration.     

The effect of the acute and chronic administration of CP 96,345, a selective neurokinin1 receptor antagonist,on midbrain dopamine neurons in the rat: A single unit,extracellular recording study

In this study, we examined the effect of acute and chronic administration of the selective neurokinin₁ receptor antagonist CP 96,345 on the basal activity of spontaneously active dopamine (DA) neurons in the substantia nigra pars compacta (SNC) and the ventral tegmental area (VTA). This was accomplished using the technique of in vivo, extracellular single unit recording in anesthetized rats. The intravenous (i.v.) administration of CP 96,345 (0.01–1.28 mg/kg) did not significantly alter the firing rate of spontaneously active DA neurons in the SNC and VTA areas. The acute administration of 5 or 10 mg/kg, i.p., of CP 96,345 produced a significant decrease in the number of spontaneously active SNC and VTA dopamine cells compared to vehicle-treated rats. In contrast to its effect on the number of spontaneously active DA neurons, the administration of 5 mg/kg, i.p., of CP 96,345 did not significantly alter the basal firing pattern of either SNC or VTA DA neurons. The acute administration of CP 96,345 (10 mg/kg, i.p.) significantly potentiated the suppressant action of (+)-apomorphine on the basal firing rate of spontaneously active SNC and VTA DA cells. The chronic administration of CP 96,345 (5 or 10 mg/kg, i.p.) for 21 days also produced a significant decrease in the number of spontaneously active SNC and VTA DA cells compared to vehicle controls. This effect was not reversed by the systemic administration of (+)-apomorphine (50 μg/kg, i.v.), suggesting that the reduction in the number of spontaneously active DA cells produced by CP 96,345 is probably not the result of depolarization inactivation. Overall, our results indicate that the tonic activation of NK₁ receptors by substance P may be necessary to maintain the spontaneous activity of a proportion of midbrain DA neurons. © 1996 Wiley-Liss, Inc.     

Acute and repeated administration of the selective 5-HT(2A) receptor antagonist M100907 significantly alters the activity of midbrain dopamine neurons: an in vivo electrophysiological study

We examined the effect of the acute and repeated administration of M100907 (formerly MDL 100907), a selective 5-HT(2A) receptor antagonist, on spontaneously active dopamine (DA) neurons in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) of rats. This was accomplished using in vivo, extracellular single unit recording. The i.v. administration of M100907 (0.01-0.64 mg/kg) did not significantly alter the basal firing rate or pattern of spontaneously active SNC and VTA DA neurons. A single injection of either 0.01 or 0.03 mg/kg i.p. of M100907 did not significantly alter the number of spontaneously active DA neurons in either the SNC or VTA areas. However, 0.1 mg/kg i.p. of M100907 significantly increased the number of spontaneously active SNC and VTA DA neurons compared to vehicle-treated animals. A single injection of all doses of M100907 significantly decreased the degree of bursting in VTA DA neurons, whereas the 0.1 mg/kg dose increased the degree of bursting in SNC DA neurons. The repeated administration (one injection per day for 21 days) of 0.03 and 0.1 mg/kg i.p. of M100907 produced a significant decrease in the number of spontaneously active SNC and VTA DA neurons compared to vehicle-treated animals. The repeated administration of M100907 did not significantly alter the firing pattern of VTA DA neurons but significantly altered the firing pattern of SNC DA neurons. The results of this study indicate that M100907 administration alters the activity of midbrain DA neurons in anesthetized rats.     

