Amphetamine-induced changes in nigrostriatal terminal excitability are modified following repeated amphetamine pretreatment

To investigate neural mechanisms associated with behavioral sensitization to amphetamine, we studied the effect of an intrastriatal infusion of amphetamine on nigrostriatal axon terminal electrical excitability in rats following withdrawal from repeated systemic treatment. Rats were injected with amphetamine 2.5 mg/kg s.c. or saline daily for 4 days. Either 24 h or 14 days after the last injection, extracellular recordings were obtained from dopaminergic neurons of the substantia nigra, in a blind design in which the experimenter did not know the pretreatment regime. In order to assess the electrical excitability of the nigrostriatal axonal field, neurons were activated antidromically by stimulating their terminal fields in the striatum. As previously reported, striatal infusion of amphetamine (1 μM/0.3 μl) in control animals resulted in a significant reduction in excitability as indicated by an increase in striatal stimulus current necessary to evoke antidromic activity. In contrast, intrastriatal amphetamine administration to amphetamine-pretreated animals did not decrease excitability. Spontaneous firing rates and patterns of cell discharge did not differ between saline and amphetamine-treated animals. The chronic amphetamine-induced change in the effect of an acute intrastriatal amphetamine infusion on nigrostriatal terminal excitability may be due to enduring alterations in the amphetamine-induced release of dopamine and other striatal neurotransmitters or to changes in the sensitivity of presynaptic hetero and/or autoreceptors on the dopaminergic axons.     

On central muscle relaxants,strychnine-insensitive glycine receptors and two old drugs: zoxazolamine and HA-966

Summary Zoxazolamine is in the centrally-acting muscle relaxant class of drugs, which reportedly act by decreasing CNS interneuronal activity. These drugs, but not anxiolytics, decrease dopaminergic turnover and induce a pacemakerlike discharge pattern in dopaminergic neurons. A mechanism for these effects was not found in previous reports. We observed that (+)-HA-966, an inhibitor of the glycine modulatory site on the NMDA receptor, has a similar effect on dopaminergic impulse flow, which suggested that this may be the possible site of action of classical muscle relaxants. However, a competitive antagonist of NMDA receptors, NPC-12626, had little effect on impulse flow. Binding of 20 nM [³H]-glycine to cortical synaptosomal membranes was inhibited by (+)-HA-966, IC 50=3.16 M, but only poorly by zoxazolamine, IC 50=474 M, and chlorzoxazone, a related drug, caused no displacement. The drugs were then tested for protection from amphetamine neurotoxicity. Neither 50 mg/kg zoxazolamine nor 30 mg/kg (+)-HA-966 prevented (+)-amphetamine (0.1 mmol/kg plus 10 mg/kg iprindole) depletion of striatal dopamine (DA), but 3.0 mg/kg of MK-801, a non-competitive NMDA receptor antagonist, did protect DA content. Since baclofen induces a regular firing rate in DA neurons, zoxazolamine and (+)-HA-966 were tested for displacement of 10 nM [³H]-1-baclofen from cortical synaptosomal GABA_b receptors, but were ineffective. Thus, the effects of these muscle relaxants on DA neurons are mediated by a mechanism other than strychnine-insensitive glycine or GABA_b receptors.     

Amphetamine-induced and spontaneous release of dopamine from A9 and A10 cell dendrites: an in vitro electrophysiological study in the mouse

Summary d-Amphetamine (d-AMP) is a potent releaser of dopamine (DA), and its central nervous system stimulant action is mediated primarily through its effect on the substantia nigra and ventral tegmental area dopaminergic neurons (nuclei A9 and A10, respectively). The purpose of the present experiment was to use electrophysiological techniques to examine dendritic release of DA in the in vitro slice preparation, and determine whether: (1) d-AMP inhibits the firing rates of both A9 and A10 cells; (2) the d-AMP-induced inhibition is mediated via the dendritic release of DA; and (3) there isspontaneous dendritic release of DA. Superfusion with d-AMP (2-100 M) produced identical inhibitory dose-response curves for A9 and A10 cells, and a dose of 6.25 M caused more than 50% inhibition in the cell firing rates. The d-AMP-induced inhibition was attenuated by blocking DA synthesis. Either D2 receptor blockade (sulpiride, 1 M), or DA synthesis inhibition (-methylparatyrosine, 50 M) resulted in a marked increase in the firing rates of dopaminergic cells. These data suggest that d-AMP comparably releases DA from both A9 and A10 cell dendrites, that it releases newly-synthesized DA to inhibit cell firing, and that DA is tonically released to regulate cell firing rates via interactions with inhibitory D2 autoreceptors.     

