PubMed Health⌕ Search

Biomedical subjects

E D Abercrombie

Publications and source records attributed to E D Abercrombie.

At least 19 recordsLinked to original sources
PubMed2005

Thalamic regulation of striatal acetylcholine efflux is both direct and indirect and qualitatively altered in the dopamine-depleted striatum.

Striatal cholinergic interneurons play a pivotal role in the integrative sensorimotor functions of the basal ganglia. The major excitatory input to these interneurons arises from glutamatergic neurons of the parafascicular nucleus of the thalamus (Pf). Thalamic regulation of cholinergic interneurons, however, may also include an indirect inhibitory component mediated by the axon collaterals of GABAergic medium spiny neurons that are also innervated by Pf. The present study examined thalamic regulation of striatal cholinergic interneurons by employing dual probe in vivo microdialysis in freely moving animals to determine the effect of pharmacological manipulation of Pf on acetylcholine (ACh) efflux in intact and dopamine-lesioned striata. In intact animals, reverse dialysis application of the GABA(A) antagonist bicuculline (50 microM) into Pf, likely disinhibiting Pf neurons, significantly decreased striatal ACh efflux. When striatal GABA(A) receptors were blocked by simultaneous reverse dialysis application of bicuculline (10 microM), however, the same manipulation significantly increased ACh efflux. Qualitatively similar results were obtained in experiments employing a higher concentration of bicuculline (200 microM). Application of the GABA agonist muscimol (500 microM) into Pf, likely inhibiting Pf neurons, decreased ACh efflux only when the experiment was conducted under blockade of striatal GABA(A) receptors. These data are consistent with the existence of an indirect, inhibitory, GABA(A) receptor-mediated component of ACh regulation that is most clearly manifested when Pf is disinhibited and with the existence of a direct excitatory component of ACh regulation, evident when Pf is inhibited. Manipulation of Pf using very high concentrations of drug (500 microM bicuculline, 2 mM muscimol), however, yielded data consistent only with direct excitatory thalamic regulation. In contrast to results obtained in intact animals, in animals with prior (3 weeks) unilateral lesion of the dopaminergic nigrostriatal pathway, bicuculline application (50 muM) in Pf significantly increased striatal ACh efflux, irrespective of simultaneous blockade of striatal GABA(A) receptors. The results of experiments in which muscimol (500 microM) was applied in Pf were similar to those obtained in intact animals, however. Baseline ACh efflux was not significantly elevated in dopamine-lesioned animals. These results indicate a qualitative alteration in the effectiveness of an inhibitory component of the thalamic regulation of ACh efflux in the dopamine depleted striatum, evident during increased thalamostriatal input. Such altered regulation of striatal ACh output is likely to have profound consequences for integrative function in the parkinsonian basal ganglia.

Acetylcholine↗
PubMed2004

Pallidal control of substantia nigra dopaminergic neuron firing pattern and its relation to extracellular neostriatal dopamine levels.

The firing patterns of dopaminergic neurons in vivo are strongly modulated by afferent input. The principal GABAergic inputs to the dopaminergic neurons of the substantia nigra originate from neurons of the neostriatum, globus pallidus and substantia nigra pars reticulata. It has previously been shown that the firing pattern of nigral dopaminergic neurons can be manipulated by pharmacologically induced excitation or inhibition of the globus pallidus with relatively little effect on firing rate. We used this technique to explore the relation between the firing pattern of dopaminergic neurons and extracellular dopamine levels in the neostriatum in vivo. Specifically, we tested whether an increase in burst firing in dopaminergic neurons produced by increased pallidal activity led to increased extracellular dopamine levels in the neostriatum. Single unit extracellular recording combined with simultaneous microdialysis was used to measure the firing rates and patterns of dopaminergic neurons and extracellular striatal dopamine levels, respectively, during bicuculline-induced excitation of the globus pallidus. Pallidal excitation resulted in a marked increase in burst firing in dopaminergic neurons along with only a slight increase in firing rate, but produced a significant elevation (approximately 45%) in neostriatal dopamine levels. These data suggest that afferent-induced burst firing in dopaminergic neurons leads to an increase in extracellular dopamine levels in the neostriatum when compared with less bursty patterns with similar overall firing rates.

