Tyrosine hydroxylase and dopamine transporter expression in residual dopaminergic neurons: potential contributors to spontaneous recovery from experimental Parkinsonism.

1-Methyl-4-phenyl-1,2,3,6-tetrahyrdropyridine (MPTP)-exposed cats develop severe Parkinsonism that spontaneously resolves in 4-6 weeks. The present study examined the extent to which compensatory changes in tyrosine hydroxylase (TH) and dopamine transporter (DAT) gene and protein expression may underlie this behavioral recovery. In normal cats, TH and DAT protein levels were higher in the dorsal vs. ventral striatum. Expression of DAT and TH mRNA was higher in substantia nigra pars compacta (SNc) than in the ventral tegmental area (VTA). In symptomatic parkinsonian animals, DAT and TH protein levels were significantly decreased in all striatal areas studied. TH and DAT mRNA expression in residual SNc neurons were decreased a mean 32% and 38%, respectively. DAT gene expression in residual VTA neurons in symptomatic animals was decreased 30% whereas TH gene expression was unaffected. In spontaneously recovered cats, TH protein levels were significantly higher than the levels in symptomatic cats only in the ventral striatum, whereas no increase in DAT protein levels were observed in any striatal area. Residual neurons in most ventral mesencephalic regions of recovered cats had increased TH mRNA expression but not increased DAT gene expression, compared with symptomatic animals. Thus, increased TH protein and mRNA and suppression of DAT protein and mRNA expression in the striatum and ventral mesencephalon were associated with functional recovery from MPTP-induced parkinsonism.

Differential binding of an SRF/NK-2/MEF2 transcription factor complex in normal versus neoplastic smooth muscle tissues.

The malignant potential of smooth muscle tumors correlates strongly with the disappearance of gamma-smooth muscle isoactin, a lineage-specific marker of smooth muscle development. In this paper, we identify a 36-base pair regulatory motif containing an AT-rich domain, CArG box, and a non-canonical NK-2 homeodomain-binding site that has the capacity to regulate smooth muscle-specific gene expression in cultured intestinal smooth muscle cells. Serum-response factor associates with an NK-2 transcription factor via protein-protein interactions and binds to the core CArG box element. Our studies suggest that the NK-2 transcription factor that associates with serum-response factor during smooth muscle differentiation is Nkx2-3. Myocyte-specific enhancer factor 2 binding to this regulatory complex was also observed but limited to uterine smooth muscle tissues. Smooth muscle neoplasms displayed altered transcription factor binding when compared with normal myometrium. Differential nuclear accessibility of serum-response factor protein during smooth muscle differentiation and neoplastic transformation was also observed. Thus, we have identified a unique regulatory complex whose differential binding properties and nuclear accessibility are associated with modulating gamma-smooth muscle isoactin-specific gene expression in both normal and neoplastic tissues.

Changes in striatal dopamine D3 receptor regulation during expression of and recovery from MPTP-induced parkinsonism.

Striatal dopamine (DA) D3 receptor density (measured by quantitative receptor autoradiography) and mRNA expression (measured by reverse transcriptase-polymerase chain reaction) were analyzed in cats symptomatic for and recovered from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism. In symptomatic cats, D3 receptor density was significantly decreased in all regions of the caudate nucleus (CD) (66--77%), the nucleus accumbens (NACC) (52--83%) and the islands of calleja (IC) (67%), all of which returned to normal values in recovered cats. In contrast, D3 receptor mRNA expression was slightly elevated in symptomatic cats, and significantly increased above normal in recovered cats (45% increase in the CD and 91% in the NACC). Thus, reduction of parkinsonian signs was related to normalization of striatal D3 receptor number. These alterations in D3 receptor expression may play an important role in the recovery process observed in this model of parkinsonism.

Effects of chronic alcohol ingestion on the mesostriatal dopamine system in the rat.