MDMA induced dopamine release in vivo: role of endogenous serotonin

Summary Acting as a substrate at the serotonin (5-HT) transporter, (+)-MDMA (3,4-methylenedioxymethamphetamine), is a potent releaser of 5-HT and causes toxicity to 5-HT neurons after repeated exposure. (+)-MDMA also releases dopamine (DA), although with less potency. Since we have shown previously that the intrastriatal application of 5-HT facilitates DA release, it was hypothesized that increased release of striatal 5-HT after MDMA may influence extracellular levels of DA. Using microdiaiysis in vivo, we found that (+)-MDMA (4.7 mol/kg, i.v.) administration increased extracellular striatal DA levels to 501% of control (p < 0.01, n=12). However, in the presence of fluoxetine (14.4 mol/kg, s.c.), which prevents (+)-MDMA effects on 5-HT release, the (+)-MDMA-induced increase in DA was significantly less (to 375% of control, p < 0.05, vs. no fluoxetine, n=8). In vitro studies with striatal slices, to test drug selectivity, showed that (+)-MDMA (0.3-3 M) increased extracellular levels of both DA and 5-HT in a dose-dependent manner. Fluoxetine (3 M) completely blocked the effects of (+)-MDMA on 5-HT release, but did not alter (+)-MDMA-induced DA release in vitro. The selective DA transport inhibitor GBR-12909 (1 M), blocked (+)-MDMA's effect on DA release. It is concluded that 5-HT release after (+)-MDMA treatment partially contributes to (+)-MDMA's effect on DA release in vivo.     

Comparison of the effects of dopamine D 1 and D 2 receptor antagonists on rat striatal,limbic and nigral dopamine synthesis and utilisation

Summary The effects of dopamine (DA) antagonists upon DA synthesis and utilisation in the rat striatum, olfactory tubercle and substantia nigra have been studied. The concentrations of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), the rate of depletion of DA afterin vivo inhibition of tyrosine hydroxylase by H 44/68, and the accumulation of L-DOPA afterin vivo inhibition of 1-aromatic amino acid decarboxylase by NSD 1015 were measured in the study. Haloperidol (0.23mol/kg i. p.), sulpiride (293mol/kg i. p.) and remoxipride (5.6mol/kg i. p.) increased both DA synthesis and utilisation in the striatum and olfactory tubercle. A lower dose of sulpiride (45mol/kg i. p.) increased DA synthesis and utilisation in the olfactory tubercle alone. None of the compounds, at the doses used, affected either DOPAC and HVA concentrations or the rate of utilisation of DA in the substantia nigra. Sulpiride (293mol/kg i. p.) and remoxipride, however, produced a modest rise in nigral DA synthesis. The dopamine D 1-selective antagonist SCH 23390 had only modest effects on striatal, limbic and nigral DA synthesis and utilisation at the doses tested (0.078 and 0.36mol/kg i. p.).     

L-DOPA infusion mode differentially affects corpus striatal dopamine efflux in the presence of reserpine

Summary In the present experiment we tested the effects of L-DOPA upon dopamine (DA) efflux in vitro from superfused corpus striatal tissue fragments in medium containing reserpine. The purposes of this experiment were first, to evaluate the effects of differing infusion modes of L-DOPA upon DA efflux under conditions in which DA storage capacity has been diminished, and second, to compare this L-DOPA stimulated DA efflux with that of other putative DA secretagogues such as amphetamine and postassium. No differences were obtained in stimulated DA efflux between superfusions performed in the presence or absence of reserpine (10 M) in the medium when L-DOPA (5 M) was infused in a continuous (70 minute) mode during the superfusion. In contrast, a continuous infusion of either amphetamine (10 M) or high potassium (30 mM) resulted in significantly greater stimulated DA efflux in superfusions performed with reserpine in the medium. In addition, when L-DOPA (5 M) was administered for a brief 10-minute infusion period, a significantly greater stimulated DA efflux was obtained with superfusions containing reserpine in the medium. These results suggest that the mode of L-DOPA infusion may be an important factor in regulating DA release under conditions of diminished DA storage capacity.     