Animals↗
PubMed2003

Relative involvement of globus pallidus and subthalamic nucleus in the regulation of somatodendritic dopamine release in substantia nigra is dopamine-dependent.

Previously, we have shown that GABA(A) receptors and glutamate receptors in substantia nigra play distinct roles in the regulation of somatodendritic dopamine release. GABAergic input to substantia nigra was found to be the primary determinant of the level of spontaneous somatodendritic dopamine release. In contrast, acute blockade of dopamine receptors by systemic haloperidol administration produced an increase in somatodendritic dopamine release in substantia nigra that was found to be dependent exclusively upon activation of nigral glutamate receptors. The focus of the present study was to identify anatomical structures that may participate in the differential regulation of somatodendritic dopamine release by GABA and glutamate under these two conditions. To this end, we pharmacologically inhibited the activity of either globus pallidus or subthalamic nucleus using microinfusion of the GABA(A) receptor agonist muscimol. The effects of these manipulations on spontaneous efflux of somatodendritic dopamine and on increases in this measure produced by systemic haloperidol administration were determined in ipsilateral substantia nigra using in vivo microdialysis. As observed previously, administration of haloperidol (0.5 mg/kg, i.p.) significantly increased extracellular dopamine in substantia nigra. Microinfusion of muscimol (400 ng/200 nl) into globus pallidus also produced a significant increase in somatodendritic dopamine efflux. When haloperidol was administered systemically in conjunction with microinfusion of muscimol into globus pallidus, an increase in nigral dopamine efflux was observed that was significantly greater than that which was produced singly by muscimol microinfusion into globus pallidus or by systemic haloperidol administration. The additive nature of the increases in somatodendritic dopamine release produced by these two manipulations indicates that independent neural circuitries may be involved. Inactivation of subthalamic nucleus by microinfusion of muscimol (200 ng/100 nl) had no effect on spontaneous somatodendritic dopamine efflux. Muscimol application into subthalamic nucleus, however, completely abolished the stimulatory effect of systemic haloperidol on dendritic dopamine efflux in substantia nigra. The present data extend our previous findings by demonstrating: 1) an important involvement of globus pallidus efferents in the GABAergic regulation of somatodendritic dopamine efflux in substantia nigra under normal conditions and, 2) an emergent predominant role of subthalamic nucleus efferents in the glutamate-dependent increase in somatodendritic dopamine efflux observed after systemic haloperidol administration. Thus, the relative influence of globus pallidus and subthalamic nucleus in the determination of the level of somatodendritic dopamine release in substantia nigra qualitatively varies as a function of dopamine receptor blockade. These findings are relevant to current models of basal ganglia function under both normal and pathological conditions, e.g. Parkinson's disease.

Animals↗
PubMed2001

Decreased striatal dopamine efflux after intrastriatal application of benzazepine-class D1 agonists is not mediated via dopamine receptors.

Previous pharmacological studies have reported that striatal dopamine efflux is negatively modulated not only by presynaptic D2 dopamine autoreceptors but also by striatal D1 dopamine receptors. The present experiments employed in vivo microdialysis to further examine the ability of widely used benzazepine-class D1 agonists to modulate striatal dopamine efflux. In the present study, both the partial D1 agonist (+/-)-SKF 38393 (10 microM) and the full D1 agonist (+/-)-SKF 82958 (10 and 100 microM) significantly reduced striatal dopamine efflux during intrastriatal application. Intrastriatal application of the less active enantiomer, S(-)-SKF 38393 (10 microM) did not decrease striatal dopamine suggesting a selective receptor-mediated mode of action of (+/-)-SKF 38393. Additional experiments were conducted with the full D1 agonist (+/-)-SKF 82958 in order to characterize the receptor(s) mediating the observed decrease in dopamine efflux. Neither local application of the D1 antagonist R(+)-SCH 23390 (100 microM) nor local application of the selective D2 antagonist raclopride (5 microM) blocked the ability of (+/-)-SKF 82958 (10 microM) to decrease striatal dopamine efflux. However, intrastriatal application of the less selective D2 antagonist haloperidol (1 microM) did prevent the decrease in striatal dopamine efflux observed during intrastriatal (+/-)-SKF 82958 application. The present data suggest that the ability of intrastriatally applied benzazepine-class D1 agonists to decrease striatal dopamine efflux is receptor-mediated, but this action apparently is not mediated at D1 or D2 receptors. There is therefore no indication for an intrastriatal population of D1 receptors capable of modulating dopamine efflux.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1999

