Cortical stimulation induces fos expression in intrastriatal striatal grafts

Innervation of intrastriatal grafts of fetal striatal tissue by host corticostriatal projections has been shown in a number of previous studies in rats. In the work reported here, induction of Fos protein in grafted striatal neurons by electrical stimulation of the host frontoparietal cortex has been used as cell-level marker of corticostriatal postsynaptic responses within the striatal grafts. Unilateral cortical stimulation 30 min before sacrifice led to bilateral widespread and intense Fos induction throughout the normal striatum, although the response was somewhat more intense ipsilaterally and in the dorsolateral rostral striatum. In adult rats whose striatum had been lesioned with ibotenic acid 10–12 days prior to implantation of fetal striatal tissue, 3- and 18-month-old striatal grafts showed Fos immunoreactivity in a considerable number of cells after either bilateral, or ipsilateral (30–40% of the density of Fos-immunoreactive cells in the normal striatum) or contralateral cortical stimulation. Double-Fos and -DARPP-32 immunohistochemistry revealed that the Fos-immunoreactive nuclei were concentrated in the DARPP-32-positive (i.e. striatum-like) patches, which contained 60% of the density of Fos-positive nuclei in the normal striatum after either ipsilateral or bilateral stimulation. However, Fos-immunoreactive nuclei were unevenly distributed within the DARPP-32-positive compartment of the graft, with some clusters of Fos-immunoreactive nuclei at 2−3 × the density observed in the normal striatum and other areas with Fos-immunoreactive nuclei present at lower density or absent. Fos induction was also observed in 4-week-old grafts, indicating that functional corticostriatal synaptic contacts develop rapidly. Striatal grafts implanted either in non-lesioned host striatum or in long-term (18 months) lesioned striatum, similarly showed Fos-positive nuclei after cortical stimulation, indicating that host corticostriatal fibers are equally capable of establishing functional synaptic contacts under these conditions. These results indicate that host corticostriatal fibres not only form an axonal network within the graft but also induce postsynaptic responses which may contribute to the observed graft-induced amelioration of lesion-induced behavioural deficits.     

Roles of dopamine D1 receptors inΔ-tetrahydrocannabinol-induced expression of Fos protein in the rat brain

We examined whether administration ofΔ⁹-tetrahydrocannabinol (THC) induces the expression of Fos protein or not in the rat brain. A single administration of 3.2 and 10 mg/kg THC produced a dose-dependent and significant increase in Fos-immunoreactive cells in the striatum, particularly in its dorsomedial portions. The peak increase was reached 2 h after THC treatment and was absent at 8 h. Fos induction was also observed in the nucleus accumbens after administration of 10 mg/kg THC. However, in the globus pallidus, hippocampus and substantia nigra pars reticula, abundant in cannabinoid receptors, there were few or no Fos-immunoreactive cells induced by 10 mg/kg THC. SCH-23390, a selective dopamine D₁ receptor antagonist, at 0.32 mg/kg produced a significant block of the effects of THC on Fos expression in the striatum and the nucleus accumbens. Administration of 100 mg/kg (-)-sulpiride, a selective dopamine D₂ receptor antagonist, failed to block the effect of THC on Fos expression in both the striatum and the nucleus accumbens. These findings indicate that THC induces the expression of Fos protein and that this expression is mediated at least by dopamine D₁ receptors.     

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.     

Interaction between the serotonergic,dopaminergic, and glutamatergic systems in fenfluramine-induced Fos expression in striatal neurons

Fenfluramine (FE) is a halogenated amphetamine derivative used in the treatment of obesity and thought to induce serotonin (5-HT) release from nerve terminals and to reduce re-uptake. However, other pathways may also be involved. In this work, the effects of FE on the major striatal afferent systems, and the possible interactions of these systems in FE-induced striatal expression of Fos, were studied by lesion of the serotonergic and/or dopaminergic system and administration of NMDA glutamate (MK-801) or D₁ dopamine (SCH-23390) receptor antagonists. Both the D₁ and NMDA receptor antagonists suppressed Fos expression in response to FE almost entirely. FE-induced Fos expression was also dramatically reduced 24 h after 6-hydroxydopamine (6-OHDA) lesion of the dopaminergic system. However, the reduction was not so marked after chronic 6-OHDA lesion, probably due to compensatory changes. Chronic (5,7-dihydroxytryptamine injection, 4 weeks before) or acute (p-chlorophenylalanine injection) lesion of the serotonergic system led to a marked reduction in Fos expression in response to FE (decrease of about 50%). After simultaneous chronic lesion of both serotonergic and dopaminergic systems, a considerable number of Fos-positive nuclei were still observed (decrease of about 70% in the dorsal and dorsomedial regions). The FE-induced expression of Fos was almost totally suppressed (decrease of about 95% in the dorsal and dorsomedial regions) after simultaneous acute lesion. Our results indicate that FE-induced striatal expression of Fos is due in large measure to DA release and dopaminergic stimulation of D₁ receptors. However, concurrent stimulation of NMDA glutamate receptors also appears to be essential, and 5-HT release (although not indispensable) doubles striatal Fos expression. Synapse 28:71–82, 1998. © 1998 Wiley-Liss, Inc.     