Blockade of NMDA receptors by MK-801 reverses the changes in striatal glutamate immunolabeling in 6-OHDA-lesioned rats.

A lesion of the dopamine (DA)-containing nigrostriatal pathway with 6-hydroxydopamine (6-OHDA) results in an increase in the density of nerve terminal glutamate immunolabeling and in the mean percentage of asymmetrical synapses containing a discontinuous postsynaptic density [Meshul et al. (1999) Neuroscience 88:1-16]. Similar alterations in striatal glutamate synapses have been reported following blockade of striatal DA D-2 receptors with subchronic haloperidol treatment [Meshul et al. (1994) Brain Res 648:181-195]. The haloperidol-induced change in glutamate synapses was blocked by coadministration of the N-methyl-D-aspartate (NMDA) noncompetitive receptor antagonist MK-801. In order to determine if blockade of NMDA receptors could alter the density of nerve terminal glutamate immunolabeling following a 6-OHDA lesion of the nigrostriatal pathway, MK-801 was administered to lesioned animals for 14 days. In addition, the number of apomorphine-induced contralateral rotations was determined prior to and following the administration of MK-801. MK-801 administration reversed the increase in the density of nerve terminal glutamate immunolabeling due to a 6-OHDA lesion. There was a small but significant decrease in the number of apomorphine-induced contralateral rotations following administration of MK-801 compared to the number of rotations prior to treatment with the NMDA antagonist. These results demonstrate that blockade of postsynaptic NMDA receptors affects the density of presynaptic glutamate immunolabeling and that this change in nerve terminal glutamate density is associated with a decreased behavioral response to direct DA receptor stimulation. Whether the effect of MK-801 is directly on the striatum or acts through other excitatory pathways of the basal ganglia remains unclear.     

Striatal membrane-bound and soluble catechol-O-methyl-transferase after selective neuronal lesions in the rat

Summary Activities of the two forms of catechol-O-methyltransferase (COMT), viz. the soluble (S-COMT) and the membrane-bound (MB-COMT), have been studied in the rat striatum to characterize their localization in relation to the nigrostriatal dopaminergic neurons. Selective unilateral nigrostriatal dopaminergic lesions were produced by an intranigral injection of 6-hydroxydopamine (6-OHDA; 8g/site). 6-OHDA caused an extensive lesion of the dopaminergic neurons as revealed by non-detectable concentrations of dopamine in the striata of the lesioned sites. In spite of that neither S-COMT nor MB-COMT activities were altered in comparison with the intact control striata. The intrastriatal injection of kainic acid significantly increased S-COMT activity but to some extent decreased MB-COMT activity. Kainic acid did not alter the striatal concentration of dopamine.These results suggest that both S-COMT and MB-COMT reside postsynaptically the nigrostriatal dopaminergic neurons. S-COMT seems to be found mainly in striatal glial cells, whereas striatal MB-COMT might be located both in postsynaptic neuronal and extraneuronal cells.     

Electrophysiological effects of MK-801 on rat nigrostriatal and mesoaccumbal dopaminergic neurons

The electrophysiological effects of the non-competitive (NMDA) antagonist (+)-MK801 (MK-801) on nigrostriatal and mesoaccumbal dopaminergic (DA) neurons were evaluated in chloral hydrate-anesthetized rats. MK-801 (0.05–3.2 mg/kg, i.v.) stimulated the firing rates of 14 (74%) of 19 nigrostriatal DA (NSDA) neurons and all 16 mesoaccumbal DA (MADA) neurons tested. Stimulatory effects of the drug were more prominent on MADA neurons. Interspike interval analysis revealed that MK-801 also regularized DA neuronal firing pattern. Acute brain hemitransection between the midbrain and forebrain attenuated the stimulatory effects of MK-801 on firing rate and blocked the effects on firing pattern. Similar to MK-801, hemitransection itself increased NSDA and MADA cell firing rates and regularized firing pattern. Both i.v. and iontophoretic MK-801 blocked the excitatory effects of iontophoretic NMDA but did not effect excitations caused by the non-NMDA glutamatergic receptor agonists quisqualate and kainate. Iontophoretic MK-801 had no effect alone. These results suggest that the excitatory effects of i.v. MK-801 on DA neuronal activity are not due to direct actions on DA neurons. Glutamatergic projections originating anterior to the hemistransection appear to play a role in the effectrs of MK-801 on DA neuronal activity.     

