Ventral striatal D(3) receptors and Parkinson's Disease

Antiparkinsonian drugs are thought to act largely through the D2 receptor family that includes the D(2) and D(3) receptors. D(2) and D(3) receptors exhibit both complementary and overlapping expression at the macro and cellular level. The D(3) receptor appears to be a primary target of the mesolimbic dopamine system, is highly enriched in expression within the "limbic" striato-pallidal-thalamic loop, and is recognized as being regulated by dopaminergic activity in distinctly different ways from the D(2) receptor. In Parkinson's Disease it has been determined that loss of dopaminergic innervation results in elevation of the D(2) receptor but reduced levels of the D(3) receptor. In many late-stage Parkinson's Disease patients there is a loss of antiparkinsonian response to L-dopa and other antiparkinsonian drugs that is often correlated with clinical signs for dementia. We have determined that the reduction of D(3) receptor, and not that of the D(2) receptor, is associated with the loss of response to L-dopa and other antiparkinsonian drugs. The reduction of D(3) receptor is also related to the presence of dementia. An elevation of D(3) receptors was evident in those Parkinson's Disease cases with continued good response to L-dopa. Thus, we believe that reduced D(3) receptor number is correlated with certain subgroups of Parkinson's Disease and may also be related to a further diminishment in the mesolimbic DA system.     

Kinetic and pharmacologic characterization of dopamine binding in the mouse cerebellum and the effects of the reeler mutation

The purpose of this study was to characterize the dopaminergic system in the mouse cerebellum and to determine whether the dyskinesia of the reeler mutant is accompanied by alterations in cerebellar and/or striatal dopamine binding. From the analysis of (3H) dopamine ((3H)DA) and (3H)spiperone ((3H)Sp) binding, the study of the effects of several drugs on this binding, and the comparison of these parameters between the cerebellum and striatum, we conclude that a dopaminergic system exists in the cerebellum with properties common to the striatal system but also with some differences. That is, 1) with (3H)DA as ligand, we find two binding sites in cerebellum with similar Kd to those of striatum but of lower density, 2) with (3H)Sp as ligand we observe two binding sites in cerebellum and one in striatum, and 3) the competition of (3H)DA binding by various drugs shows that among the cerebellar sites, relative to striatum, there is a higher proportion that corresponds to high affinity D3 and D4 (D2 high) binding sites. In cerebellum and striatum of reeler mice, (3H)DA binding increases 125-174% and 14%, respectively.     

Comparative development of D1-dopamine and mu opiate receptors in normal and in 6-hydroxydopamine-lesioned neonatal rat striatum: dopaminergic fibers regulate mu but not D1 receptor distribution.

The postnatal development of D1 dopaminergic receptors (D1 receptors) was investigated in the rat striatum in relation to distribution of mu opiate receptor patches and islandic tyrosine hydroxylase (TH)-immunoreactive fibers. The possible influence of dopaminergic (DA) fibers originating from the substantia nigra on the postnatal distribution of striatal D1 and mu receptors was also examined by producing an early 6-hydroxydopamine (6-OHDA) lesion of DA fibers. D1 and mu receptors were labeled with selective ligands: [3H]SCH 23390 and [3H]DAGO, respectively. During the first postnatal week, control rats showed patches of dense D1 binding sites in the entire rostro-caudal extension of the striatum. The localization of D1 receptor patches corresponded to striosomes identified by TH-immunoreactive islands. The striatal distribution of mu receptors was relatively homogeneous at postnatal day 0 (P0) but was clearly patchy at P3-P4. During the second postnatal week the striosomal pattern of D1 binding sites disappeared along a dorso-ventral gradient whereas mu binding sites remained distributed in patches. Densitometric measurements showed that there was a parallel increase of D1 binding sites in both striosomes and the surrounding matrix from P0 to P4. The disappearance of D1 receptor patches observed in the dorsal striatum at P9 was due to a faster increase of D1 binding sites in the matrix than in striosomes between P4 and P9 whereas a significant difference was still observed between these two compartments in the ventral striatum of P9 rats. During the third postnatal week, the density of D1 binding sites still increased but became progressively uniform in the whole striatum. The intrastriatal injection of 6-OHDA in 2-day-old rats produced a local disappearance of TH-immunoreactive fibers in the striatum and a distal degeneration of TH-immunoreactive cell bodies in the substantia nigra. However an early lesion of striatal DA fibers did not modify the pattern of development or the density of D1 binding sites during the postnatal period examined (1 and 3 weeks after the lesion). The distribution of mu receptors was unchanged 1 week after the lesion but showed a clear disorganization 3 weeks after the lesion. We discuss the differential influence of DA fibers on the distribution of D1 and mu receptors in the rat striatum and the possible role of DA in the regulation of the expression of mu receptors.     