Discrete local application of corticotropin-releasing factor increases locus coeruleus discharge and extracellular norepinephrine in rat hippocampus.

The most prominent afferents impinging upon the noradrenergic neurons of the locus coeruleus (LC) utilize GABA and glutamate. However, peptide neurotransmitters such as galanin, neuropeptide Y, and corticotropin-releasing factor (CRF) have also been localized to LC afferents. The evidence for CRF modulation of LC activity was examined in the present studies. Specifically, the impact of local CRF administration on both LC-NE discharge characteristics and release of norepinephrine (NE) in hippocampus was determined. First, the ability of CRF microinfused into the LC area to increase NE efflux in the dorsal hippocampus was determined using in vivo microdialysis techniques in awake rats. CRF into the LC dose-dependently increased extracellular NE in the ipsilateral hippocampus. Second, a more detailed analysis was performed in halothane-anesthetized rats by characterizing the electrophysiological activity of LC-NE neurons in response to local application of CRF. Changes in the firing rate and pattern of single LC-NE neurons were measured while simultaneously monitoring the extracellular level of NE in hippocampus. A dose of 30 ng CRF applied directly into LC via pressure ejection elicited an 88% increase in the discharge rate of LC-NE neurons and increased the incidence of burst firing from 14% to 33%. This manipulation simultaneously increased extracellular NE in hippocampus by 63%. The CRF-induced increases in discharge rate of LC-NE neurons and extracellular NE efflux in hippocampus were prevented by prior i.c.v. administration of the CRF antagonist, d-PheCRF(12-41 )(3 microg / 3 microl). The present findings demonstrate that CRF applied directly into the LC increases both the activity of LC-NE neurons and the release of NE in an LC terminal region. The shift in activity of LC-NE neurons to more burst-like firing in response to CRF may provide a means for enhanced release of NE in LC projection fields. This is the first report to demonstrate a dose-dependent increase in extracellular NE levels evoked by intra-LC infusion of CRF in unanesthetized animals.

Analysis of Variance↗
PubMed1999

Enhanced acetylcholine release in striatum after chronic amphetamine is NMDA-dependent.

Behavioral sensitization to chronic amphetamine develops in parallel with an enhancement of amphetamine-stimulated efflux of acetylcholine (ACh) in striatum. The present study investigated the role of NMDA receptors in the latter phenomenon. Rats were treated with either saline (1.0 ml/kg, i.p.) or amphetamine (4.0 mg/kg, i.p., b.i.d.) for 12 days followed by a withdrawal period of 2-3 weeks. In vivo microdialysis was employed to measure striatal ACh efflux. Amphetamine challenge (4.0 mg/kg, i.p.) evoked a significant increase in striatal ACh efflux in rats withdrawn from chronic amphetamine while having no significant effect on ACh efflux in saline-pretreated rats. Inclusion of the NMDA receptor antagonist (+/-)-2-amino-5-phoshonopentanoic acid (APV; 100 microM) in the perfusion solution blocked the amphetamine-induced increase in striatal ACh efflux observed in amphetamine-pretreated rats. In saline-pretreated animals, the presence of APV had no apparent effect on the profile of striatal ACh efflux following amphetamine challenge. Thus, the stimulatory effect of amphetamine challenge on striatal ACh efflux that selectively is observed in animals withdrawn from chronic amphetamine is dependent upon NMDA receptor activation.

Acetylcholine↗
PubMed1999

Relationship between locus coeruleus discharge rates and rates of norepinephrine release within neocortex as assessed by in vivo microdialysis.