Electroconvulsive therapy in Parkinson's syndrome with “on-off” phenomenon

Summary During long-term treatment with L-dopa in Parkinson's syndrome on-off phenomenon develops in many cases, often entailing considerable therapeutic problems. Decreased sensitivity in postsynaptic striatal dopamine (DA) receptors has been shown to occur in parkinsonian patients during long-term treatment with L-dopa. This has been suggested as one possible mechanism for development of the on-off phenomenon. In contrast to L-dopa treatment electroconvulsions have been shown to increase sensitivity in the DA receptors, when administered to animals.The antiparkinsonian effect of electroconvulsive therapy (ECT) was investigated in five parkinsonian patients with on-off phenomenon, with or without concomitant signs of mental depression. ECT was administered according to praxis in treatment of mental depression. Drug therapy, including L-dopa, was maintained on previously adjusted doses during and after ECT.A marked improvement in the parkinsonian symptoms as well as in the on-off phenomenon occurred in three of the patients, persisting for several months. The other two patients showed only slight and transient improvement.It thus seems that ECT may be useful as a supplementary treatment in parkinsonian patients with on-off phenomenon. The antiparkinsonian effect of ECT is probably mediated by increased sensitivity in postsynaptic DA structures.     

Pharmacologically induced cessation of burst activity in nigral dopamine neurons: Significance for the terminal dopamine efflux

Results obtained previously indicate that the firing pattern of midbrain dopamine (DA) neurons is of importance for the terminal DA release. In the present combined electrophysiological and microdialysis study, the influence of the firing pattern on striatal DA release was studied by using the previously observed ability of low doses of β-hydroxybutyrate (GHBA) to profoundly regularise the firing pattern of rat DA neurons in the substantia nigra (SN). Administration of GHBA (200 mg/kg, i.v.) did not significantly reduce the firing rate of any of the DA neurons recorded from, but rather caused a slight transient excitation. However, this dose of the drug caused a profound regularisation of the firing pattern and abolished burst activity of the DA neurons. The DA concentration in the dialysate obtained from the striatum (10 min sampling periods) decreased with the lowest value (67% of predrug value) observed at the sampling period 20-30 min after the GHBA administration. As a complement to microdialysis, the 3-methoxytyramine (3-MT) accumulation in striatal tissue following monoamine oxidase inhibition was determined as an indirect measure of DA release in vivo. The 3-MT concentrations in the striatum decreased to 84% of controls following 200 mg/kg of GHBA. To exclude an effect on DA release conceivably mediated by GHBA locally in the striatum, GHBA (10^?7-10^?3 M) was given locally in the dialysis probe and was found to increase DA in the dialysate (maximally to 140% of controls). The present results are in line with previous electrophysiological studies which have demonstrated that artificially induced burst firing by electrical stimulation is associated with an increased extracellular level of striatal DA (as determined by in vivo voltammetric techniques or microdialysis) and support the idea that firing pattern may be an important physiological modulatory mechanism for the release of terminal neurotransmitter. © 1994 Wiley-Liss, Inc.     

Firing regulation in dopaminergic cells: effect of the partial degeneration of nigrostriatal system in surviving neurons

Two mechanisms for firing rate regulation were identified in dopaminergic nigrostriatal cells (DA cells), one of a renewal nature which prevents short and long interspike intervals (ISIs) and the other of a no-renewal nature which compensates long ISIs with short ISIs and vice versa. Renewal regulation was found in 96% of DA cells and less frequently in nigrocollicular (63%), nigrothalamic (61%) and nigropeduncular (50%) nigral GABA cells. No-renewal regulation was found in 77% of DA cells, and was only observed in 8% of GABA cells. Thus, most DA cells showed both regulatory mechanisms, which justifies the low variability in their firing rate and the low oscillation of extracellular striatal dopamine previously reported. DA cells surviving a partial degeneration of the nigrostriatal system did not show alterations in their firing rate and burst firing but presented a marked disturbance for no-renewal regulation. Under these conditions, small fluctuations in firing rate are not compensated for in time, which could be one of the factors responsible for the motor fluctuations often observed in advanced Parkinson's disease.     