Substantia nigra glutamate antagonists produce contralateral turning and basal ganglia Fos expression: interactions with D1 and D2 dopamine receptor agonists

Experiments measuring behavior and immediate-early gene expression in the basal ganglia can reveal interactions between dopamine (DA) and glutamate neurotransmission. Nigrostriatal DA projections influence two striatal efferent pathways that, in turn, directly and indirectly influence the activity of the substantia nigra pars reticulata (SNr). This report tests the interactions between striatal DA receptors and nigral glutamate receptors on basal ganglia function by examining both contralateral turning and Fos immunoreactivity in striatum and pallidum following unilateral intranigral microinfusions of glutamate antagonists given to intact and 6-OHDA-lesioned rats. The NMDA antagonist AP5 (1 microg), or the AMPA/kainate antagonist DNQX (0.015-1.5 microg), injected into the SNr (0.5 microl) elicited contralateral turning as well as both striatal and pallidal Fos expression. Moreover, intranigral DNQX elicited more turning and greater numbers of Fos-positive striatal neurons in 6-OHDA-lesioned animals than in unlesioned controls, suggesting that the 6-OHDA injection induces functional changes in nigral glutamate transmission. In 6-OHDA-lesioned rats, systemic injections of the DA D1 receptor agonist SKF38393 (0.5 mg/kg, i.p.) increased striatal Fos expression due to intranigral DNQX. In contrast, the D2 agonist quinpirole (0.1 mg/kg, i.p.) decreased striatal Fos expression but increased the pallidal Fos arising from intranigral AP5. In additional experiments, both intact and 6-OHDA-lesioned rats were given simultaneous intranigral and intrastriatal infusions and turning and pallidal Fos expression were measured. 6-OHDA-lesioned rats given 5 microg of intrastriatal quinpirole exhibited both turning and pallidal Fos that was significantly increased by intranigral AP5. These results indicate that the opposing influences of D2 agonists and endogenous nigral glutamate transmission are mediated by striatal D2 receptors. Finally, the behavioral effects of intranigral glutamate antagonism can be dissociated from the effects on striatal or pallidal immediate-early gene expression.     

NMDA receptor blockade attenuates the haloperidol induction of Fos protein in the dorsal but not the ventral striatum.

Neuroleptic blockade of dopamine receptors is known to produce an increase in the expression of Fos. This increase may be related to elevations in glutamate transmission which in turn activates N-methyl-D-aspartate (NMDA) receptors. In the present study, we examine the role of these receptors in the haloperidol-induced augmentation of Fos in the caudate-putamen and nucleus accumbens of Wistar rats. Animals were divided into four groups for each experiment and each was injected either with saline; a noncompetitive NMDA antagonist, dizocilpine maleate (MK801, 5 mg/kg); haloperidol (0.5 mg/kg); or MK801 followed by an injection of haloperidol. Fos-immunoreactive cells appear in large numbers in all parts of the striatum 3 h after the administration of haloperidol. Pretreatment with MK801 attenuates the haloperidol-induced increase in Fos in the caudate-putamen. However, antagonism of the NMDA receptor does not significantly reduce the density of Fos-immunoreactive cells in any territory of nucleus accumbens, i.e., shell, core, or rostral pole. These data suggest that haloperidol acts in an NMDA-dependent manner in the caudate-putamen, but independently in parts of nucleus accumbens traditionally considered to be targets of antipsychotic drugs.     