Activation of dopamine D1-like receptors excites LTS interneurons of the striatum

Dopamine (DA) has a crucial role in the modulation of striatal neuron activity. Along with projection cells, striatal interneurons receive dense dopaminergic innervation from midbrain neurons, thus, also suggesting that these intrinsic cells represent a synaptic target for DA action in the striatum. In the present study, we investigated the effects of DA on low-threshold spike (LTS) interneurons of the rat striatum, by means of in vitro whole-cell patch-clamp electrophysiological recordings. Dopamine depolarized LTS cells, a pharmacological effect prevented by D1- but not D2-like DA receptor antagonists. The membrane depolarization produced by DA was sufficient to trigger action potential discharge in the recorded cells and was insensitive to tetrodotoxin and glutamate receptor antagonists. In addition, this pharmacological effect was mimicked by D1- but not D2-like DA receptor agonists, implying the selective involvement of D1-like receptors in this action.     

Dopaminergic regulation of cholecystokinin mRNA content in rat striatum.

The nigrostriatal dopaminergic activity was pharmacologically changed to assess whether dopamine (DA) regulates cholecystokinin (CCK) mRNA steady state in rat striatum. Cocaine and benztropine, two dopaminergic agonists known to induce DA release and to block its re-uptake, produced a time dependent increase in CCK mRNA content in rat striatum. A significant increase in striatal CCK mRNA was observed 8 h after a single injection of cocaine (15 mg/kg, i.p.) or benztropine (15 mg/kg, i.p.) whereas a two-fold increase was observed after a daily treatment for one week with these two dopaminergic agonists. Cocaine and benztropine failed to change CCK mRNA content in the cerebral cortex. Haloperidol, a dopaminergic receptor blocker, injected at 1 mg/kg, i.p., daily for 7 days, decreased CCK mRNA content in striatum but not in the cerebral cortex. Moreover, haloperidol blocked the effect of cocaine and benztropine, suggesting that the stimulation of striatal dopaminergic receptors is necessary for the induction of CCK biosynthesis. The neurotoxin 6-hydroxydopamine injected into the medial forebrain bundle, elicited a 50% decrease in striatal CCK mRNA, supporting the hypothesis that DA tonically regulates CCK biosynthesis in postsynaptic neurons. To characterize the dopaminergic receptor subtype involved in this regulation, BHT 920, a specific D2 receptor agonist and SKF 38393, a specific D1 receptor agonist were used. While one week treatment with BHT 920 (1 mg/kg, i.p.) increases striatal CCK mRNA content, SKF 38393 (3 mg/kg, i.p.) failed to change this parameter. These data suggest that the increase of striatal CCK mRNA is mediated by the activation of the D2 receptor subtype.     

Basal ganglia cholinergic and dopaminergic function in progressive supranuclear palsy.

Progressive Supranuclear Palsy (PSP) is a progressive neurodegenerative disorder. In contrast to Parkinson's disease (PD) and dementia with Lewy bodies (DLB), replacement therapy with dopaminergic and cholinergic agents in PSP has been disappointing. The neurochemical basis for this is unclear. Our objective was to measure dopaminergic and cholinergic receptors in the basal ganglia of PSP and control brains. We measured, autoradiographically, dopaminergic (dopamine transporter, 125I PE2I and dopamine D2 receptors, 125I epidepride) and cholinergic (nicotinic alpha4beta2 receptors, 125I 5IA85380 and muscarinic M1 receptors, 3H pirenzepine) parameters in the striatum and pallidum of pathologically confirmed PSP cases (n=15) and controls (n=32). In PSP, there was a marked loss of dopamine transporter and nicotinic alpha4beta2 binding in the striatum and pallidum, consistent with loss of nigrostriatal neurones. Striatal D2 receptors were increased in the caudate and muscarinic M1 receptors were unchanged compared with controls. These results do not account for the poor response to dopaminergic and cholinergic replacement therapies in PSP, and suggest relative preservation of postsynaptic striatal projection neurones bearing D2/M1 receptors.     