(—)-Sulpiride activates the firing rate and tyrosine hydroxylase activity of dopaminergic neurons in unanesthetized rats

The effect of i.v. sulpiride on the firing rate of dopaminergic neurons in the substantia nigra, pars compacta (SN-DA cells) and tyrosine hydroxylase (TH) activity in the caudate nucleus was studied. In rats, paralyzed with succinylcholine and artificially respirated, (-)-sulpiride (10-50 mg/kg) produced a dose-related increase in the firing rate of SN-DA cells and in TH activity. On the contrary, in rats anesthetized with halothane, (-)-sulpiride (up to 50 mg/kg) activated neither dopaminergic firing nor TH activity. However, (-)-sulpiride (10-25 mg/kg) readily reversed the inhibitory effect of i.v. apomorphine (25 micrograms/kg) on dopaminergic firing in both anesthetized and unanesthetized rats. Since sulpiride fails to inhibit DA-sensitive adenylate cyclase, it may be concluded that DA receptors, whose blockade results in increased dopaminergic firing and TH activation, are not coupled with this enzyme. Moreover, the results indicate that the mechanism responsible for firing and TH stimulation is inhibited by halothane anesthesia. The latter significantly decreased also the stimulant effect of i.v. haloperidol on striatal TH activity.     

Microiontophoretic studies of the effects of D-1 and D-2 receptor agonists on type I caudate nucleus neurons: lack of synergistic interaction.

Several lines of evidence have suggested there may be a physiologically relevant form of synergistic interaction between D-1 and D-2 dopamine (DA) receptors located on postsynaptic neurons in the forebrain that receive a dopaminergic innervation. Because of the theoretical importance of such an interaction with respect to understanding the normal physiology of dopaminergic systems, we evaluated effects of D-1 and D-2 selective agonists, applied microiontophoretically, on the spontaneous electrical activity of a single, identifiable subpopulation of neurons within the caudate nucleus, the type I striatal neuron, in locally anesthetized, gallamine-paralyzed rats. It was observed that the D-2 receptor agonist quinpirole (QUIN) produced biphasic effects on cell firing rate. Low ejection currents significantly increased firing rate, while higher currents produced an inhibition. Similar effects were observed for the D-1 agonists SKF 38393; however, the overall excitations observed at low ejection currents were far less than those observed for QUIN. When these two agonists were applied concurrently, a simple additive effect (but not synergism) was always observed. The acute reduction of striatal levels of DA, by as much as 84% (with pretreatment with alpha-methyl-p-tyrosine, AMPT), did not alter the responsiveness of type I striatal neurons to the DA receptor agonists applied alone or in combination. These observed effects were not altered either by chloral hydrate anesthesia (in which glutamate-driven activity was studied) or by a more severe depletion of striatal DA levels (98% depletion produced by combined pretreatment with AMPT and reserpine).     

Chloral hydrate anesthesia alters the responsiveness of identified midbrain dopamine neurons to dopamine agonist administration

Single-unit electrophysiological recording techniques were used to sample the basal activity of antidromically identified nigrostriatal and mesoaccumbens dopamine (NSDA and MADA, respectively) neurons and to examine the responsiveness of these cells to dopamine agonist-induced inhibition of cell firing rate in either chloral hydrate-anesthetized or paralyzed rats. Paralyzed rats exhibited a greater percentage of burst-firing cells (69%) than did anesthetized animals (37%). Furthermore, paralyzed rats were less sensitive to the mixed D1/D2 DA receptor agonist apomorphine and the selective D2 DA receptor agonist quinpirole. However, significantly higher doses of d-amphetamine were required in paralyzed animals only with respect to inhibiting MADA neurons. The abilities of apomorphine and quinpirole to inhibit NSDA cell firing were rate-dependent in both anesthetized and paralyzed rats, whereas d-amphetamine-induced inhibition was rate dependent only in anesthetized animals. In contrast, apomorphine- and quinpirole-induced inhibition of MADA neurons were rate-dependent only in anesthetized rats, whereas d-amphetamine-induced inhibition was rate-dependent only in paralyzed animals. These results suggest that general anesthesia exerts subtle effects on the basal activity and pharmacological responsiveness of midbrain dopamine neurons.     