The relationship between discharge rates of locus coeruleus noradrenergic neurons and rates of norepinephrine release was examined in the anesthetized rat. Neuronal discharge rates of locus coeruleus neurons were altered and quantified using a combined recording-infusion probe. Peri-locus coeruleus infusions of either the cholinergic agonist, bethanechol, or the alpha2-agonist, clonidine, were used to enhance or suppress neuronal discharge activity, respectively. Alterations in concentrations of extracellular norepinephrine within the prefrontal cortex were determined using in vivo microdialysis and high-pressure liquid chromatography with electrochemical detection. A linear relationship between locus coeruleus activity and norepinephrine dialysate concentration was observed between complete suppression of locus coeruleus discharge activity and approximately 300-400% of basal discharge levels (1.58+/-0.29 Hz). Above these levels, increases in locus coeruleus discharge rates were not accompanied by similar increases in dialysate norepinephrine concentrations. In general, neither activation nor suppression of locus coeruleus neuronal discharge rates appeared to alter the relationship between discharge activity and norepinephrine efflux during subsequent epochs. The one exception to this was observed during recovery from relatively high-magnitude locus coeruleus activation. In two out of three cases in which locus coeruleus discharge rates were increased greater than 450%, a recovery of norepinephrine concentrations to basal levels occurred more quickly than the recovery of locus coeruleus neuronal discharge rates to basal levels. Although limited, these latter observations suggest that dysregulation of norepinephrine release may occur following sustained activation of locus coeruleus at the highest rates examined, which may mimic those associated with intense arousal or stress.

Animals↗
PubMed1999

Individual differences in behavioral reactivity: correlation with stress-induced norepinephrine efflux in the hippocampus of Sprague-Dawley rats.

The present studies investigate the hypothesis that the locus coeruleus-norepinephrine (LC-NE) system plays a role in the neural substrates underlying individual differences in behavioral reactivity to stress. Individuals were selected from a random sample of Sprague-Dawley rats and categorized as a high responder (HR), middle responder (MR), or low responder (LR) based on the initial locomotor response to a novel open field. Rats with behavioral scores at least 1 SD away from the mean for the subject sample were categorized as HR or LR rats. Middle responder rats exhibited locomotor scores representative of the mean locomotor activity of the population sample. Locomotor activity scores measured 6 days after the initial determination were similar to scores obtained in the original screening, suggesting that the locomotor response to novelty is a stable individual trait. Additionally, locomotor activity during the dark phase of the diurnal cycle was not different among the groups, suggesting that differences in locomotor activity in response to a novel open field are an index of behavioral reactivity to the stressful situation rather than an indicator of global differences in motoric activity. In vivo microdialysis was used to measure extracellular levels of hippocampal NE in the hippocampus. During baseline conditions, the efflux of hippocampal NE was similar among HR, MR, and LR rats. In response to tail-pinch stress, hippocampal NE release was elevated in all groups. This response was significantly greater in HR compared to LR rats. Across all groups, locomotor response in the novel open field was significantly correlated with the magnitude of NE release in response to subsequent application of tail-pinch stress. In contrast, administration of 1.5 mg/kg, i.p., amphetamine resulted in a similar elevation of extracellular NE level among HR, LR, and MR rats. These data suggest that activation of the LC-NE system may be involved in determining the behavioral response of individuals to environmental stress.

Amphetamine↗
PubMed1999

Role of high-affinity dopamine uptake and impulse activity in the appearance of extracellular dopamine in striatum after administration of exogenous L-DOPA: studies in intact and 6-hydroxydopamine-treated rats.