Alterations in dopamine uptake sites and D1 and D2 receptors in cats symptomatic for and recovered from experimental parkinsonism

The administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to adult cats severely disrupts the dopaminergic innervation of the striatum. Animals display a parkinson-like syndrome, consisting of akinesia, bradykinesia, postural instability, and rigidity, which spontaneously recovers by 4–6 weeks after the last administration of MPTP. In this study we used quantitative receptor autoradiography to examine changes in DA uptake sites and DA receptors in the basal ganglia of normal, and symptomatic and recovered MPTP-treated cats. Consistent with the destruction of the nigrostriatal DA pathway, there was a severe loss of DA uptake sites, labeled with [³H]-mazindol, in the caudate nucleus (64–82%), nucleus accumbens (44%), putamen (63%), and substantia nigra pars compacta (SNc, 53%) of symptomatic cats. Following behavioral recovery, there were no significant changes in DA uptake site density. Significant increases of [³H]-SCH 23390 binding to D1 DA receptors were observed in the dorsal caudate (>24%; P < 0.05) of symptomatic cats and in all regions of the caudate-putamen (>30%; P < 0.05) of recovered animals. [³H]-SCH 23390 binding in tree substantia nigra pars reticulata was half of that in the striatum and showed no changes in symptomatic or recovered animals. No alterations in the binding of [¹²⁵1]-epidepride to D2 receptors was observed in any region of the striatum in either, symptomatic or recovered animals. [¹²⁵1]-Epidepride binding in the SNc was decreased by >36% (P < 0.05) following MPTP treatment. These data show that cats made parkinsonian by MPTP exposure have a significant decrease in the number of DA reuptake sites throughout the striatum and that recovery of sensorimotor function in these animals is not correlated with an increase in the number of striatal reuptake sites. Behavioral recovery, however, does seem to be correlated with a general elevation of Dl receptors throughout the striatal complex. The present data also show that direct correlations between changes in DA receptor regulation after a large DA depleting lesion and behavioral deficits or recovery from those deficits are difficult and that the relationships between DA receptors/transporters and behavior require further study. © 1995 Wiley-Liss, Inc.     

Striatal plasticity in Parkinson's disease and L-dopa induced dyskinesia

Striatal function adapts to the loss of nigrostriatal dopaminergic input in Parkinson's disease (PD) to initially maintain voluntary movement, but subsequently changes in response to drug treatment leading to the onset of motor complications, notably dyskinesia. Alterations in presynaptic dopaminergic function coupled to changes in the response of post-synaptic dopaminergic receptors causing alterations in striatal output underlie attempts at compensation and the control of movement in early PD. However, eventually compensation fails and persistent changes in striatal function ensue that involve morphological, biochemical and electrophysiological change. Key alterations occur in cholinergic and glutamatergic transmission in the striatum and there are changes in motor programming controlled by events involving LTP/LTD. Dopamine replacement therapy with L-dopa modifies altered striatal function and restores motor function but non-physiological dopamine receptor stimulation leads to altered signalling through D1 and D2 receptor systems and changes in striatal function causing abnormalities of LTP/LTD mediated through glutamatergic/nitric oxide (NO) mechanisms. These lead to the onset of dyskinesia and underlie the priming process that characterise dyskinesia and its persistence.     

Steele-Richardson-Olszewski-syndrome: reduction of dopamine D2 receptor binding relates to the severity of midbrain atrophy in vivo: (123)IBZM SPECT and MRI study.

Patients with the clinical diagnosis of progressive supranuclear palsy (PSP) show heterogeneous neuropathological findings. In neuropathologically proven cases with numerous neurofibrillary tangles of neuropil threads, the brainstem and striatum are always affected. We compared (123)I-iodobenzamide single photon emission computed tomography (IBZM-SPECT) for imaging of striatal dopamine D(2) receptors in vivo with high-resolution magnetic resonance imaging (MRI) in 13 patients with possible or probable PSP. Clinically, all patients exhibited similar signs including supranuclear vertical-down-gaze palsy, axial rigidity especially involving the neck, bradykinesia, instability of balance with easy falls, and a poor response to dopaminergic drugs.Specific striatal dopamine D(2) receptor binding in IBZM-SPECT was reduced in 10 patients but was normal in three patients. Mean midbrain diameter was 23.7 mm. The reduction of IBZM-binding was statistically significantly correlated to midbrain atrophy (P = 0.010) either in all 13 patients or in those without striatal or white matter lesions (P = 0.015). We suggest that technical investigations, mainly MRI, are able to corroborate the in vivo diagnosis, if PSP is clinically suspected.     

