Biomedical subjects

J L Labandeira-Garcia

Publications and source records attributed to J L Labandeira-Garcia.

At least 19 recordsLinked to original sources

PubMed2006

Angiotensin type-1-receptor antagonists reduce 6-hydroxydopamine toxicity for dopaminergic neurons.

Angiotensin II activates (via type 1 receptors) NAD(P)H-dependent oxidases, which are a major source of superoxide, and is relevant in the pathogenesis of several cardiovascular diseases and certain degenerative changes associated with ageing. Given that there is a brain renin-angiotensin system and that oxidative stress is a key contributor to Parkinson's disease, we investigated the effects of angiotensin II and angiotensin type 1 (AT(1)) receptor antagonists in the 6-hydroxydopamine model of Parkinson's disease. Rats subjected to intraventricular injection of 6-hydroxydopamine showed bilateral reduction in the number of dopaminergic neurons and terminals. Injection of angiotensin alone did not induce any significant effect. However, angiotensin increased the toxic effect of 6-hydroxydopamine. Rats treated with the AT(1) receptor antagonist ZD 7155 and then 6-hydroxydopamine (with or without exogenous administration of angiotensin) showed a significant reduction in 6-hydroxydopamine-induced oxidative stress (lipid peroxidation and protein oxidation) and dopaminergic degeneration. Dopaminergic degeneration was also reduced by the NAD(P)H inhibitor apocynin. Angiotensin may play a pivotal role, via AT(1) receptors, in increasing the oxidative damage of dopaminergic cells, and treatment with AT(1) antagonists may reduce the progression of Parkinson's disease.

Adrenergic Agents↗

PubMed2005

Angiotensin-converting enzyme inhibition reduces oxidative stress and protects dopaminergic neurons in a 6-hydroxydopamine rat model of Parkinsonism.

It is now established that the brain possesses a local renin-angiotensin system and that angiotensin II exerts multiple actions in the nervous system, including regulation of striatal dopamine release. Furthermore, angiotensin activates NADPH-dependent oxidases, which are a major source of superoxide, and angiotensin-converting enzyme inhibitors, commonly used in the treatment of hypertension and chronic heart failure, have shown antioxidant properties in several tissues. Oxidative stress is a key contributor to the pathogenesis and progression of Parkinson's disease. In the present study, we treated rats with intraventricular injections of the dopaminergic neurotoxin 6-hydroxydopamine and subcutaneous injections of the angiotensin-converting enzyme inhibitor Captopril to study the possible neuroprotective effect of the latter on the dopaminergic system and on 6-hydroxydopamine-induced oxidative stress. Rats treated with Captopril and 6-hydroxydopamine showed significantly less reduction in the number of dopaminergic neurons (i.e., immunoreactive to tyrosine hydroxylase) in the substantia nigra and in the density of striatal dopaminergic terminals than 6-hydroxydopamine-lesioned rats not treated with Captopril. In addition, Captopril reduced the levels of major oxidative stress indicators (i.e., lipid peroxidation and protein oxidation) in the ventral midbrain and the striatum of 6-hydroxydopamine-lesioned rats. Our results suggest that angiotensin-converting enzyme inhibitors may be useful for treatment of Parkinson's disease and that further investigation should focus on the neuroprotective capacity of these compounds.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2005

Expanded mesencephalic precursors develop into grafts of densely packed dopaminergic neurons that reinnervate the surrounding striatum and induce functional responses in the striatal neurons.

The search for alternative sources of dopaminergic cells, other than primary fetal tissue for transplantation in Parkinson's disease has become a major focus of research. Different methodological approaches have led to generation in vitro of cells expressing DA-cell markers, although these cells are frequently unable to survive for a long time in vivo after transplantation and/or induce functional effects in the host brain. In the present study, we grafted cell aggregates treated with antibodies against fibroblast growth factor 4 into dopaminergic-denervated striata in rats. Furthermore, we grafted cell suspensions from primary mesencephalic fetal tissue. Grafts from expanded precursors were able to survive (at least 3 months postgrafting) and most decreased the lesion-induced ipsiversive rotation. In addition, immunolabeling for tyrosine hydroxylase and/or Fos showed that the grafts reinnervated the surrounding striatal tissue with dopaminergic terminals, and induced the expression of Fos in the striatal neurons of the reinnervated area after administration of amphetamine to the host rat. The number of dopaminergic cells in grafts from expanded precursors inducing rotational recovery was usually lower (1,226+/-314) than that in grafts from primary fetal tissue (1,671+/-122), but they were more densely packed in grafts that were of smaller volume and did not have the characteristic central nondopaminergic area observed in grafts from primary fetal tissue. The results suggest that long-term survival and functional integration into the DA-denervated striatum can be achieved with grafts of expanded mesencephalic precursors.