The differential behavioral and neurochemical effects of exogenous L-DOPA in animals with intact versus dopamine (DA)-denervated striata raise questions regarding the role of DA terminals in the regulation of dopaminergic neurotransmission after administration of exogenous L-DOPA. In vivo microdialysis was used to monitor the effect of exogenous L-DOPA on extracellular DA in intact and DA-denervated striata of awake rats. In intact striatum, a small increase in extracellular DA was observed after administration of L-DOPA (50 mg/kg i.p.) but in DA-denervated striatum a much larger increase in extracellular DA was elicited. Additional experiments assessed the role of high-affinity DA uptake and impulse-dependent neurotransmitter release in the effect of exogenous L-DOPA on extracellular DA in striatum. Pretreatment with GBR-12909 (20 mg/kg i.p.), a selective DA uptake inhibitor, enhanced the ability of L-DOPA to increase extracellular DA in intact striatum. However, in DA-denervated striatum, inhibition of DA uptake did not alter the extracellular DA response to L-DOPA. Impulse-dependent neurotransmitter release was blocked by the infusion of tetrodotoxin (TTX; 1 microM), an inhibitor of fast sodium channels, through the dialysis probe. Application of TTX significantly attenuated the L-DOPA-induced increase in extracellular DA observed in striatum of intact rats pretreated with GBR-12909. In a similar manner, TTX infusion significantly attenuated the increase in extracellular DA typically observed in striatum of 6-OHDA-lesioned rats after the administration of L-DOPA. The present results indicate that DA terminals, via high-affinity uptake, play a crucial role in the clearance of extracellular DA formed from exogenous L-DOPA in intact striatum. This regulatory mechanism is absent in the DA-denervated striatum. In addition, this study has shown that DA synthesized from exogenous L-DOPA primarily is released by an impulse-dependent mechanism in both intact and DA-denervated striatum. The latter result suggests an important role for a nondopaminergic neuronal element in striatum that serves as the primary source of extracellular DA formed from exogenous L-DOPA.

Animals↗
PubMed1998

Role of excitatory amino acids in the regulation of dopamine synthesis and release in the neostriatum.

We have explored the role of excitatory amino acids in the increased dopamine (DA) release that occurs in the neostriatum during stress-induced behavioral activation. Studies were performed in awake, freely moving rats, using in vivo microdialysis. Extracellular DA was used as a measure of DA release; extracellular 3,4-dihydroxyphenylalanine (DOPA) after inhibition of DOPA decarboxylase provided a measure of apparent DA synthesis. Mild stress increased the synthesis and release of DA in striatum. DA synthesis and release also were enhanced by the intra-striatal infusion of N-methyl-D-aspartate (NMDA), an agonist at NMDA receptors, and kainic acid, an agonist at the DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate (AMPA)/kainate site. Stress-induced increase in DA synthesis was attenuated by co-infusion of 2-amino-5-phosphonovalerate (APV) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), antagonists of NMDA and AMPA/kainate receptors, respectively. In contrast, intrastriatal APV, CNQX, or kynurenic acid (a non-selective ionotropic glutamate receptor antagonist) did not block the stress-induced increase in DA release. Stress-induced increase in DA release was, however, blocked by administration of tetrodotoxin along the nigrostriatal DA projection. It also was attenuated when APV was infused into substantia nigra. Thus, glutamate may act via ionotropic receptors within striatum to regulate DA synthesis, whereas glutamate may influence DA release via an action on receptors in substantia nigra. However, our method for monitoring DA synthesis lowers extracellular DA and this may permit the appearance of an intra-striatal glutamatergic influence by reducing a local inhibitory influence of DA. If so, under conditions of low extracellular DA glutamate may influence DA release, as well as DA synthesis, by an intrastriatal action. Such conditions might occur during prolonged severe stress and/or DA neuron degeneration. These results may have implications for the impact of glutamate antagonists on the ability of patients with Parkinson's disease to tolerate stress.

Animals↗
PubMed1997

Substantia nigra D1 receptors and stimulation of striatal cholinergic interneurons by dopamine: a proposed circuit mechanism.