Dopaminergic neurotransmission in somatodendritic and terminal areas of the rat brain: susceptibility to modulation by D 1 and D2 receptors and to axotomy

Summary We have investigated the influence of D1 and D2 dopamine receptor active drugs on dopamine (DA) release in substantia nigra (SN), striatum and limbic forebrain in intact and in hemisected rats in vivo. DA release was indirectly assessed as 3-methoxytyramine (3-MT) accumulation following monoamine oxidase inhibition by pargyline. Hemisection per se had no effect on the 3-MT accumulation in the SN. Neither, had SCH 23390, SK & F28393, or cisflupentixol any effect in the SN in intact animals or in the lesioned side in hemisected animals. SCH 23390 slightly increased the 3-MT accumulation both in the striatum and limbic forebrain, indicating a stimulatory action on DA release, but SK & F38393 had no effect in these brain regions. A difference between the striatum and the limbic forebrain was that the effects of SCH 23390, and cis-FPX were almost abolished following hemisection in the limbic fore-brain, but only partially reduced in the striatum. In summary, our data give further support for the concept that neither D 1 nor D 2 dopamine receptors have any pronounced influence on the DA release in the SN. The data also indicate operational differences in the feedback regulation of limbic versus striatal dopaminergic transmission.     

Phenotypical characterization of the neurons expressing the D1 and D2 dopamine receptors in the monkey striatum

The striatum is regulated by dopaminergic inputs from the substantia nigra. Several anatomical studies using in situ hybridization have demonstrated that in rodents, dopamine D1 and D2 receptors are segregated into distinct striatal efferent populations: dopamine D1 receptor into gamma-aminobutyric acid (GABA)/substance P striatonigral neurons, and dopamine D2 receptor into GABA/enkephalin striatopallidal neurons. The existence of such a segregation has not been investigated in primates. Therefore, to quantify the efferent striatal GABAergic neurons in the adult Cynomolgus monkey, we detected GAD67 mRNA expression while considering that only a minority of the GABAergic population is composed of interneurons. To characterize the peptidergic phenotype of the neurons expressing dopamine D1 or D2 receptors, we examined the mRNA coding for these receptors in the striatum at the cellular level using single- and double in situ hybridization with digoxigenin and 35S ribonucleotide probes. Double in situ hybridization demonstrated a high coexpression of dopamine D1 receptor and substance P mRNAs (91-99%) as well as dopamine D2 receptor and preproenkephalin A mRNAs (96-99%) in medium-sized neurons throughout the nucleus caudatus, putamen, and nucleus accumbens. Only a small subpopulation (2-5%) of the neurons that contained dopamine D1 receptor mRNA also expressed dopamine D2 receptor mRNA in all regions. Large-sized neurons known to be cholinergic expressed D2R mRNA. However, within the nucleus basalis of Meynert, the large cholinergic neurons expressed D2R mRNA, but the neurons producing enkephalin expressed neither D1R nor D2R mRNA. These results demonstrate that the striatal organizational pattern of D1 and D2 receptor segregation in distinct neuronal populations described in rodent also exists in primate.     

Intermittent morphine administration induces a long-lasting synergistic effect of corticosterone on dopamine D1 receptor functioning in rat striatal GABA neurons