The effects of chronic alcohol use on the mesostriatal dopamine (DA) system remain relatively unknown. The aim of the present study was to assess multiple measures of the status of the mesostriatal DA system in rats chronically fed an alcohol diet for approximately 1 year. Tissue levels of DA and its metabolite, 3,4-dihydroxyphenylacetic acid, were significantly decreased in both the dorsal striatum (34 and 33%, respectively) and ventral striatum (33 and 36%, respectively) in alcohol-fed rats compared to pair-fed matched controls. Western blotting revealed a mean 20% decrease in tyrosine hydroxylase protein levels in the dorsal and ventral striatum of alcohol-fed animals while dopamine transporter protein levels from the same animals were significantly increased compared to controls (mean 60% increase for the dorsal and ventral striatum). The present results demonstrate significant alterations in the mesostriatal DA system after 1 year of chronic alcohol use. It is possible that the observed changes in DA synthesis and re-uptake measures result in altered intracellular and extracellular DA levels, perhaps contributing to the addictive properties of alcohol.

Changes in striatal dopamine D(2) receptors in relation to expression of and recovery from experimental parkinsonism.

Changes in dopamine D(2) receptor number in 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-treated cats during various stages of experimental parkinsonism were examined. In the normal adult cat, D(2) receptors were expressed throughout the striatum. In symptomatic cats (assessed 7 days after the last MPTP administration), there was a slight elevation of D(2) receptors in all striatal regions. At 2 weeks after MPTP (animals still grossly symptomatic), D(2) receptor number was increased 60-75% above normal. At 3 weeks after MPTP (partial functional recovery), D(2) receptor number remained elevated at a level slightly less than that observed at 2 weeks. At 6 weeks after MPTP (full functional recovery), D(2) receptor levels were back to normal. Changes in D(2) receptor mRNA expression in the striatum essentially mirrored the changes in receptor number. Increases in D(2) receptor number and mRNA expression did not coincide with the onset of parkinsonian signs and peaked after the parkinsonism was established. Permanent reduction of parkinsonian signs corresponded to normalization of D(2) receptor number.

Regional differences in striatal dopamine uptake and release associated with recovery from MPTP-induced parkinsonism: an in vivo electrochemical study.

This study directly assessed striatal dopamine (DA) uptake rates and peak release in response to KCl in normal, symptomatic, and recovered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated cats using in vivo electrochemistry. DA uptake rates measured after direct application of known concentrations of DA to the striatum were slowed significantly in both dorsal and ventral striatum in symptomatic cats compared with rates recorded in normal animals. DA uptake rates remained significantly slowed in recovered cats and were not significantly different from the rates recorded in symptomatic animals. In symptomatic cats, both DA uptake rates and the signal recorded in response to KCl stimulation were significantly decreased from normal in all dorsal and ventral striatal regions sampled. Reduction/oxidation (redox) ratios recorded in response to KCl stimulation suggested DA to be the predominant electroactive species. In spontaneously recovered MPTP-treated cats, recordings in the ventral striatum subsequent to KCl stimulation again suggested DA to be the predominant electroactive species released, and peak levels were significantly higher than those recorded in symptomatic animals. In the dorsal striatum of recovered cats, redox ratios recorded subsequent to KCl stimulation suggested serotonin rather than DA to be the predominant electroactive species released. Peak levels of release in the dorsal striatum were not significantly greater than those recorded in symptomatic animals. These results suggest that in spontaneously recovered MPTP-treated cats, there is partial recovery of ventral striatal DAergic terminals, persistent loss of dorsal striatal DAergic terminals, and a down-regulation of DA transporter number/function throughout the striatum. These processes may contribute to volume transmission of DA in the striatum and promote functional recovery.

Differential recovery of sensorimotor function in GM1 ganglioside-treated vs. spontaneously recovered MPTP-treated cats: partial striatal dopaminergic reinnervation vs. neurochemical compensation.

Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to cats results in a parkinsonian syndrome characterized by rigidity, akinesia, bradykinesia, decreased response to external sensory stimuli and depletion of nigrostriatal dopamine. Cats spontaneously recover gross sensorimotor functions despite little recovery of the dopaminergic innervation of the striatum. In contrast, GM1 ganglioside administration accelerates gross behavioral recovery and causes an increased dopaminergic innervation of the striatum. This study examined whether these two recovery conditions are characterized by different degrees of functional recovery. Cats were trained to perform a sensorimotor reaching task prior to MPTP exposure and were then re-tested on the task 6 weeks later after spontaneously recovering gross motor functioning or after 6 weeks of GM1 treatment. Gross motor recovery was similar in both groups. However, the spontaneously recovered cats had significant difficulty in performing the task while GM1-treated cats performed normally. GM1-treated cats also had significant increases in striatal [3H]mazindol binding compared to spontaneously recovered cats. These results suggest that while gross motor functions may improve to a similar extent with spontaneous and GM1-induced recovery from experimental parkinsonism, complex sensorimotor behavior recovers to different extents under the different recovery conditions. More complete behavioral recovery may depend upon at least a partial recovery of striatal dopaminergic terminals rather than neurochemical compensation.

Effects of GM1 ganglioside treatment on dopamine innervation of the striatum of MPTP-treated mice.

GM1 ganglioside has been shown to stimulate repair of the nigrostriatal dopamine system after injury. This has been particularly evident in the mouse MPTP model of Parkinsonism. Systemic administration of GM1 has been shown to increase striatal dopamine levels and lead to increased density of substantia nigra pars compacta neurons after MPTP administration versus mice treated with MPTP and saline. The purpose of the present study was to assess regional changes in dopaminergic innervation of the striatum of mice treated with MPTP then GM1. Studies consisted of [3H] mazindol binding of dopamine uptake sites, postmortem striatal tissue dopamine levels, and peak dopamine release in response to KCl stimulation measured in vivo. Results showed that measures of dopamine innervation were significantly increased in most striatal areas in MPTP+GM1-treated mice compared to MPTP+saline-treated controls. The results indicate that GM1 treatment increases measures of dopaminergic innervation after an MPTP lesion, possibly through sprouting of new terminals or increased dopamine production and release from remaining terminals.

Parkinson's disease: improved function with GM1 ganglioside treatment in a randomized placebo-controlled study.

BACKGROUND/OBJECTIVE: Studies in animal models of Parkinson's disease (PD) suggest that GM1 ganglioside treatment can restore neurologic and dopaminergic function. In view of positive preclinical findings and the results of a previous open-label study demonstrating efficacy of GM1 in PD patients, this study compared effects of GM1 ganglioside and placebo on motor functions in PD patients. METHODS: Forty-five patients with mild to moderate PD were studied. The primary efficacy measure was change in the Unified Parkinson's Disease Rating Scale (UPDRS) motor score. After three independent baseline assessments, patients received IV infusion of the test drug (1,000 mg GM1 or placebo) and then self-administered either GM1 or placebo twice daily (200 mg/day, subcutaneously) for 16 weeks. Patients were examined during monthly follow-up visits. RESULTS: There was a significant difference between groups in UPDRS motor scores at 16 weeks (p=0.0001). The activities of daily living portion of the UPDRS (off-period assessment) also showed a significant effect in favor of the GM1-treated patients (p=0.04). GM1-treated patients also had significantly greater mean improvements than placebo-treated patients in performance of timed motor tests including tests of arm, hand, and foot movements, and walking. GM1 was well tolerated and no serious adverse events were reported. CONCLUSIONS: This study demonstrates that GM1 ganglioside treatment enhances neurologic function significantly in PD patients. Further study is warranted to evaluate long-term effects of GM1 in PD patients and to elucidate further the mechanisms underlying patient improvements.

The effects of L-deprenyl treatment, alone and combined with GM1 ganglioside, on striatal dopamine content and substantia nigra pars compacta neurons.