Dopamine release can regulate striatal acetylcholine efflux in vivo through at least two receptor mechanisms: (1) direct inhibition by dopamine D2 receptors on the cholinergic neurons, and (2) excitation initiated by dopamine D1 receptors. The neuroanatomical locus of the latter population of D1 receptors and the pathway(s) involved in the expression of their influence are controversial issues. We have tested the hypothesis that D1 receptors in substantia nigra pars reticulata are involved in the excitatory component of dopaminergic actions on striatal acetylcholine output. In vivo microdialysis was used in awake rats. Infusion of the selective D1 receptor agonist R(+)-1-Phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol (SKF 38393) hydrochloride into pars reticulata of substantia nigra elicited a significant increase in striatal acetylcholine efflux. Likewise, D-amphetamine applied into pars reticulata of substantia nigra by reverse dialysis produced an elevation in acetylcholine output measured at a second microdialysis probe in the striatum. Application of D-amphetamine in the striatum by reverse dialysis elicited a decrease in striatal acetylcholine efflux that could be reversed subsequently by local application of D-amphetamine in substantia nigra pars reticulata. A 2 mg/kg intraperitoneal dose of D-amphetamine, which has no net effect on striatal acetylcholine output under control conditions, elicited a significant decrease in acetylcholine efflux when the D1 receptor antagonist R(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine (SCH 23390) hydrochloride was applied simultaneously via a second microdialysis probe in substantia nigra pars reticulata. Thus, an excitatory D1-mediated influence on striatal acetylcholine output is initiated in substantia nigra pars reticulata, and this influence contributes to the effects of indirect dopaminergic agonists such as D-amphetamine on striatal acetylcholine efflux. These results indicate an important role of somatodendritic dopamine release, in addition to nerve terminal dopamine release, in the regulation of activity in basal ganglia circuits.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1997

An analysis of the effects of acute and chronic fluoxetine on extracellular norepinephrine in the rat hippocampus during stress.

The locus coeruleus (LC) noradrenergic system is activated by a range of arousing and stressful stimuli. The serotonergic inputs to this structure have been shown to attenuate LC activation under some conditions. The present study examined the effect of fluoxetine, a selective serotonin reuptake inhibitor (SSRI) known to be a clinically effective antidepressant, on basal and stress-induced norepinephrine (NE) release. Basal and stress-induced NE efflux in the rat hippocampus were assessed using in vivo microdialysis techniques. The effect of a 30 minute tailpinch stressor on extracellular concentration of NE was compared in rats treated with fluoxetine either once prior to tailpinch or twice daily for 14 days and, respectively, in unhandled controls and vehicle-treated control animals. A single fluoxetine injection prior to tailpinch did not significantly alter the tailpinch-induced increase of extracellular NE as compared to naive controls. However, there was an enhanced NE response to tailpinch in chronic fluoxetine versus chronic vehicle-treated control rats. Thus, acute blockade of 5-HT uptake by fluoxetine does not affect NE release in response to tailpinch stress. Chronic fluoxetine administration, however, results in a potentiated evoked response of the LC-NE system. One action of chronic fluoxetine, which may relate to therapeutic efficacy, is an increase in responsivity of LC neurons.

Animals↗
PubMed1997

Striatal acetylcholine release correlates with behavioral sensitization in rats withdrawn from chronic amphetamine.

Stimulant sensitization is defined as an enhancement of the behavioral response to drug after repeated drug exposure. We have examined the relation between the expression of behavioral sensitization and the release of the striatal neurotransmitters acetylcholine (ACh) and dopamine (DA). Rats were treated with amphetamine (4 mg/kg i.p., b.i.d.) for 12 days. The behavioral response to amphetamine challenge was assessed during the chronic treatment, at short withdrawal (2 days) and at long withdrawal (2-3 wk) from the drug. Neurochemical responses to amphetamine challenge were assessed in separate groups of rats at the two withdrawal timepoints using in vivo microdialysis. The expression of behavioral sensitization in response to a low challenge dose of amphetamine (0.5 mg/kg) was only observed after long withdrawal; indeed, tolerance was observed at the short withdrawal timepoint. In contrast, sensitization of the behavioral response to challenge with 4 mg/kg amphetamine developed progressively over the course of drug treatment and continued to increase throughout withdrawal. Striatal ACh release was enhanced by amphetamine challenge (4 mg/kg) in the chronically treated animals and this response also was greater at long withdrawal vs. short withdrawal. However, amphetamine administration had no net effect on striatal ACh release in animals previously given chronic saline injections. Amphetamine challenge increased striatal DA release but this response did not differ between drug- or saline-treated animals at either withdrawal timepoint. Thus, an enhancement of the drug-induced stimulation of striatal ACh release correlates with the temporal profile of the expression of behavioral sensitization to amphetamine. In contrast, amphetamine-induced DA release does not appear to correlate with the expression of behavioral sensitization in the same manner.