Glucocorticoid receptor (GR)-mediated facilitation of striatal dopaminergic (DA) neurotransmission has been proposed to play a role in behavioral sensitization induced by intermittent exposure to drugs of abuse or stressors. Searching for possible common neuronal substrates acted upon by drugs of abuse and corticosterone, we addressed the question as to whether such a facilitatory effect is apparent (i.e., persists) in primary cultures of rat striatum subsequent to intermittent (prenatal) morphine administration. As previously observed in striatal slices of morphine-treated rats, intermittent morphine exposure in vivo caused a long-lasting increase in DA D1 receptor-stimulated adenylyl cyclase activity, that appeared to persist in primary cultures of rat striatal γ-aminobutyric acid (GABA) neurons. Subsequent in vitro exposure of these striatal neurons to corticosterone or dexamethasone, simultanously activating GR and mineralocorticoid receptors (MR), about doubled this adaptive effect of previous in vivo morphine administration. The selective MR agonist aldosterone was ineffective in this respect. Prior in vivo morphine treatment also enhanced the stimulatory in vitro effect of corticotropin releasing hormone (CRH) on adenylyl cyclase in cultured GABA neurons. However, the enhanced CRH receptor functioning was not potentiated by in vitro corticosterone exposure. Activation of GR by corticosterone did not facilitate the increase in D1 receptor efficacy induced by sustained activation of muscarinic receptors in cultured striatal neurons. These data indicate that previous intermittent morphine administration induces a long-lasting synergistic effect of corticosterone on enhanced striatal DA neurotransmission at the level of postsynaptic D1 receptors. Moreover, the induction of this neuroadaptation seems to display opioid receptor selectivity and its long-term expression may be confined to D1 receptors. Since exposure to drugs of abuse or stressors not only increase striatal DA release but also plasma corticosterone levels, we hypothesize that this adaptive phenomenon in DA-sensitive GABA neurons is involved in the expression of morphine-induced long-term behavioral sensitization to drugs of abuse and stressors. Synapse 25:381–388, 1997. © 1997 Wiley-Liss, Inc.     

Activation of dopamine D(3) receptors induces c-fos expression in primary cultures of rat striatal neurons

A modulation of the expression of immediate-early genes (IEGs) such as c-fos is likely involved in the long-term influence of dopaminergic ligands on the activity of basal ganglia neurons. The roles of individual dopamine receptor types in this regard remain unclear, and the present study employed primary cultures of rat striatal neurons to examine the potential modulation of c-fos expression by D(3) receptors. Neurons were treated with the preferential D(3) receptor agonists, (+/-)-7-OH-DPAT and PD 128,907, which showed, respectively, 16-fold and 56-fold selectivity for recombinant rat D(3) vs. D(2) receptors (K(i) values, rD(2)/rD(3) = 59.5/3.7 nM and 251/4.5 nM, respectively). At concentrations of 3 and 30 nM, respectively, (+/-)-7-OH-DPAT and PD 128,907 significantly increased the expression of c-fos mRNA. The action of (+/-)-7-OH-DPAT was expressed stereospecifically; its (+)-isomer (K(i) values, D(3)/D(2) = 1.6/56.7 elicited a 26% +/- 7.6% increase in c-fos expression whereas its (-)-isomer (K(i) values, D(3)/D(2) = 59/1,060 nM) was ineffective. Further, stimulation of c-fos mRNA expression by PD 128,907 (20 nM) was markedly and significantly (P < 0.05) attenuated (-91.8% +/- 5.3%) by 30 nM of the selective D(3) receptor antagonist, (+)-S 14297 (K(i) values, D(3)/D(2) = 11/401 nM). In contrast, the action of PD 128,907 was significantly less affected (-24.5% +/- 7.8%) by 30 nM of its less active distomer, (-)-S 17777 (K(i) values, D(3)/D(2) = 294/3,191 nM). An examination of the concentration-response relationship revealed that (+/-)-7-OH-DPAT and PD 128,907 both produced bell-shaped dose-response curves for c-fos induction. The sequential activation of D(2) receptors-which inhibit striatal c-fos expression (Simpson and Morris [1995] Neuroscience 68:97-106)-by higher concentrations of (+/-)-7-OH-DPAT and PD 128,907 is presumably involved in the inflexion at higher doses. In conclusion, the present data demonstrate that activation of D(3) receptors results in a selective induction of c-fos mRNA expression in cultured striatal neurons. These data show that neuronal D(3) receptors control the expression of IEGs and suggest that D(3) receptors may mediate long-term adapative changes in the activity of neurons in the basal ganglia.     