Adrenergic Agents↗

PubMed2004

Angiotensin II increases differentiation of dopaminergic neurons from mesencephalic precursors via angiotensin type 2 receptors.

In addition to the well-known actions of the humoral renin-angiotensin system, all components of this system are present in many tissues, including the brain, and may play a major role in brain development and differentiation. We investigated the possible effects of angiotensin II on the generation of dopaminergic phenotype neurons from proliferating neurospheres of mesencephalic precursors. We observed immunoreactivity for both angiotensin type 1 and type 2 (AT(1) and AT(2)) receptors in the cell aggregates. Double immunolabeling studies revealed that both receptor types are located in neurons and astrocytes. Interestingly, neurons with a dopaminergic phenotype (i.e. tyrosine hydroxylase activity) showed double labeling for AT(1) and AT(2) receptors although the labeling for AT(2) was more intense. Treatment of the neurospheres with angiotensin II (100 nm) during the differentiation period induced a marked increase (about 400%) in the generation of dopaminergic neurons. This was not affected by treatment with the AT(1) antagonist ZD 7155 but was blocked by treatment with the AT(2) antagonist PD 123319. This suggests that AT(2) receptors mediate the stimulatory effect of angiotensin II on the generation of dopaminergic neurons. Apoptotic cell death studies and bromodeoxyuridine immunohistochemistry indicated that the increase in generation of dopaminergic neurons is not due to increased survival or proliferation of dopaminergic cells during treatment with angiotensin and suggested that angiotensin induces increased differentiation of mesencephalic precursors towards the dopaminergic phenotype. Manipulation of the renin-angiotensin system may be useful for increasing production of dopaminergic neurons for transplantation in Parkinson's disease.

Angiotensin II↗

PubMed2003

Interaction between the noradrenergic and serotonergic systems in locomotor hyperactivity and striatal expression of Fos induced by amphetamine in rats.

It is classically considered that Amphetamine acts by increasing extracellular dopamine levels. However, some data suggest a relevant role of other neurochemical systems. The striatum is of particular interest to the study of this question. We have investigated the involvement of the noradrenergic and serotonergic systems and their possible interaction in the striatal responses to Amphetamine using a double behavioral and immunohistochemical approach (i.e., changes in locomotor activity and striatal expression of Fos). In normal rats, Amphetamine induced locomotor hyperactivity and striatal expression of Fos. Pretreatment with the alpha1-adrenergic-receptor antagonist Prazosin or lesion of the serotonergic system significantly reduced the locomotor hyperactivity and striatal Fos expression induced by Amphetamine. Administration of Prazosin to rats with serotonergic denervation did not produce any further reduction in the Amphetamine-induced locomotor hyperactivity or striatal Fos expression compared with that observed in rats with serotonergic denervation only. Amphetamine did not induce a detectable increase in Fos expression in dopamine-denervated striata, and elicited intense rotation towards the dopamine-denervated side. This suggests that striatal dopamine release is essential in the Amphetamine-induced effects on striatal neurons. However, the noradrenergic system plays an important role, and the serotonergic system is necessary for mediating the effects of the Amphetamine-induced noradrenergic stimulation. Concurrent stimulation of dopaminergic and serotonergic receptors appears necessary to regulate Amphetamine-induced responses in the striatal neurons.

Adrenergic alpha-Antagonists↗

PubMed2001

N-acetylcysteine enhances production of dopaminergic neurons from mesencephalic-derived precursor cells.

Epidermal growth-factor-responsive rat mesencephalic precursor cells incubated in differentiation media produce only a small number of dopaminergic (DA) cells. Supplementation of the differentiation medium with N-acetylcysteine (NAC) induced a marked increase (approximately 400%) in the number of tyrosine hydroxylase (TH)-positive cells. Treatment with interleukin-1 alpha also induced a significant increase (approximately 300%) in the number of TH-positive cells. However, we did not find additive effects between these drugs. The results suggest that NAC is effective in the production of DA cells from precursors, and that this may be related to enhancement of generation and/or survival of DA cells.