Alterations in striatal dopamine overflow during rotational behavior induced by amphetamine,phencyclidine, and MK-801

Rats lesioned unilaterally in the medial forebrain bundle with 6-OHDA rotated ipsilateral to the lesion following injections of amphetamine, phencyclidine (PCP), and MK-801. Concurrent measurement of striatal dopamine (DA) in the intact striatum with in vivo microdialysis revealed a dissociation between rotational behavior and alterations in DA overflow induced by the three drugs. Amphetamine produced robust ipsilateral rotational behavior and a substantial elevation in striatal DA (∼130% increase at asymptote). PCP produced comparable increases in rotational behavior, but only ∼30% increase in striatal DA. MK-801 also had a comparable behavioral effect but failed to alter DA overflow in the intact striatum. Since MK-801, a noncompetitive NMDA antagonist which does not enhance extracellular dopamine in the striatum, is able to produce ipsilateral rotational behavior in rats with unilateral nigrostriatal lesions, it is likely that the effects of PCP may also be determined predominantly through NMDA blockade in this model. Synapse 26:218–224, 1997. © 1997 Wiley-Liss Inc.     

MK-801 protection against methamphetamine-induced striatal dopamine terminal injury is associated with attenuated dopamine overflow.

Repeated administrations of methamphetamine (m-AMPH) produce high extracellular levels of dopamine (DA) and subsequent striatal DA terminal damage. Pharmacological blockade of N-methyl-D-aspartate (NMDA) receptors has been shown previously to prevent m-AMPH-induced striatal DA terminal injury, but the mechanism for this protection is unclear. In the present study, in vivo microdialysis was used to determine the effects of blockade of NMDA receptors with the noncompetitive antagonist MK-801 on m-AMPH-induced striatal DA overflow. Four injections of MK-801 (0.5 mg/kg, ip) alone did not significantly change extracellular striatal DA concentrations from pretreatment values. Four treatments with m-AMPH (4.0 mg/kg, sc at 2-hr intervals) increased striatal DA overflow, and the overflow was particularly extensive following the fourth injection. This m-AMPH regimen produced a 40% reduction in striatal DA tissue content 1 week later. Treatment with MK-801 15 min before each of the four m-AMPH injections or prior to only the last two m-AMPH administrations attenuated the m-AMPH-induced increase in striatal DA overflow and protected completely against striatal DA depletions. Other MK-801 treatment regimens less effectively reduced the m-AMPH-induced striatal DA efflux and were ineffective in protecting against striatal DA depletions. Linear regression analysis indicated that cumulative DA overflow was strongly predictive (r = -.68) of striatal DA tissue levels measured one week later. These findings suggest that the extensive DA overflow seen during a neurotoxic regimen of m-AMPH is a crucial component of the subsequent neurotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of a 5-HT3 receptor antagonist,ondansetron, on brain stimulation reward,and its interaction with direct and indirect stimulants of central dopaminergic transmission

Summary 5-HT₃ receptors are abundant in central dopamine (DA) terminal areas. They do not affect basal DA turnover but appear to modulate DA release by e.g. morphine and nicotine. The interpretation of these findings is uncertain, and it is unclear whether 5-HT₃ receptors also influence the activity of compounds such as amphetamine and cocaine, which act more directly on the DA synapse. Variable-interval (VI), threshold-current hypothalamic self-stimulation can provide a continuous index of central dopaminergic activity, but is relatively insensitive to changes in 5-HT and thus offers a means of investigating this question. In the present study, a selective 5-HT₃ receptor antagonist, ondansetron (GR 38032F) (1.0 to 1000 g/kg sc), had no effect on VI self-stimulation, nor did a 100 g/kg dose affect facilitation of responding byd-amphetamine (500 jig/kg ip). Ondansetron (100 g/kg) reduced the initial depression of self-stimulation by high-dose nicotine (400 g/kg), but not the ensuing facilitation. Similar results were obtained in rats sensitized to nicotine by prior chronic exposure. These results support the proposal that 5-HT₃ receptors, normally quiescent under basal conditions, mediate the excitatory effect of compounds acting upstream from the DA neuron, such as nicotine, but do not affect the dopaminergic synapse directly.     