Enhanced response of subfornical organ neurons projecting to the hypothalamic paraventricular nucleus to angiotensin II in spontaneously hypertensive rats

Thirty subfornical organ (SFO) neurons in normotensive Wistar-Kyoto (WKY) rats and 32 SFO neurons in spontaneously hypertensive rats (SHR) were antidromically activated by electrical stimulation of the hypothalamic paraventricular nucleus (PVN) under urethane anesthesia. The spontaneous firing rate was significantly higher in SHR than in WKY rats. No significant differences in the latency, conduction velocity, and threshold of antidromic response were observed between WKY and SHR. All the identified SFO units were tested for a response to intracarotid injection of angiotensin II (ANG II, 20-ng/kg b.w.t.). Injections of ANG II elicited an increase in the activity of 21 units in WKY and 20 units in SHR and a depression in the firing of one unit in WKY rats, but did not affect the remaining units. The magnitude of the excitatory response caused by the ANG II injection was much greater in SHR than in WKY rats. These results show that there are differences between WKY and SHR in the spontaneous discharge rate of SFO neurons projecting to the PVN and in their response to circulating ANG II.     

Acute and chronic administration of the selective sigma1 receptor agonist SA4503 significantly alters the activity of midbrain dopamine neurons in rats: An in vivo electrophysiological study.

In this study, we examined the effect of the acute and repeated administration of the selective sigma (sigma)1 receptor agonist 1-(3, 4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) on the number and firing pattern of spontaneously active dopamine (DA) neurons in substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized, male Sprague-Dawley rats. This was accomplished using the technique of in vivo extracellular single unit recording. The intravenous administration of SA4503 (0.01-1.28 mg/kg) did not significantly alter the firing rate or pattern of spontaneously active DA neurons in either the SNC or VTA. A single injection of either 0.1 or 0.3 mg/kg i.p. of SA4503 did not alter the number of spontaneously active SNC and VTA DA neurons. In contrast, a single injection of 1 mg/kg i.p. of SA4503 produced a significant decrease and increase in the number of spontaneously active SNC and VTA DA neurons, respectively. Overall, the firing pattern parameters of spontaneously active SNC DA neurons were altered more significantly than those of spontaneously active VTA DA neurons following the acute administration of SA4503. The repeated administration (one injection per day for 21 days) of 0.3 and 1 mg/kg i.p. of SA4503 produced a significant increase in the number of spontaneously active VTA DA neurons. In addition, the repeated administration of SA4503 produced a greater alteration of the firing pattern of spontaneously active VTA compared to SNC DA neurons. Our results suggest that the administration of SA4503 significantly alters the activity of spontaneously active midbrain DA neurons, particularly those in the VTA following repeated administration.     

The acute and chronic administration of (+/-)-8-hydroxy-2-(Di-n-propylamino)tetralin significantly alters the activity of spontaneously active midbrain dopamine neurons in rats: an in vivo electrophysiological study

This study examined the effect of the acute and chronic systemic administration of (+/-)-8-Hydroxy-2-(Di-n-propylamino)Tetralin(8-OH-DPAT) on the number and firing pattern of spontaneously active dopamine (DA) neurons in the ventral tegmental area (VTA or A10) and substantia nigra pars compacta (SNC or A9) in anesthetized male rats. These parameters were measured using extracellular in vivo electrophysiology. A single s.c. injection of 0.01, 0.1, or 1 mg/kg of 8-OH-DPAT did not significantly alter the number of spontaneously active SNC DA neurons compared to vehicle-treated animals (controls). The acute administration of 0.01 or 0.1 mg/kg of 8-OH-DPAT did not significantly alter, whereas the 1 mg/kg dose significantly decreased the number of spontaneously active VTA DA neurons compared to controls. The acute administration of 8-OH-DPAT significantly increased the percentage of VTA DA neurons firing in a bursting pattern. In contrast, there was a significant decrease in the percentage of SNC DA neurons firing in a bursting pattern following the acute administration of 8-OH-DPAT. The number of spontaneously active SNC DA neurons was not significantly altered by the chronic s.c. administration of 8-OH-DPAT (0.01, 0.1, or 1 mg/kg s.c.) as compared to controls. However, the chronic s.c. administration of all doses of 8-OH-DPAT significantly decreased the number of spontaneously active VTA DA neurons compared to controls. The i.v. administration of (+)-apomorphine (50 microg/kg) did not reverse the 8-OH-DPAT-induced decrease in the number of spontaneously active VTA DA neurons, suggesting that this effect is unlikely due to depolarization blockade. The percentage of VTA DA neurons exhibiting burst firing was significantly increased by 0.01 and 0.1 mg/kg, but significantly decreased by 1 mg/kg of 8-OH-DPAT. Overall, the systemic administration of 8-OH-DPAT preferentially affects the activity of spontaneously active A10 DA neurons in rats.     