Role of NMDA and AMPA glutamate receptors in the induction and the expression of dopamine-mediated sensitization in 6-hydroxydopamine-lesioned rats

Rats with unilateral 6-hydroxydopamine (6-OHDA) lesions exhibit behavioral sensitization following repeated treatment with dopamine agonists, a phenomenon called "priming." Priming has two distinct phases: induction and expression. Priming induction using three injections with D1/D2 agonist apomorphine (0.5 mg/kg) or D1 agonist SKF38393 (10 mg/kg) allows priming expression, robust contralateral rotational behavior and striatal Fos expression, following a challenge with the D2 agonist quinpirole (0.25 mg/kg). We examined the roles of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) glutamate receptors on dopamine agonist priming. Administration of the NMDA antagonist (+)5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK801) (0.5 mg/kg) blocked apomorphine-priming of quinpirole-mediated responses, while MK801 dose-dependently attenuated SKF38393-priming of quinpirole-mediated striatal Fos expression and had no effect on SKF38393-priming of quinpirole-mediated rotational behavior. In contrast, administration of the AMPA antagonist 2,3-dihydroxy-6-nitro-7sulfamoyl-benzo[f]quinoxaline (NBQX) (5 or 10 mg/kg) potentiated apomorphine- and SKF38393-priming of quinpirole-mediated striatal Fos expression, but had no effect on their priming of quinpirole-mediated rotational behavior. In SKF38393-primed 6-OHDA rats, administration of MK801 (0.5 mg/kg) blocked the expression of quinpirole-mediated responses, while administration of NBQX (10 mg/kg) or the noncompetitive AMPA antagonist 4-(8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-5-yl)-benzenamine dihydrochloride (GYKI52466) (5 or 15 mg/kg) had no effect. These results suggest that NMDA and AMPA glutamate receptors have differing roles in dopamine agonist priming-with NMDA receptors required for D1/D2 priming induction and D2-mediated priming expression, and AMPA receptors inhibiting priming induction of D2-mediated immediate early gene expression in the striatum, but not affecting priming induction of D2-mediated rotational behavior or the expression of D2-mediated responses.     

Stimulant-mediated c-fos induction in striatum as a function of age, sex, and prenatal cocaine exposure

Induction of the immediate-early gene c-fos by the stimulants cocaine and amphetamine (AMPH) was analyzed by Fos immunocytochemistry at different ages in the brains of prenatally cocaine-treated and control rats. Cocaine and AMPH induced c-fos in patches of striatal neurons during the first postnatal week, and thereafter produced a progressively more homogeneous pattern that was more dense medially. Quantification of Fos-immunoreactive cells in older rats revealed differences related to sex and prenatal cocaine treatment. Both cocaine and AMPH produced dose-dependent increases in the number of Fos-immunoreactive cells in striatum. Prenatal cocaine exposure resulted in increased Fos in males in response to AMPH (2 mg/kg) at P18 and cocaine (10 mg/kg) at 1–2 months. In females, prenatal cocaine treatment resulted in a reduced response to cocaine at 1–2 months. Increased c-fos induction was observed in control females compared to control males in response to low doses of stimulants; no such sex difference was observed in prenatally cocaine-treated rats. The dopamine D1 antagonist SCH23390 blocked cocaine-mediated c-fos induction in all groups. The NMDA antagonist MK-801 blocked cocaine-mediated c-fos induction in the medial striatum. In females only, MK-801 pretreatment resulted in a dramatic increase in the number of Fos-immunoreactive cells in lateral striatum. These findings indicate differences in the neural basis of c-fos induction in males and females, and changes in stimulant-mediated c-fos induction resulting from prenatal cocaine exposure.     

Time dependence and role of N-methyl- -aspartate glutamate receptors in the priming of D2-mediated rotational behavior and striatal Fos expression in 6-hydroxydopamine lesioned rats