Acetylcholine↗
PubMed1996

Spontaneous release of acetylcholine in striatum is preferentially regulated by inhibitory dopamine D2 receptors.

The dose-related effects of the direct dopamine D2 receptor agonist quinpirole [trans-(-)-4aR-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1 H-pyrazolo[3,4-g]quinoline] on the extracellular concentrations of dopamine and acetylcholine in rat striatum were measured using in vivo microdialysis. Quinpirole was administered intraperitoneally at doses of 3, 30, 300, and 3000 micrograms/kg. Acetylcholine measurements were conducted in the presence of 10 nmol/l of the acetylcholinesterase inhibitor neostigmine in the microdialysis perfusate. The 3 micrograms/kg dose of quinpirole elicited a significant 26% decrease in extracellular dopamine level in striatum whereas the extracellular level of acetylcholine was significantly increased by 15%. At the higher doses tested, quinpirole administration produced significant decreases in the extracellular concentrations of both dopamine and acetylcholine. The maximum inhibition of striatal dopamine efflux by quinpirole was 74% and this effect was observed at the 300 micrograms/kg dose. Inhibition of striatal acetylcholine output reached a maximum of 78% after administration of 3000 micrograms/kg quinpirole. ED50 values (microgram/kg) for quinpirole-induced inhibition of release were 12.4 and 240 for striatal dopamine and acetylcholine, respectively. We conclude from these data that dopamine exerts a tonic inhibitory control over spontaneous acetylcholine efflux in striatum that is directly mediated by dopamine D2 receptors.

Acetylcholine↗
PubMed1996

Amphetamine-induced release of dendritic dopamine in substantia nigra pars reticulata: D1-mediated behavioral and electrophysiological effects.

Dopamine (DA) released from dendrites of substantia nigra dopaminergic neurons potentially is in a position to modulate basal ganglia outputs from the substantia nigra pars reticulata (SNR) via stimulation of D1 receptors on the terminals of striatonigral afferents. The effects of endogenous DA release in the SNR were examined in rats using behavioral activation, multiunit activity of SNR neurons, and cortical EEG pattern as dependent measures. Unilateral infusion of amphetamine (AMPH) into SNR (10 micrograms/0.5 microliter; 5 min) produced a short-lasting behavioral activation that was blocked by coinfusion of the D1 DA receptor antagonist SCH 23390 (0.5 micrograms). Multiunit recordings of SNR neurons in anesthetized rats showed that AMPH, infused as above, produced a rapid decrease in SNR activity. This decrease was maximal (approximately 90%) during the first 10 min postinfusion, followed by a gradual return to baseline levels. Coinfusion of SCH 23390 blocked the AMPH-induced decrease in SNR activity, although by itself this drug produced a 40% decrease in activity. Cortical EEG acquired during the SNR infusions/recordings showed a short-duration change in pattern immediately after AMPH infusion. A relative shift in power from the lowest frequency interval determined (0.8-2.7 Hz) to the next higher frequency interval (2.7-6.8 Hz) was observed which could be prevented by coinfusion of SCH 23390. Thus, dendritically released DA can inhibit the activity of SNR neurons via local stimulation of D1 receptors. This effect is associated with a brief behavioral activation and EEG desynchronization.

Afferent Pathways↗
PubMed1996

Effects of MK-801 on spontaneous and amphetamine-stimulated dopamine release in striatum measured with in vivo microdialysis in awake rats.