Striatal NMDA receptors gate cortico-pallidal synchronization in a rat model of Parkinson's disease

Anomalous patterns of synchronization between basal ganglia and cortex underlie the symptoms of Parkinson's disease. Computational modeling studies suggest that changes in cortical feedback loops involving trans-striatal and trans-subthalamic circuits bring up this anomalous synchronization. We asked whether striatal outflow synchronizes globus pallidus neurons with cortical activity in a rat model of Parkinson's disease. We found that striatal firing is highly increased in rats with chronic nigrostriatal lesion and that this hyperactivity can be reduced by locally infusing a competitive NMDA receptor antagonist. Moreover, NMDA receptor-dependent striatal output had frequency dependent effects on distinct pathological patterns of cortico-pallidal coupling. Blockade of striatal NMDA receptors almost completely abolished an anomalous ~1Hz cortico-pallidal anti-phase synchronization induced by nigrostriatal degeneration. Moreover, under striatal NMDA receptor blockade, synchronization with 2.5-5Hz cortical oscillations falls to negligible levels and oscillations at 10-20Hz are markedly attenuated, whereas beta synchronization (with a peak at ~26Hz) is marginally reduced. Thus, tonic activation of striatal NMDA receptors allows different forms of anomalous oscillations along the cortico-striato-pallidal axis. Moreover, the frequency dependent effects of NMDA receptors suggest that low and high frequency parkinsonian oscillations stem from partially different mechanisms. Finally, our results may help to reconcile views about the contributions of changes in firing rate and oscillatory synchronization to Parkinson's disease symptoms by showing that they are related to each other.     

The effects of dopamine-depleting brain lesions on the electrophysiological activity of rat substantia nigra dopamine neurons

Extensive damage to the nigrostriatal dopamine (DA) system initiates a number of compensatory changes that may be involved in counterbalancing the effects of the lesion. In this study, we examined whether changes in the electrophysiological activity of the remaining DA cells play a role in compensating for 6-hydroxydopamine (6-OHDA)-induced depletions of striatal DA. DA cell activity in lesioned rats was assessed along three dimensions: (1) the relative proportion of the remaining DA neurons firing spontaneously, (2) their firing rate, and (3) their firing pattern. Histofluorescence studies revealed a sparing of DA neurons in the midbrain of 6-OHDA-lesioned rats relative to the levels of DA remaining in the striatum. With respect to DA cell activity, depletions of up to 96% of striatal DA did not result in substantial alterations in the proportion of DA neurons active, their mean firing rate, or their firing pattern. Increases in these parameters only occurred when striatal DA depletions exceeded 96%. These results suggest that the biochemical and receptor compensations produced in the DA system in response to injury are of sufficient magnitude to allow the DA cells to maintain baseline levels of activity. In this way, the remaining DA neurons would maintain the wide dynamic range of electrophysiological responsivity that may be necessary for the normal function of the extrapyramidal motor system.     

Excitatory amino acid-induced excitation of dopamine-containing neurons in the rat substantia nigra: Modulation by kynurenic acid