Acetylcysteine↗

PubMed2001

Mechanisms of the effects of exogenous levodopa on the dopamine-denervated striatum.

The efficacy of exogenous levodopa (L-DOPA) is attributed to its conversion to dopamine by the enzyme aromatic L-amino-acid decarboxylase in striatal dopaminergic terminals. However, there is controversy about the mechanisms underlying the therapeutic and adverse effects of L-DOPA after almost all striatal dopaminergic afferents have disappeared (i.e. in the later stages of Parkinson's disease). After administration of 30mg/kg or 100mg/kg of L-DOPA, rats subjected to unilateral dopaminergic denervation showed intense contraversive rotation and a high density of Fos-immunoreactive nuclei throughout the denervated striatum, with no significant induction of Fos in the intact striatum. Injection of the central aromatic L-amino-acid decarboxylase inhibitor NSD-1015 30min before and 15min after the injection of L-DOPA suppressed the rotational behavior and the striatal induction of Fos. Comparison of results obtained in rats subjected to unilateral and bilateral dopaminergic denervation indicated that the presence of contralateral dopaminergic innervation does not significantly modulate the effects of L-DOPA on the denervated striatum. Serotonergic denervation led to slight and statistically non-significant decrease in the rotational behavior and Fos expression induced by high doses of L-DOPA (100mg/kg) in the dopamine-denervated striatum, but totally suppressed the rotational behavior and Fos expression induced by low doses of L-DOPA (30mg/kg). The present data indicate that the major effects observed after administration of exogenous L-DOPA are not due to a direct action of L-DOPA on dopamine receptors, or to extrastriatal release of dopamine, but to conversion of L-DOPA to dopamine by serotonergic terminals and probably some intrastriatal cells. Given that serotonergic neurons appear to play an important role in the action of L-DOPA in the later stages of Parkinson's disease, strategies targeting the serotonergic system should be considered for the treatment of Parkinson's disease and for combating undesirable side effects of L-DOPA therapy.

Animals↗

PubMed2000

Fenfluramine-induced increase in preproenkephalin mRNA levels in the striatum: interaction between the serotonergic, glutamatergic, and dopaminergic systems.

Fenfluramine (FE) is a halogenated amphetamine derivative that has been used in the treatment of obesity. It has been suggested that the effects of FE on the striatum are mediated by serotonergic mechanisms. However, several major afferent systems may be involved, and administration of FE may be useful to study interactions between these systems. In this work, the effects of FE on striatopallidal neurons and the possible involvement of the major striatal afferent systems were studied in rats by determination of FE-induced changes in striatal levels of preproenkephalin (PPE) mRNA using in situ hybridization. Injection of FE induced a significant increase (60%) in striatal levels of PPE mRNA. This increase was blocked by pretreatment with the D(1) dopamine receptor antagonist SCH-23390 or with the NMDA glutamate receptor antagonist MK-801, or by lesion of the serotonergic system with 5,7-dihydroxytryptamine or p-chlorophenylalanine. In 6-hydroxydopamine lesioned rats, the lesion-induced increase in PPE mRNA levels was not affected by injection of FE, but was reduced by simultaneous serotonergic deafferentation. The results suggest that the serotonergic, glutamatergic, and dopaminergic system interact to increase striatal PPE mRNA levels after FE administration.

5,7-Dihydroxytryptamine↗

PubMed2000

Autoxidation and neurotoxicity of 6-hydroxydopamine in the presence of some antioxidants: potential implication in relation to the pathogenesis of Parkinson's disease.