The present study examined the effects of GM1 ganglioside and the monoamine oxidase B (MAO-B) inhibitor L-deprenyl, alone and in combination, on striatal dopamine (DA) and DOPAC levels, and the density of tyrosine hydroxylase (TH) positive neurons in the substantia nigra pars compacta (SNc) of C57bl/6J mice following MPTP administration (20 mg/kg, s.c., twice daily for 5 days). GM1 treatment (30 mg/kg, i.p., daily for 3 weeks, beginning 24 h after the last MPTP injection) partially restored striatal DA levels and rescued SNc neurons. A high dose of L-deprenyl, inhibiting MAO-B activity, (10 mg/kg, i.p. every other day for 3 weeks beginning 3 days after the last MPTP injection) increased striatal DA content, but did not rescue TH-positive SNc neurons. A low dose of L-deprenyl (0.01 mg/kg, i.p. every other day for 3 weeks beginning 3 days after the last MPTP injection) had no effect on either striatal neurochemistry or the rescue of SNc TH-positive neurons. Co-administration of GM1 and high dose L-deprenyl caused a synergistic increase in striatal DA levels, above that obtained with either GM1 or high dose L-deprenyl alone. Co-administration of GM1 and low dose L-deprenyl was not only not synergistic, but caused GM1s effects to be antagonized. The results do not confirm previous findings that low dose L-deprenyl administration in vivo after MPTP can rescue SNc neurons. Given GM1's potential as an adjunct to present anti-parkinsonian medications which include L-deprenyl, it will be important to further investigate the interactions between these two potential therapies.

Regionally specific effects of haloperidol and clozapine on dopamine reuptake in the striatum.

This study examined the extent to which local application of the typical neuroleptic haloperidol (HAL) or the atypical neuroleptic clozapine (CLOZ) influences dopamine (DA) transporter function in the dorsal and ventral striatum. Using urethane-anesthetized rats, DA was pressure ejected and monitored with in vivo electrochemistry, into the dorsal and ventral striatum to establish regional baseline DA reuptake rates. Haloperidol or CLOZ (10 microM) was then applied, followed 5 min later by DA, in order to assess drug effects on DA reuptake rates. Haloperidol caused a 62% decrease in dorsal striatal DA reuptake rates while CLOZ had no effect on reuptake rates. Neither neuroleptic significantly altered DA reuptake rates in the ventral striatum. It is possible that HAL-induced decrease in DA reuptake in the sensorimotor striatum could be related to the motor side effect profile of this neuroleptic. Additional studies with other typical and atypical neuroleptics are needed to further evaluate the relationship between slowing of DA reuptake and the side effect potential of neuroleptic agents.

Alterations in intralaminar and motor thalamic physiology following nigrostriatal dopamine depletion.

The response of central median/central lateral (CM/CL) and ventral anterior/ventral lateral (VA/VL) thalamic neurons to tactile sensory stimulation of the face and electrical stimulation of the striatum was assessed in awake cats before and after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure. When cats exhibited Parkinson-like motor deficits, there was a significant decrease in the number of CM/CL and VA/VL neurons responsive to tactile stimulation of the face. Mean spontaneous firing rates decreased by 58% in the CM/CL nuclei, 65% in the VA, and 49% in the VL. The number of thalamic neurons responding to electrical stimulation of the striatum was also significantly decreased in parkinsonian animals. Approximately 6 weeks after MPTP exposure, when cats had spontaneously recovered gross motor function, thalamic responses to peripheral sensory stimulation, electrical stimulation of the CD, and spontaneous activity rates, returned to approximately normal levels in all thalamic areas studied. These findings support the concept that abnormalities in the transmission of information through the thalamus, and in particular, a decrease in sensory responsiveness in intralaminar and motor thalamic regions subsequent to nigrostriatal dopamine depletion, may contribute to the generation of Parkinson-like motor and sensorimotor deficits.

Alterations in pallidal neuronal responses to peripheral sensory and striatal stimulation in symptomatic and recovered parkinsonian cats.