Effect of the acute and chronic administration of the selective neurokinin2 receptor antagonist SR 48968 on midbrain dopamine neurons in the rat: An in vivo extracellular single cell study

In this study, we examined the effect of the acute and chronic administration of the selective neurokinin₂ (NK₂) receptor antagonist SR 48968 on the activity of spontaneously active dopamine (DA) cells in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized, male rats. This was accomplished using the technique of in vivo, extracellular single cell recording. The intravenous (i.v.) administration of SR 48968 (10–1280 μg/kg) did not significantly alter the basal firing rate or pattern of either spontaneously active SNC or VTA DA neurons compared to control. However, the acute administration of 1 mg/kg, i.p., of SR 48968, but not its inactive enantiomer SR 48965, produced a significant increase in the number of spontaneously active DA cells in the SNC (48%) and VTA (28%) compared to vehicle controls. The i.p. administration of SR 48968 did not alter the basal firing pattern of either SNC or VTA DA neurons compared to vehicle controls. The pretreatment of animals with 1 mg/kg, i.p., of SR 48968 significantly potentiated the suppressant action of (+)-apomorphine on spontaneously active SNC and VTA DA cells. In contrast to its acute effects, the administration of 1 mg/kg, i.p., of SR 48968 once daily for 21 days produced a significant decrease in the number of spontaneously active DA cells in the SNC and VTA. The decrease in the number of spontaneously active VTA DA cells was not reversed by (+)-apomorphine administration; in fact, a further decrease in the number of VTA DA cells was observed. This suggests that the SR 48968-induced decrease in the number of spontaneously active DA neurons may not be the result of depolarization block. Overall, these results suggest that the acute and chronic administration of SR 48968 alters the number of spontaneously active midbrain DA neurons in anesthetized rats. Synapse 25:196–204, 1997. © 1997 Wiley-Liss, Inc.     

Identification and characterization of striatal cell subtypes using in vivo intracellular recording in rats. I. Basic physiology and response to corticostriatal fiber stimulation