6-Hydroxydopamine (6-OHDA) is a dopaminergic neurotoxin putatively involved in the pathogenesis of Parkinson's disease (PD). Its neurotoxicity has been related to the production of reactive oxygen species. In this study we examine the effects of the antioxidants ascorbic acid (AA), glutathione (GSH), cysteine (CySH), and N-acetyl-CySH (NAC) on the autoxidation and neurotoxicity of 6-OHDA. In vitro, the autoxidation of 6-OHDA proceeds rapidly with the formation of H2O2 and with the participation of the H2O2 produced in the reaction. The presence of AA induced a reduction in the consumption of O2 during the autoxidation of 6-OHDA and a negligible presence of the p-quinone, which demonstrates the efficiency of AA to act as a redox cycling agent. The presence of GSH, CySH, and NAC produced a significant reduction in the autoxidation of 6-OHDA. In vivo, the presence of sulfhydryl antioxidants protected against neuronal degeneration in the striatum, which was particularly remarkable in the case of CySH and was attributed to its capacity to remove the H2O2 produced in the autoxidation of 6-OHDA. These results corroborate the involvement of oxidative stress as the major mechanism in the neurotoxicity of 6-OHDA and the putative role of CySH as a scavenger in relation to PD.

Acetylcysteine↗

PubMed1999

Recovery after nigral grafting in 6-hydroxydopamine lesioned rats is due to graft function and not significantly influenced by the remaining ipsilateral or contralateral host dopaminergic system.

The aim of this study was to evaluate whether the recovery observed after grafting of fetal nigral cells in 6-hydroxydopamine lesioned rats is due to the graft itself, and whether the participation of the remaining host dopaminergic system is necessary. The effects of unilateral 6-hydroxydopamine lesion on rotational behavior were not significantly affected by sham grafting or by sham grafting plus repeat ipsilateral lesion, but were suppressed by nigral grafting, and by contralateral lesion. Immunohistochemical and in situ hybridization study of right striata of rats subjected to right-side lesion then right-side sham-grafting, and of right and left striata from rats subjected to right-side lesion then right-side sham-grafting then repeat right-side lesion then left-side lesion, revealed (a) no significant amphetamine-induced Fos activation, (b) marked increases in preproenkephalin mRNA levels, and (c) decreases in preprotachykinin levels, with no significant differences in any of these variables among these three types of striata. After nigral grafting, however, intense Fos expression was observed in the striatum, and preproenkephalin and preproenkephalin mRNA levels returned to normal. This recovery was maintained after subsequent repeat ipsilateral 6-hydroxydopamine lesion followed by contralateral lesion. The results demonstrate that, after dopaminergic denervation, the nigral graft itself is able to induce recovery in the assessed parameters, and that these effects of grafting into striata with maximal unilateral 6-hydroxydopamine lesion are due to graft function, and are not significantly influenced by the remaining ipsilateral or contralateral host dopaminergic system. Additionally, it is interesting to note that bilateral denervation led to changes in striatal preproenkephalin and preproenkephalin mRNA levels similar to those observed after unilateral lesion.

Animals↗

PubMed1999

Locomotor-activity-induced changes in striatal levels of preprotachykinin and preproenkephalin mRNA. Regulation by the dopaminergic and glutamatergic systems.

The mechanisms by which dopaminergic and glutamatergic inputs interact to regulate striatal neuropeptide expression during physiological motor activity are poorly understood. In this work, striatal expression of preprotachykinin (PPT) and preproenkephalin (PPE) mRNA was studied by in situ hybridization in rats killed 2 h after treadmill running (36 m/min for 20 min). Treadmill running induced a significant increase in the levels of both PPT (60% increase) and PPE (90% increase) mRNA in the striatum of normal rats. The increase in the level of PPT mRNA was blocked in rats previously subjected to nigrostriatal deafferentation (i.e., 6-hydroxydopamine lesion) or pretreated with D1-receptor antagonist SCH-23390 (0.1 mg/kg), the D2-receptor antagonist eticlopride (0.5 mg/kg), or the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist MK-801 (0.1 mg/kg). The running-induced increase in the level of PPE mRNA was blocked in rats pretreated with SCH-23390 or MK-801. Rats subjected to nigrostriatal deafferentation or pretreated with eticlopride showed an increase in PPE mRNA levels (around 150% and 40% increase, respectively), that was enhanced by running (around 230% and 160% increase, respectively). These results suggest that locomotor activity increases, in a NMDA receptor dependent fashion, the excitatory influence of the corticostriatal glutamatergic system on the two populations of striatal projection neurons, as reflected by increases in the levels of PPT and PPE mRNA. The results obtained after dopamine depletion or injection of dopamine receptor antagonists suggest that a concomitant increase in dopamine release may enhance PPT mRNA level in striatonigral neurons via D1 receptors, and reduce PPE mRNA level in striatopallidal neurons via D2 receptors. Additionally, levels of dopamine and glutamate may be regulated by other complex indirect mechanisms.