Administration of dopamine agonists to 6-hydroxydopamine (6-OHDA) lesioned rats enhances the rotational response to subsequent administration of dopamine agonist, an effect called ‘priming'. Previously, we have shown that 6-OHDA rats primed with three injections of the D1/D2 dopamine agonist apomorphine (0.5 mg/kg) permitted a challenge with an otherwise inactive dose of the D2 agonist quinpirole (0.25 mg/kg) to elicit robust rotational behavior and to induce Fos expression in striatoentopeduncular neurons. In this study, the time-course and role of N-methyl- -aspartate (NMDA) glutamate receptors on apomorphine-priming of these D2 responses were investigated. The enhanced rotational behavior and striatal Fos expression observed following challenge with quinpirole (0.25 mg/kg) peaked 1 day following the third apomorphine priming injection and persisted, in reduced form, for at least 4 months. Pretreatment with the NMDA antagonists MK-801 or 3-[(+)-2-carboxypiperazin-4-yl]-propyl-1-phosphonate (CPP) dose-dependently attenuated apomorphine-priming of quinpirole-mediated rotational behavior and striatal Fos induction compared to 6-OHDA rats primed with apomorphine alone. Taken together, these data suggest that priming of these D2-mediated responses in 6-OHDA rats develops rapidly, persists for several months, and is dependent on concomitant NMDA receptor stimulation. Since this priming effect resembles response fluctuations observed in patients with Parkinson's disease receiving long-term -dihydroxyphenylalanine therapy, the results of the present study suggest that interventions that prevent the development of this enhanced response, such as NMDA antagonists, could prove useful in reducing the incidence these response fluctuations.     

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.     

Regional distribution of pre- and postsynaptic glutamatergic function in Alzheimer''s disease

The selective D₁-dopamine receptor antagonist SCH23390 and the more D₂-selective antagonist haloperidol produced marked catalepsy in rats. The novel excitotoxin quinolinic acid (QA) selectively destroys striatal neurons when injected directly into the striatum. Bilateral QA lesions of the rat striatum (150 nmol and 225 nmol per side) abolished the cataleptic response to both SCH23390 and haloperidol. These data indicate that the D₁- and/or D₂-dopamine receptors which mediate the cateleptic response are restricted to QA-sensitive neurons in the rat striatum.     

Striatal glutamatergic function: Modifications following specific lesions

The effects of specific lesions of the striatum: (a) hemidecortication; (b) striatal injection of(±) ibotenate; and (c) 6-hydroxydopamine injections into the substantia nigra, were investigated on specific [³H]glutamate binding to striatal membranes. One month after decortication, there was a substantial reduction of calcium-dependent, stimulated glutamate release from striatal slices, indicating effective loss of glutamatergic fibres. Striatal glutamate binding increased by approximately 30% and this supersensitivity could be attributed solely to an increased receptor density. Ibotenate lesions which destroy target neurones for the glutamatergic fibres (sparing terminals), reduced glutamate binding in the striatum, as did nigral 6-OHDA lesions which delete striatal dopaminergic terminals. This finding supports the concept of there being glutamate receptors on pre-synaptic dopamine terminals in the striatum, involved in regulation of dopamine release. 6-OHDA lesions also result in a supersensitivity of the dopamine receptors localized on the cortico-striatal afferent terminals, as evidenced by the enhanced ability of dopamine to inhibit the K⁺-evoked, calcium-dependent release of endogenous striatal glutamate.     

Cortically driven Fos induction in the striatum is amplified by local dopamine D2-class receptor blockade

Dopamine D2-class receptors have been shown to control the excitability of striatal neurons in response to cortical activation. It has been unclear, however, whether such receptors could regulate the number of striatal neurons activated by cortical stimulation, and thus affect the population response of the striatum to its cortical inputs. We used Fos induction as a readout to measure the ensemble response of striatal neurons to localized stimulation of the frontal cortex and tested for the effects of D2-class dopamine receptor blockade on this response. In freely moving rats, we stimulated the frontal cortex by local epidural application of a dose of a GABAA receptor antagonist (picrotoxin) just threshold for inducing Fos in the striatum. We combined this treatment with D2-class dopamine receptor antagonist treatments at dose levels also just threshold for inducing Fos, using either (i) systemic haloperidol or (ii) intrastriatal (-)sulpiride. Both systemic and intrastriatal blockade of D2-class receptors sharply increased the numbers of striatal neurons exhibiting cortically evoked Fos induction. These findings suggest that local activation of intrastriatal D2-class dopamine receptors can regulate the number of striatal neurons responsive to cortical inputs, thus dynamically shaping the flow of information through the striatum.     