The electrophysiological characteristics of two subtypes of striatal neurons, identified by their distinct patterns of response to paired impulse stimulation of corticostriatal afferents, were compared using in vivo intracellular recordings in rats. As observed in previous extracellular recording studies, the majority of neurons (73%) were found to be of the Type II class, with the remaining cells exhibiting the Type I response patern. For all cells, cortical stimulation elicited 5–30 mV EPSPs at latencies ranging from 2.0–5.3 msec; Increasing the stimulating current intensity caused a progressive increase in the amplitude of the evoked EPSPs without altering their latencies, suggesting that the EPSPs are monosynaptically mediated. Both the average amplitude and duration of the evoked EPSPs at spike threshold in Type I neurons (9.8 ± 1.7 mV, 11.8 ± 2.8 msec; mean ± SEM) were significantly smaller than those of Type II cells (20.3 ± 1.4 mV, 22.7 ± 2.1 msec). Although the average latency to the onset of the EPSP was similar for both cell classes (Type I cells: 2.3 ± 0.3 msec; Type II cells: 2.2 ± 0.2 msec), the EPSPs in Type I cells reached peak amplitude and the spikes were triggered at significantly longer latencies than in the Type II cells (peak I: 11.2 ± 2.5 msec vs. II: 7.6 ± 0.7 msec; spike I: 8.0 ± 1.2 msec vs. II: 5.7 ± 0.4 msec). Striatal neurons had a comparatively hyperpolarized resting membrane potential (?70.2 ± 2.1 mV) and had an average input resistance of 35.4 ± 7.6 MΩ. Overall, striatal neurons exhibited low levels of spontaneous activity (0.6 ± 0.7 Hz) with 50% of the neurons being quiescent. Type I cells exhibited significantly higher firing rates (3.2 ± 0.8 Hz) than Type II cells (0.8 ± 0.3 Hz), although their resting membrane potentials were not significantly different. Spontaneously occurring spikes had an average amplitude of 72.7 ± 3.4 mV and spike thresholds of ?50.1 ± 1.5 mV. Irregularly occurring depolarizing plateau potentials, which typically gave rise to spike discharge, were frequently observed in both spontaneously firing and quiescent neurons. A small proportion of the cells recorded (3/55) exhibited a Type I response pattern but had unique physiological characteristics that were similar to those described by others as arising from large, aspiny striatal neurons. The present study shows that these two physiologically distinct neuron types appear to be similar in terms of their passive membrane properties (e.g., resting membrane potentials, input resistance, etc.) and firing characteristics, despite their unique patterns of response to corticostriatal stimulation. Therefore, the source of the distinct paired impulse response profiles of these neurons is more likely to arise from differences in their afferent drive than from a heterogeneity in their membrane properties. © 1994 Wiley-Liss, Inc.     

Effect of the acute and chronic administration of the putative atypical antipsychotic drug Y-931 (8-fluoro-12- (4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3b][1,5] benzodiazepine maleate) on spontaneously active rat midbrain dopamine neurons: an in vivo electrophysiological study

This study examined the effect of the p.o. administration of the putative atypical antipsychotic drug Y-931 (8-fluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3b][1,5] benzodiazepine maleate) on the activity of spontaneously active dopamine (DA) neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNC) in anesthetized male Sprague-Dawley rats. This was accomplished using in vivo electrophysiology. The acute p.o. administration of Y-931 did not significantly alter the number of spontaneously active SNC DA neurons compared to vehicle-treated animals. A single p.o. administration of 3 and 10 mg/kg of Y-931 significantly increased and decreased, respectively, the number of spontaneously active VTA DA neurons compared to vehicle-treated animals. The acute administration of 3 mg/kg of Y-931 significantly altered the firing pattern parameters for all spontaneously active SNC DA. The 3 and 10 mg/kg doses of Y-931 significantly increased the degree of bursting and irregular activity of spontaneously active VTA and SNC DA neurons firing in a bursting pattern. The repeated p.o. administration (21 days) of 1, 3, or 10 mg/kg of Y-931 significantly decreased the number of spontaneously active VTA DA neurons but had no significant effect on SNC DA neurons compared to vehicle-treated animals. The repeated administration of Y-931 did not significantly alter the firing pattern of all spontaneously active SNC or VTA DA neurons. Our findings indicate that the acute and chronic administration of Y-931 significantly alters the activity of midbrain DA neurons in rats and the electrophysiological profile of chronic Y-931 resembles that of atypical antipsychotic agents.     

Rat hypothalamic arcuate neuron response in electroacupuncture-induced analgesia

Electroacupuncture (EA) effects on activity of arcuate neurons of the hypothalamus (ARH) and on magnitude of the digastric electromyogram (dEMG) in the jaw opening reflex were investigated, in both p-chlorophenylalanine pretreated and normal Wistar rats. EA stimulation (300-500 microA, 5 msec pulses, for 15 min) was delivered unilaterally to a meridian Ho-Ku point of anesthetized rats at 3, 45 and 100 Hz. In control animals, EA stimulation at 3, 45 or 100 Hz induced long-lasting suppression of the magnitude of the dEMG activity and changed the spontaneous firing rate of most of the ARH neurons: the rate either increased (type I) or decreased (type II). After low-frequency stimulation, there were significantly more type I neurons than type II; after high-frequency stimulation, there were significantly more type II neurons than type I. In serotonin-depleted rats, however, high-frequency stimulation suppressed dEMG activity only slightly and induced a smaller proportion of type II neurons.     