In vivo microdialysis was used to examine the effects of the noncompetitive NMDA receptor antagonist dizocilpine maleate (MK-801) on basal and d-amphetamine (AMPH)-induced release of dopamine (DA) in the striatum of freely moving rats. MK-801 [0.2 or 0.5 mg/kg, intraperitoneally (IP)] significantly increased spontaneous DA release in the striatum, whereas treatment with vehicle elicited no change in this variable. These data suggest that endogenous NMDA receptor activation exerts a tonic inhibitory influence upon striatal DA efflux. Systemic administration of AMPH (2.0 mg/ kg, IP) produced an 18-fold increase in extracellular DA; this effect was potentiated to 33-fold by pretreatment with 0.5 mg/kg MK-801. Pretreatment with 0.2 mg/kg MK-801 did not alter AMPH-induced DA release in striatum. Intrastriatal application, via the microdialysis probe, of 10 microM AMPH increased striatal DA efflux by 19-fold, but this local effect of AMPH was not altered by the MK-801 pretreatment. Thus, MK-801 increased DA efflux in response to systemic but not local AMPH, suggesting that a mechanism requiring the involvement of basal ganglia circuitry underlies this effect. It is hypothesized that NMDA receptor blockade indirectly activates the nigrostriatal DA system by opposing activation of inhibitory striatonigral GABAergic projection neurons.

Amphetamine↗
PubMed1996

Physiological release of striatal acetylcholine in vivo: modulation by D1 and D2 dopamine receptor subtypes.

Our experiments assessed the modulation of striatal acetylcholine (ACh) output by dopamine (DA) receptor subtypes under physiological conditions using in vivo microdialysis in awake rats. The degree to which the dopaminergic modulation of striatal cholinergic neurons might vary as a function of local extracellular ACh level also was examined by application of varying concentrations of the acetylcholinesterase (AChE), inhibitor neostigmine (NEO) in the microdialysis perfusate. Under physiological conditions (O NEO), the amount of ACh in the dialysates was 25.1 +/- 2.2 fmol/20-microliters sample (n = 20) whereas values of 67.9 +/- 3.5 (n = 35) and 527.7 +/- 56.1 (n = 13) fmol/20-microliters sample were obtained when the applied NEO concentration was 10 and 100 nM, respectively. In the absence of NEO, a low dose of the indirect DA agonist amphetamine (AMPH; 2 mg/kg i.p.) failed to affect striatal ACh output; a higher AMPH dose (10 mg/kg i.p.) significantly decreased the amount of ACh in dialysates. Under physiological conditions, the direct D2-selective agonist quinpirole (3 mg/kg i.p.) decreased extracellular ACh in striatum to nondetectable levels and the direct D1-selective agonist SKF-38393 (10 mg/kg i.p.) produced a significant increase in this measure. Analysis of the changes in striatal ACh output produced by administration of these DA compounds in the absence vs. presence of local NEO revealed that 10 nM NEO did not qualitatively alter the pharmacological responsivity of this system as compared to the physiological condition. However, in the presence of 100 nM NEO, 2 mg/kg AMPH elicited a significant increase in striatal ACh output. At the 100 nM NEO concentration it also was observed that the amplitude of the quinpirole-induced inhibition of ACh efflux did not increase further in proportion to basal ACh levels whereas the amplitude of the increase in ACh output produced by SKF-38393 was linearly related to basal ACh levels across all NEO concentrations. Under conditions where cholinergic pharmacological responsivity was minimally affected (10 nM NEO), the D2 receptor antagonist haloperidol (1 mg/kg i.p.) increased striatal ACh output by 50% and the D1 receptor antagonist SCH-23390 (0.5 mg/kg i.p.) decreased this variable by 41%. Under these conditions, the inhibitory action of quinpirole on ACh output could be reversed by subsequent administration of AMPH (5 mg/kg i.p.) and this effect of AMPH could then be blocked by administration of SCH-23390. Thus, under physiological or low NEO (10 nM) conditions a prevalent D2-mediated inhibition as well as an opposing D1-mediated excitation of striatal ACh output can be demonstrated. At a higher NEO concentration (100 nM), regulation of the striatal ACh system by DA receptor subtypes is differentially affected such that the D2-mediated inhibitory influence no longer predominates over the D1-mediated excitatory drive. Caution should be exercised when interpreting ACh efflux data obtained using microdialysis under conditions of AChE inhibition.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