Expression of Fos protein in rat brain following administration of a nicotinic acetylcholine receptor agonist epibatidine

Epibatidine (exo-2-(6-chloro-3-pyridyl)-7-azabicyclo-[2.2.1]heptane), an extract of frog skin, is a novel and highly potent agonist for the nicotinic acetylcholine (ACh) receptor. The present study was undertaken to examine the expression of Fos protein in several rat brain regions following an acute administration of epibatidine. Furthermore, we also studied the role of the dopamine D₁ and D₂ receptors and the N-methyl-d-aspartate (NMDA) receptor, and nicotinic ACh receptor in the expression of Fos protein by epibatidine. A single administration of epibatidine (5, 10, 50 μg/kg) caused a marked induction of Fos-immunoreactivity in the prefrontal cortex, medial striatum, nucleus accumbens, amygdala and superior colliculus of rat brain. In these regions, pretreatment with SCH 23390 (1.0 mg/kg), a dopamine D₁ receptor antagonist, MK-801 (1.0 mg/kg), a NMDA receptor antagonist, and mecamylamine (5.0 mg/kg), a nicotinic Ach receptor antagonist, inhibited the induction of Fos protein by epibatidine (10 μg/kg). Pretreatment with sulpiride, a dopamine D₂ receptor antagonist, blocked the induction of Fos protein in the prefrontal cortex and the core region of accumbens nucleus, but not in the medial striatum and the shell division of nucleus accumbens of rat brain. These results suggest that epibatidine induced the expression of Fos protein in several regions of rat brain, and that dopamine D₁ receptor, NMDA receptor, and nicotinic ACh receptor may play a role in the expression of Fos protein by epibatidine in rat brain. Furthermore, dopamine D₂ receptor may, in part, play a role in epibatidine induced expression of Fos protein in the prefrontal cortex and the core region of nucleus accumbens, but not in the medial striatum and the shell division of nucleus accumbens of rat brain.     

Cortical Regulation of Striatal Neuropeptide Y (NPY)-Containing Neurons in the Rat

This study examined the functional relationships established by nigral, cortical, and thalamic striatal afferent pathways with neuropeptide Y (NPY)-containing neurons in the rat rostral striatum by coupling selective deafferentation procedures and NPY immunohistochemistry. Previous experiments have shown that after unilateral 6-hydroxydopamine (6-OHDA)-induced degeneration of nigrostriatal dopaminergic neurons, the mean number of NPY-immunoreactive (Ir) neurons per frontal section was increased in the striatum ipsilateral to the lesion side and unaltered in the contralateral striatum. The present topographical analysis of the 6-OHDA lesion effects led us to state that the increase in NPY-Ir neuron density occurs in restricted ventral and medial zones of the ipsilateral striatum. Unilateral ablation of the frontoparietal cerebral cortex by thermocoagulation was moreover shown to elicit, 20 - 30 days later, a significant bilateral increase in the number of striatal NPY-Ir cells. The increase was more marked in the striatum ipsilateral to the hemidecortication where it was similar in amplitude to that induced by the 6-OHDA lesion. The topographical analysis of the cortical lesion effects also revealed an uneven striatal response, but, in contrast to that observed for the 6-OHDA lesion, changes were restricted to dorsolateral areas of the striatum in both brain sides, revealing an apparent complementarity of nigral dopaminergic and cortical influences over striatal NPY neuronal system. Combined unilateral nigral and cortical lesions surprisingly counteracted in a survival time dependent manner the effects of each lesion considered separately. In that condition topographical changes related to the 6-OHDA lesion totally disappeared and those related to the cortical lesion were attenuated but still present. These results suggest that expression of striatal dopamine - NPY interaction is dependent on corticostriatal transmission. Interestingly lesion of thalamic areas projecting to the striatum did not significantly modify the mean number of NPY-Ir neurons determined per section from the whole striatal surface, but selectively increased the NPY neuron density in the mediodorsal region of the striatum, suggesting that the striatal NPY-containing neuronal system is also influenced by thalamostriatal projections.     

Time dependence and role of N-methyl-D-aspartate glutamate receptors in the priming of D2-mediated rotational behavior and striatal Fos expression in 6-hydroxydopamine lesioned rats.