Effect of the acute and chronic administration of the selective 5-HT6 receptor antagonist SB-271046 on the activity of midbrain dopamine neurons in rats: an in vivo electrophysiological study

This study examined the effect of the acute and repeated per os (p.o.) administration of the selective 5-HT(6) receptor antagonist SB-271046, on the number, as well as the firing pattern of spontaneously active dopamine (DA) neurons in the rat substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized male Sprague-Dawley rats. This was accomplished using the technique of extracellular in vivo electrophysiology. A single p.o. administration of either 1, 3, or 10 mg/kg of SB-271046 did not significantly alter the number of spontaneously active SNC DA neurons per stereotaxic electrode tract compared to vehicle-treated animals. The acute administration of either 1 or 3 mg/kg of SB-271046 did not significantly alter the number of spontaneously active VTA DA neurons. In contrast, a significant decrease in the number of spontaneously active VTA DA neurons was observed after a single administration of 10 mg/kg of SB-271046 compared to vehicle-treated animals. The acute p.o. administration of SB-271046 significantly altered the firing pattern parameters of all (bursting + nonbursting DA neurons) DA neurons, particularly those in the VTA, compared to vehicle-treated animals. The repeated p.o. administration (once per day for 21 days) of 1, 3, or 10 mg/kg of SB-271046 did not significantly alter the number of spontaneously active VTA DA neurons compared to vehicle-treated animals. The repeated administration of 3 or 10 mg/kg of SB-271046 significantly increased the number of spontaneously active SNC DA neurons compared to vehicle controls. Overall, the repeated administration of SB-271046 had relatively little effect on the firing pattern of midbrain DA neurons. The results obtained following the chronic administration of SB-271046 show that this compound has a profile different from that of typical or atypical antipsychotic drugs in this model. Clinical studies are required to understand what role 5-HT(6) receptor blockade might eventually play in the treatment of schizophrenia.     

Effects of electroacupuncture on the neuronal activity of the arcuate nucleus of the rat hypothalamus

Electroacupuncture (EA) effects on the spontaneous unit activities of 143 neurons in the hypothalamic arcuate nucleus (ARH) which were electrophysiologically identified to project to the median eminence were investigated using anesthetized rats weighing about 300 g. Stimuli were delivered unilaterally to a meridian point of Ho-Ku in the forepaw as rectangular pulses of 5 ms duration, intensity 300 to 500 microA, for 15 min at 3 and 45 Hz. Unit activities of ARH cells were extracellularly recorded and the mean firing rates were compared before and after EA stimulation. Stimulation at 3 or 45 Hz induced a long-lasting and naloxone-reversible suppression of the magnitude of the digastric electromyogram (dEMG) in the jaw opening reflex to 48 to 56% of the control value. Based upon the EA effects on the spontaneous firing rate, the ARH cells were classified into three types: the rate either increased (type I), decreased (type II), or did not change (type III). Type I, II, and III neurons composed 56, 40, and 4% of the recorded neurons (N = 45) when EA stimulation was applied at 3 Hz, and 27, 70, and 3% (N = 37) at 45 Hz, respectively. The distribution of the three types of ARH neurons after EA stimulation at 3 Hz was significantly different (P less than 0.05, chi-square test) from that at 45 Hz.     