Kynurenic acid (KYNA), an endogenous antagónist of ionotropic excitatory amino acid (EAA) receptors, was tested for its ability to modulate N-methyl-D-aspartate (NMDA)- and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)induced excitation of dopamine (DA)-containing neurons in the zona compacta of the rat substantia nigra (SNc). Experiments were conducted using extracellular recording techniques in conjunction with an in vitro brain slice preparation. Bath application of NMDA (1–20 μ) or AMPA (0.5–10 μ) produced a concentration-dependent increase in the firing rate of SNc DA neurons but had no effect on firing pattern. The highest concentration of both agonists produced a rapid and reversible cessation of activity that was attributed to acute induction of depolarization block. Addition of glycino (GLY) (up to 100 μ) to the bathing solution had no effect on either basal firing rate or the increase in activity produced by NMDA. KYNA (10 μ–1 mM) antagonized the excitatory effects of both NMDA (15 μ) and AMPA (3 μ) in a concentration-dependent fashion (IC50: 102 μ and 64 μ, respectively) without affecting basal firing rate. Perfusion of tissue slices with a modified Ringer's solution containing low Mg²⁺ (0.12 mM) increased NMDA-induced excitation but did not affect the antagonist properties of KYNA. D-serine (100 μ) reversed the ability of KYNA to block the excitatory effects of NMDA, suggesting that KYNA attenuates NMDA-induced excitation of SNc DA neurons via blockade of the GLY allosteric site on the; NMDA receptor. The ability of KYNA to modulate the excitatory effects of both NMDA and non-NMDA agonists implies that endogenous KYNA may play a physiological role it regulating DA cell excitability. © 1994 Wiley-Liss, Inc.     

The effect of reserpine treatment in vivo upon L-dopa and amphetamine evoked dopamine and DOPAC efflux in vitro from the corpus striatum of male rats

Summary In the present experiment we tested the effects of L-DOPA and amphetamine upon dopamine and DOPAC efflux in vitro from superfused corpus striatal tissue fragments of male rats who had been pretreated with reserpine. Male rats were treated with reserpine (5mg/kg) or its vehicle at 24 hours prior to sacrifice and superfusion of the corpus striatum. Two different modes of L-DOPA (5 M) and amphetamine (10 M) stimulation, a brief 10-minute and a continuous 60-minute infusion, were tested for their ability to evoke striatal dopamine and DOPAC efflux. Depletion of monoamine storage capacity as achieved with reserpine significantly reduced the amount of basal dopamine and DOPAC released from superfused striatal tissue fragments of male rats. Although basal release rates were significantly reduced, the amount of dopamine and DOPAC released in response to in vitro L-DOPA infusions (10 or 60 minute infusions) was equivalent between reserpine and vehicle treated animals. In contrast, amphetamine stimulated DA release was significantly reduced in male rats treated with reserpine. For both L-DOPA and amphetamine, significantly greater amounts of dopamine were obtained with the 60-versus 10-minute infusion modes. These results demonstrate that the capacity for L-DOPA, but not amphetamine, to evoke dopamine efflux is unaltered under conditions when monoamine storage ability is diminished.     

Effect of repeated administration of dopamine agonists on striatal neuropeptide mRNA expression in rats with a unilateral nigral 6-hydroxydopamine lesion

Summary Striatal mRNA expression for preproenkephalin (PPE) and preprotachykinin (PPT) was studied in unilateral 6-OHDA lesioned rats treated subchronically with a range of selective and non-selective D-1 or D-2 dopamine (DA) agonists. Apomorphine (5mg/kg sc), pergolide (0.5mg/kg sc), SKF 38393 (5mg/kg sc), SKF 80723 (1.5mg/kg sc), and quinpirole (5mg/ kg sc), or 0.9% saline (150l sc) were all given twice daily (except pergolide: once daily) for 7 days. The abundance of PPE mRNA was not altered by any of these DA agonists in the intact striatum contralateral to the 6-OHDA lesion. Only apomorphine and quinpirole increased the abundance of PPT mRNA in the intact striatum. In saline treated 6-OHDA lesioned animals PPE mRNA was elevated (+160%, p < 0.005) and PPT mRNA decreased (–36%, p < 0.005) in the denervated striatum. The up-regulation of striatal PPE mRNA in the lesioned striatum was reversed only by pergolide. The downregulation of striatal PPT mRNA in the lesioned striatum was reversed only by apomorphine. The differential sensitivity of the striatal PPE message to the long-acting DA agonist pergolide, and of the striatal PPT message to the mixed D-1/D-2 DA agonist apomorphine suggests that the striatopallidal enkephalinergic pathways are mainly regulated by prolonged DA receptor stimulation, whereas the striatonigral substance P pathways are mainly regulated by mixed D-1/D-2 DA receptor stimulation.