Administration of dopamine agonists to 6-hydroxydopamine (6-OHDA) lesioned rats enhances the rotational response to subsequent administration of dopamine agonist, an effect called 'priming'. Previously, we have shown that 6-OHDA rats primed with three injections of the D1/D2 dopamine agonist apomorphine (0.5 mg/kg) permitted a challenge with an otherwise inactive dose of the D2 agonist quinpirole (0.25 mg/kg) to elicit robust rotational behavior and to induce Fos expression in striatoentopeduncular neurons. In this study, the time-course and role of N-methyl-d-aspartate (NMDA) glutamate receptors on apomorphine-priming of these D2 responses were investigated. The enhanced rotational behavior and striatal Fos expression observed following challenge with quinpirole (0.25 mg/kg) peaked 1 day following the third apomorphine priming injection and persisted, in reduced form, for at least 4 months. Pretreatment with the NMDA antagonists MK-801 or 3-[(+)-2-carboxypiperazin-4-yl]-propyl-1-phosphonate (CPP) dose-dependently attenuated apomorphine-priming of quinpirole-mediated rotational behavior and striatal Fos induction compared to 6-OHDA rats primed with apomorphine alone. Taken together, these data suggest that priming of these D2-mediated responses in 6-OHDA rats develops rapidly, persists for several months, and is dependent on concomitant NMDA receptor stimulation. Since this priming effect resembles response fluctuations observed in patients with Parkinson's disease receiving long-term l-dihydroxyphenylalanine therapy, the results of the present study suggest that interventions that prevent the development of this enhanced response, such as NMDA antagonists, could prove useful in reducing the incidence these response fluctuations.     

Increased responsivity of glutamate release from the substantia nigra pars reticulata to striatal NMDA receptor blockade in a model of Parkinson's disease. A dual probe microdialysis study in hemiparkinsonian rats

Dual probe microdialysis was employed in freely moving 6-hydroxydopamine (6-OHDA) hemilesioned rats to investigate the effects of blockade of N-methyl-D-aspartate (NMDA) receptors in the dorsolateral striatum on glutamate (Glu) release from the ipsilateral substantia nigra pars reticulata (SNr). Perfusion for 60 min with the NMDA antagonist dizocilpine (0.1 and 1 microM) in the dopamine (DA)-denervated striatum stimulated nigral Glu release (peak effect of 139 +/- 7% and 138 +/- 9%, respectively). The lower (0.01 microM) and higher (10 microM) concentrations were ineffective. In sham-operated rats, dizocilpine failed to affect nigral Glu release up to 1 microM but induced a prolonged stimulation at 10 microM (153 +/- 9% at the end of perfusion). The present results show that DA-deficiency in the striatum of hemiparkinsonian rats is associated with increased responsivity of nigral Glu release to striatal NMDA receptor blockade. This suggests that changes of NMDA receptor mediated control of the striatofugal pathways occur during Parkinson's disease (PD).     

Role of NMDA glutamate receptors in regulating D2 dopamine-dependent Fos induction in the rat striatopallidal pathway

Acute administration of reserpine induces Fos expression in striatopallidal neurons, an effect blocked by pretreatment with the D2 dopamine agonist quinpirole. Pretreatment with the NMDA antagonists (+)MK-801 or CPP attenuated reserpine-mediated striatal Fos induction whereas pretreatment with ketamine or the inactive isomer (-)MK-801 did not. These results support a role of NMDA glutamate receptors in regulating the activity of the striatopallidal pathway.     

Selective stimulation of striatal dopamine receptors of the D1- or D2-class causes opposite changes of fos expression in the rat cerebral cortex

It has been suggested that activation of striatal neurons expressing D1 or D2 dopamine receptors elicits opposite changes in the net output of the basal ganglia circuitry and, consequently, in the functional interactions of the circuit with the cerebral cortex. In particular, it has been recently reported that striatal D1 receptors may regulate cortex function. To further address this issue, we mapped cerebral expression of Fos protein following intrastriatal stimulation of D1- or D2-class receptors in freely moving animals. Using permanent cannulas implanted in the right striatum, Sprague-Dawley rats received intrastriatal microinfusions of SKF 38393 (D1 agonist) or quinpirole (D2 agonist) or saline (controls), combined with systemic administration of D1 antagonist SCH 23390 or D2 antagonist eticlopride or saline. Animals treated with SKF 38393 showed dose-dependent, massive Fos increases in the motor, somatosensory, auditory, visual and limbic regions of the cerebral cortex, ipsilaterally to the injected striatum. Consistent Fos expression was also found in the injected striatum and, bilaterally, in the nucleus accumbens shell. These increases were effectively counteracted by systemic SCH 23390. Conversely, quinpirole did not induce significant cortical or striatal expression of Fos, which was instead observed after the systemic administration of eticlopride. Fos was not detected in any of the other basal ganglia nuclei, regardless of the dopamine agonists or antagonists used. Our results confirm that striatal D1 dopamine receptors play a central role in the modulation of cortical activity, thus providing additional information on the functional interaction between basal ganglia circuitry and cerebral cortex.