Animals↗

PubMed1998

Sprouting of the serotonergic afferents into striatum after selective lesion of the dopaminergic system by MPTP in adult mice.

Neonatal destruction of the nigrostrial dopaminergic (DA) system with 6-hydroxydopamine leads to serotonergic (5-HT) hyperinnervation of the striatum. However, it is not clear whether this occurs in adult animals. We investigated whether serotonergic sprouting occurs in adult mice subjected to bilateral lesion of the DA system by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The effects of the lesion were evaluated using a new rotarod test and immunohistochemistry. One hundred days after the last MPTP lesion, there was a clear bilateral serotonergic hyperinnervation throughout the striatum. Additionally, those mice showing the highest reductions in striatal tyrosine hydroxylase (TH) immunoreactivity and in rotarod performance showed the highest density of serotonergic innervation (116% increase). The functional consequences of this process in Parkinson's disease and secondary parkinsonism remain to be clarified.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1998

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.

Animals↗

PubMed1998

The corticostriatal system mediates the "paradoxical" contraversive rotation but not the striatal hyperexpression of Fos induced by amphetamine early after 6-hydroxydopamine lesion of the nigrostriatal pathway.

In rats with unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway, amphetamine produces ipsiversive rotational behavior and activation of Fos in the intact striatum, but practically no activation of Fos in the denervated striatum. However, a seemingly paradoxical contraversive rotation, accompanied by intense striatal Fos activation in the lesioned striatum, has been observed during the first few days postlesion. In the present work, behavioral tests and immunohistochemistry for Fos protein and tyrosine hydroxylase (TH) were combined to study striatal changes 36 h after 6-OHDA lesion and particularly the possible involvement of glutamatergic corticostriatal afferents. Injection of amphetamine (0.5 mg/kg or 5 mg/kg) induced contraversive rotation and strong and evenly distributed Fos expression in the lesioned striatum; in the contralateral striatum, however, Fos density was lower than in nonlesioned rats. Pretreatment with the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist MK-801 (either 0.5 mg/kg or 5 mg/kg) did not significantly affect the hyperexpression of Fos in the lesioned striatum, but suppressed the contraversive rotation. Similarly, rats that were subjected to corticostriatal deafferentation (confirmed by sensory neglect tests) and 6-OHDA lesion (1 week or 3 weeks later) showed no significant reduction in the striatal Fos hyperexpression induced by amphetamine (0.5 mg/kg or 5 mg/kg) and no significant rotational asymmetry. In conclusion, the present results indicate that glutamatergic corticostriatal afferents are essential for the contraversive rotational behavior but not the striatal hyperexpression of Fos observed in response to amphetamine early after 6-OHDA lesion, and suggest that intense dopaminergic stimulation of striatal neurons is sufficient for induction of Fos, but that concurrent glutamatergic stimulation is necessary for the motor response.

Afferent Pathways↗

PubMed1997

GABA(A) receptor subunit expression in intrastriatal striatal grafts comparison between normal developing striatum and developing striatal grafts.

Expression of the alpha1, alpha2 and beta2/3 GABA(A) receptor subunits in maturing cell-suspension striatal grafts and in normal developing striatum was studied by immunocytochemistry. During normal postnatal development, the alpha1 subunit was present in the striatum only at very low density, while the alpha2 and beta2/3 subunits were present with a patchy distribution, in some patches at high density. Double-staining techniques indicated that DARPP-32 (a marker of striatal projection neurons) was not colocalized with alpha1, but was present in some beta2/3-positive areas and all alpha2-positive areas. In striatal grafts, alpha1 immunoreactivity was first detected 2 weeks post-grafting (p.g.), and by 3-10 weeks p.g. the pattern was similar to that observed in mature grafts (1 year p.g.), in which alpha1-immunopositive patches surrounding DARPP-32-positive (i.e. striatum-like) areas are observed. Alpha2 and beta2/3 immunoreactivity was observed within the first week p.g., and by 3-10 weeks p.g. was similar to that observed in mature grafts (i.e. immunoreactivity throughout the graft but with patches of different intensity). During graft maturation there was a marked decline in alpha2 immunoreactivity in DARPP-32-negative areas, as is observed during normal development of the globus pallidus and ventral pallidum. Interestingly, alpha1- and beta2/3-positive fibers (perhaps mostly dendrites) entered DARPP-32-positive patches from DARPP-32-negative areas. This study indicates that the time course of expression of GABA(A) receptor subunits in grafted striatal neurons, closely matches that of morphological maturation of the transplant, that of the development of functional synaptic activity and that of GABA(A) receptor subunit immunoreactivity in normal developing striatum. Our results also suggest that there are significant interactions between DARPP-32-positive and DARPP-32-negative areas with respect to the expression of GABA(A) receptors, and support the suggestion that miniature 'striatopallidal systems' may develop within grafts; such interactions may be important for the functional integration of striatal grafts with the host brain.