Antidromic identification of dopaminergic and other output neurons of the rat substantia nigra

In the present study dopamine (DA)-containing and other output neurons of the substantia nigra (SN) wer identified by antidromic stimulation from postulated target nuclei, the caudate-putamen, the thalamus, the cortex and the pontine reticular formation. To guide electrode placements, the topography of the nigrostriatal projection system was determined by retrograde tracing methods. Spontaneously active cells present in the SN were then classified in two groups according to the shape of their action potentials and their firing rate. Type I cells were located mainly in the pars compacta and could be antidromically-activated (AD-activated) from various locations along the course of the nigrostriatal pathway (caudate-putamen, globus pallidus, MFB) but not from other brain areas (ventromedial thalamus, motor cortex, pontine reticular formation). These neurons had a slow bursting pattern of firing, a very slow conduction velocity (0.58 m/sec), and a wide action potential. Their firing rate was dramatically reduced following the intravenous administration of apomorphine (ID 50: 9.3 microgram/kg), or the iontophoretic application of DA and GABA. Type II cells were located predominantly in the pars reticulata; most of them could be AD-activated from the ventromedial thalamus and the MFB but not from the motor cortex. A few of these cells could be AD-activated from the pontine reticular formation and the thalamus. A minority of type II cells, located in or near the pars compacta could be AD-activated from the caudate-putamen. In addition, their conduction velocuty was much higher (2.8 m/sec) and their firing rate far in excess of that exhibited by type I neurons. These neurons were inhibited by the iontophoretic application of GABA but not of DA. The microinjection of 6-hydroxydopamine (a neurotoxin relatively specific against catecholamine-containing neurons) in the vicinity of the MFB blocked selectively the propagation of antidromic spikes in type I but not type II cells. It is concluded that type I cells are the DA neurons of the nigrostriatal pathway. Type II cells are mainly oupput neurons that project to the ventromedial thalamus, the pons and the forebrain. This telencephalic projection most likely constitutes a second, non-DA, fast-conducting nigrostriatal pathway.     

The acute and chronic administration of the 5-HT(2B/2C) receptor antagonist SB-200646A significantly alters the activity of spontaneously active midbrain dopamine neurons in the rat: An in vivo extracellular single cell study

This study examined the effect of the acute and chronic administration of the 5-HT(2B/2C) receptor antagonist N-(1-methyl-5-indolyl)-N'-(3-pyridyl) urea hydrochloride (SB-200646A) on the activity of spontaneously active DA cells in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized, male Sprague-Dawley rats. This was accomplished using in vivo extracellular single cell recording. The i.v. administration of 4-16 mg/kg of SB-200646A significantly increased the firing rate and % events as bursts in spontaneously active VTA DA neurons and significantly increased the % events as burst in SNC DA neurons. The acute i.p. administration of 20 and 40 mg/kg of SB-200646A significantly increased the number of spontaneously active VTA DA neurons when compared with vehicle-treated controls. The acute administration of 10 mg/kg of SB-200646A significantly increased the coefficient of variation in spontaneously active SNC and DA neurons when compared with vehicle-treated controls. However, the acute i.p. administration of 20 mg/kg of SB-200646A significantly decreased the degree of bursting of VTA DA neurons. Similary, chronic i.p. administration of 10 mg/kg of SB-200646 did not significantly alter firing, whereas chronic administration of 20 mg/kg of SB-200646A or 20 mg/kg of clozapine significantly decreased the number of spontaneously active VTA DA neurons when compared with vehicle-treated controls. The SB-200646A-induced decrease in the number of spontaneously active VTA DA neurons was reversed by the i.v. administration of (+)-apomorphine or (-)-baclofen. The chronic i.p. administration of either 10 or 20 mg/kg of SB-200646A did not significantly alter the firing pattern of spontaneously active SNC DA neurons. However, the chronic administration of 20 mg/kg of SB-200646A significantly increased the degree of bursting in VTA DA neurons when compared with vehicle. Overall, the acute and chronic administration of SB-200646A produces in vivo electrophysiological effects, resembling that of atypical antipsychotic drugs.