Dopamine D2 receptor-mediated antioxidant and neuroprotective effects of ropinirole, a dopamine agonist

Recent information suggests that free radicals are closely involved in the pathogenesis and/or progression of Parkinson's disease (PD). High-dose levodopa therapy has been suggested to increase oxidative stress, thereby accelerating the progression of PD. Based on this viewpoint, free radical scavenging, antioxidant and neuroprotective agents which may prevent the progression of PD have recently attracted considerable attention. For example, ergot derivative dopamine (DA) agonists have been reported to scavenge free radicals in vitro and show a neuroprotective effect in vivo. Non-ergot DA agonists have also recently been used in the treatment of PD despite the lack of substantial evidence for any free radical scavenging activity or antioxidant activity. The present study was conducted to assess the in vitro free radical scavenging and antioxidant activities of ropinirole, a non-ergot DA agonist, as well as its glutathione (GSH), catalase and superoxide dismutase (SOD) activating effects and neuroprotective effect in vivo. Ropinirole scavenges free radicals and suppresses lipid peroxidation in vitro, but these activities are very weak, suggesting that the antioxidant effect of ropinirole observed in vitro may be a minor component of its neuroprotective effect in vivo. Administration of ropinirole for 7 days increased GSH, catalase and SOD activities in the striatum and protected striatal dopaminergic neurons against 6-hydroxydopamine (6-OHDA) in mice. Pre-treatment with sulpiride prevented ropinirole from enhancing striatal GSH, catalase and SOD activities and abolished the protection of dopaminergic neurons against 6-OHDA. Our findings indicate that activation of GSH, catalase and SOD mediated via DA D2 receptors may be the principal mechanism of neuroprotection by ropinirole.     

Organization of dopamine D1 and D2 receptors in human striatum: receptor autoradiographic studies in Huntington's disease and schizophrenia

The technique of quantitative autoradiography was used to examine the effects of Huntington's disease (HD) and schizophrenia on the organization of striatal dopamine (DA) D1 and D2 receptors. Whereas the striatum of HD cases showed a reduction in the density of D1 ([3H]SCH 23390) and D2 ([3H]spiroperidol) receptors, the patterning of D2 receptor loss did not match that of the D1 receptor loss. The HD loss of D1 D1 receptors (65%) is far greater than the loss of D2 receptors (28%). Whereas there was a dorsal-ventral gradient of effect on both receptor subtypes, the effects of HD on D2 receptors in the ventral putamen (PUT) and nucleus accumben septi (NAS) were minimal. Similarly, muscarinic M1 and M2 receptors demonstrate different patterns of alteration in HD. The M2 subtype, labeled with [3H]N-methylscopolamine (in the presence of excess pirenzepine to occlude M1 sites), was depleted far more than the M1 receptor subtype, labeled with [3H]pirenzepine. Although the effects of HD on [3H]mazindol labeling of DA terminals were more heterogeneous, there appeared to be a relative preservation of this afferent input to the striatum of the HD cases. In the schizophrenic cases, our autoradiographic studies confirm previous reports of an elevation of D2 receptor density in the striata of many schizophrenics. This increase was evident even though two of the three cases were known to have not been treated with neuroleptics, and the third case may also have been drug naive. However, the increase was far greater in the NAS (164%) and ventral PUT (173%) than more dorsally in the striatum (68%). The density of D1 receptors and DA terminals labeled with [3H]mazindol in the striatum of schizophrenics was not significantly different from that of control cases. Thus in both HD and schizophrenia, the ratio of D2/D1 receptors is altered in favor of the D2 population, particularly in the NAS.     

Dopamine receptor agonists reverse behavioral abnormalities of alpha-synuclein transgenic mouse, a new model of Parkinson's disease

Parkinson's disease (PD) is characterized by loss of nigral dopaminergic (DAergic) neurons and presence of Lewy bodies, whose major component is alpha-synuclein. We had previously generated transgenic mice termed Syn130m that express truncated human alpha-synuclein (amino acid residues 1-130) in DAergic neurons. Syn130m mice showed significant loss of DAergic neurons in the substantia nigra pars compacta. Subsequently, the striatal DA level and spontaneous locomotor activity of the mice were decreased significantly. In the present study, we investigated behavioral responses of Syn130m mice to L-DOPA and DA receptor agonists. Administration of L-DOPA dose dependently ameliorated the reduction of spontaneous locomotor activity of Syn130m mice. Similarly, D(2) agonists, quinpirole and talipexole, and a D1/D2 agonist, pergolide, were effective against the reduction. Syn130m mice also showed significant reduction in exploratory behavior compared with non-Tg littermates when they were placed in a novel environment, but this abnormality was ameliorated by treatment with pergolide. These results strongly suggest that the behavioral abnormalities of Syn130m mice were caused by low striatal DA content. On the other hand, the expression of postsynaptic D(2)-like receptors (DRD2) in the striatum was not increased in Syn130m mice, although the low striatal DA level is known to induce compensatory expression of DRD2. Because the abnormalities could be rectified by treatment with DA receptor agonists, it is likely that Syn130m mice provide a useful tool to explore therapeutic possibilities for PD as a new animal model of the disease.     