Aging↗

PubMed1997

Effects of lesions of the nigrostriatal pathway and of nigral grafts on striatal serotonergic innervation in adult rats.

Neonatal destruction of the nigrostriatal dopaminergic system leads to serotonergic hyperinnervation of the striatum. However, it is not clear whether this occurs in adult animals. We investigated whether serotonergic sprouting occurs in adult animals, and also studied the effects of prior or subsequent implantation of dopamine-rich intrastriatal grafts. One group of adult rats received maximal 6-hydroxydopamine lesions. Other rats received maximal lesions and intrastriatal grafts 2 months later, or vice versa. The lesioned non-grafted rats showed clear serotonergic hyperinnervation throughout the striatum ipsilateral to the lesion. Intrastriatal grafts did not prevent or revert this serotonergic hyperinnervation, and were themselves densely innervated by serotonergic fibers. Serotonergic neurons usually present in the grafted cell suspension also contributed to the serotonergic innervation of the graft and the surrounding striatum.

Animals↗

PubMed1997

Treadmill running induces striatal Fos expression via NMDA glutamate and dopamine receptors.

Several non-physiological stimuli (i.e. pharmacological or electrical stimuli) have been shown to induce Fos expression in striatal neurons. In this work, striatal Fos (i.e. Fos-like) expression was studied after physiological stimulation, i.e. motor activity (treadmill running at 36 m/min for 20 min). In rats killed 2 h after the treadmill session, Fos expression was observed in the medial region of the rostral and central striatum, and in the dorsal region of the caudal striatum. Fos expression was prevented by pretreatment with the non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist MK-801 (0.1 mg/kg) or the D1 dopamine receptor antagonist SCH-23390 (0.1 mg/kg), but not by pretreatment with the D2 receptor antagonist eticlopride (0.5 mg/kg). Thirty-six hours after 6-hydroxydopamine lesion, a considerable reduction in treadmill-induced Fos expression was observed in both sides; however, Fos expression in the lesioned striatum was higher than in the contralateral intact striatum. Several weeks after unilateral 6-hydroxydopamine lesion of the nigrostriatal system, treadmill-induced Fos expression was significantly, but not totally, reduced in the lesioned striatum. Corticostriatal deafferentation also led to considerable reduction in treadmill-induced Fos expression. The present results indicate that exercise induces striatal Fos expression and that, under physiological stimulation, concurrent activation of D1 and NMDA receptors is necessary for such expression to occur. Reduction of Fos expression is practically absolute after acute blockage of these receptors, but not after lesions, possibly due partially to compensatory changes.

Afferent Pathways↗

PubMed1996

Previous dopaminergic innervation is not necessary for the development of dopamine supersensitivity in rat striatal neurons.

The development of supersensitivity to dopamine by striatal neurons is widely considered to be a response to interruption of dopaminergic synaptic function. However, it is not clear whether pre-existing dopaminergic innervation is in fact necessary for supersensitivity to develop. In this study, rat foetal striatal cells were obtained prior to their innervation by dopaminergic fibres, and grafted into the cortex or thalamus of adult rats. In the absence of dopaminergic innervation, the grafts developed and became organized into striatum-like and non-striatum-like patches. Both in animals with intrathalamic and in animals with intracortical grafts, systemic administration of a low dose of apomorphine (0.25 mg/kg) induced intense fos expression in striatum-like patches not innervated by dopaminergic fibres. These results indicate that pre-existing dopaminergic innervation is not required for the development of supersensitivity, and that dopaminergic innervation is necessary to develop an adequate synergistic interaction between D1 and D2 receptors.

Animals↗