Effects of repeated and acute aripiprazole or haloperidol treatment on dopamine synthesis in the dorsal striatum of young rats: comparison to adult rats

The purpose of the present study was to determine whether repeated treatment with the D2 partial agonist aripiprazole or the D2 antagonist haloperidol alters dopamine (DA) synthesis characteristics in the dorsal striatum of young rats. To this end, rats received a daily pretreatment regimen of aripiprazole or haloperidol on postnatal days (PD) 10–20 and were tested 24 or 72 h later after an acute injection of vehicle, aripiprazole, haloperidol, or quinpirole (a D2 agonist). For comparison purposes, adult rats were pretreated with an 11-day regimen of saline or haloperidol on PD 70–80 and DA synthesis was measured after acute drug treatment on PD 83. Dorsal striatal DA synthesis was determined by measuring l-dihydroxyphenylalanine accumulation after NSD-1015 treatment. In a separate experiment, the ability of repeated drug treatment to up-regulate dorsal striatal D2 receptors was assessed in young and adult rats 72 h after drug discontinuation. The major findings of this study were that: (a) acute treatment with haloperidol and aripiprazole increased DA synthesis while quinpirole reduced it; (b) pretreatment with haloperidol and aripiprazole blunted the synthesis-modulating effects of acutely administered dopaminergic drugs; and (c) DA synthesis of young and adult rats was affected in a qualitatively similar manner by DA agonist, antagonist, and partial agonist drugs. In conclusion, results from the present study suggest that synthesis-modulating autoreceptors in the dorsal striatum are functionally mature by the end of the preweanling period and DA synthesis declines to near basal levels during the course of repeated aripiprazole treatment.     

Striatal dysfunctions associated with mitochondrial DNA damage in dopaminergic neurons in a mouse model of Parkinson's disease

Parkinson's disease (PD) is one of the most common progressive neurodegenerative disorders, characterized by resting tremor, rigidity, bradykinesia, and postural instability. These symptoms are associated with massive loss of tyrosine hydroxylase-positive neurons in the substantia nigra (SN) causing an estimated 70-80% depletion of dopamine (DA) in the striatum, where their projections are located. Although the etiology of PD is unknown, mitochondrial dysfunctions have been associated with the disease pathophysiology. We used a mouse model expressing a mitochondria-targeted restriction enzyme, PstI or mito-PstI, to damage mitochondrial DNA (mtDNA) in dopaminergic neurons. The expression of mito-PstI induces double-strand breaks in the mtDNA, leading to an oxidative phosphorylation deficiency, mostly due to mtDNA depletion. Taking advantage of a dopamine transporter (DAT) promoter-driven tetracycline transactivator protein (tTA), we expressed mito-PstI exclusively in dopaminergic neurons, creating a novel PD transgenic mouse model (PD-mito-PstI mouse). These mice recapitulate most of the major features of PD: they have a motor phenotype that is reversible with l-DOPA treatment, a progressive neurodegeneration of the SN dopaminergic population, and striatal DA depletion. Our results also showed that behavioral phenotypes in PD-mito-PstI mice were associated with striatal dysfunctions preceding SN loss of tyrosine hydroxylase-positive neurons and that other neurotransmitter systems [noradrenaline (NE) and serotonin (5-HT)] were increased after the disruption of DA neurons, potentially as a compensatory mechanism. This transgenic mouse model provides a novel model to study the role of mitochondrial defects in the axonal projections of the striatum in the pathophysiology of PD.     

Ovariectomy and subchronic estradiol-17 beta administration decrease dopamine D1 and D2 receptors in rat striatum

Ovariectomy and subchronic estradiol-17β cause a down-regulation of dopamine D₁ and, to a lesser extent, D₂ receptors in rat striatum. An intracellular mechanism mediates the DA receptor down-regulation, as various estrogens do not interact with membrane-bound DA receptors in vitro. A common denominator, e.g. enhanced DA turnover, is suggested to mediate the estradiol-induced DA receptor down-regulation. Ovarian factors other than estradiol are additionally proposed to be involved in the regulation of striatal DA receptors.