The spontaneous activity, responses to peripheral sensory and ipsilateral caudate nucleus stimulation of globus pallidus (GP) and entopeduncular nucleus (ENTO) neurons were studied in cats while normal, symptomatic for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced parkinsonism, and when spontaneously recovered from gross parkinsonian motor deficits. Administration of MPTP resulted in parkinsonian motor symptoms that spontaneously recovered approximately 4-6 weeks after the MPTP administration. Post-mortem dopamine levels in recovered animals was approximately 95% below levels previously measured in normal animals. In symptomatic animals, the mean spontaneous firing rate for GP units was decreased by 50% and increased by 55% for ENTO units recorded. Spontaneous firing rates for GP and ENTO units in recovered cats were not significantly different from those observed in normal cats. In normal cats, 31.4% of GP and 29% of ENTO units tested responded to tactile stimulation of the face. Only 12.2% of GP and 13% of ENTO units responded to such stimulation in parkinsonian animals while the responses were generally less specific (larger receptive fields, more bilateral receptive fields, and more responses to multiple stimulation types) than normal. In recovered cats GP and ENTO responses resembled those observed in normal cats. There was no difference in the overall percentage of pallidal units responding to striatal stimulation across the 3 experimental conditions. There was, however, an increase in the percentage of units responding with complex response sequences (i.e. decrease in activity followed by an increase in activity) in symptomatic animals as compared to normal and recovered animals. The results suggest that loss of striatal dopamine in parkinsonian animals has profound effects on the sensory responsiveness of GP and ENTO neurons and that these effects coincide with the appearance of and recovery from parkinsonian motor deficits. These data further support the notion that sensory information processing by the basal ganglia may play an important role in influencing motor output.

GM1 ganglioside treatment of Parkinson's disease: an open pilot study of safety and efficacy.

We performed an open-label study testing the effects of GM1 ganglioside on 10 Parkinson's disease (PD) patients. Patients received 1,000 mg of GM1 by IV infusion after the last of three baseline functional assessments. Patients then self-administered GM1 at a dose of 200 mg/d, by subcutaneous injection, for 18 weeks. Under these conditions, GM1 ganglioside proved to be safe and well tolerated. There were no serious adverse events and none of the patients developed elevated anti-GM1 antibody titers. Improvements on at least some functional measures were present in most patients, beginning after 4 to 8 weeks of GM1 treatment. When functional improvements occurred, they lasted for the duration of the study. These results suggest that GM1 ganglioside is well tolerated and may be a useful adjunct to the treatment of PD, and that a double-blind, placebo-controlled study is now warranted.

Repeated exposure to MPTP does not produce a permanent movement disorder in cats recovered from MPTP-induced parkinsonism.

The effects of additional MPTP injections on striatal neurochemistry and tyrosine hydroxylase positive cell populations within the ventral mesencephalon in cats recovered from parkinson-like motor deficits resulting from previous MPTP administration was studied. A second or third series of MPTP injections in recovered cats initially reinstated parkinson-like motor deficits. All cats again recovered normalized motor function two to three weeks after MPTP administration. Neurochemical analysis of striatal tissue showed no or only minor differences in dopamine and metabolite levels within most striatal regions sampled between cats which received single or multiple sets of MPTP injections. Cell count results showed no significant differences between the two MPTP conditions for the majority of the regions studied. These results suggest that the mechanisms responsible for motor recovery from MPTP intoxication in cats can be transiently disrupted by further exposure to MPTP and that cats do not develop a permanent parkinsonian syndrome from repeated MPTP exposure.

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 the 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 [125I]-epidepride to D2 receptors was observed in any region of the striatum in either symptomatic or recovered animals. [125I]-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 D1 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.

Volume transmission of dopamine over large distances may contribute to recovery from experimental parkinsonism.

Administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to cats results in a parkinsonian syndrome that spontaneously recovers by 6 weeks after induction. Striatal dopamine depletions in these animals are heterogenous with more extensive damage dorsolaterally than ventromedially. Measures of extracellular dopamine levels by in vivo microdialysis showed that dopamine released from a relatively preserved ventral striatal innervation can diffuse over a distance of 5.5 mm to 7.0 mm to the more extensively denervated dorsolateral striatum, where it may influence sensorimotor activities and contribute to functional recovery. Diffusion of dopamine through a large volume of striatal tissue was observed in cats 6 weeks after an MPTP-induced lesion and in normal cats with pharmacologically induced dopamine reuptake inhibition, but not in normal animals without reuptake inhibition. In cats recovered from MPTP-induced parkinsonism, a greater amount of dopamine was recovered from the extracellular fluid in the dorsolateral caudate following stimulated release of dopamine from the ventromedial striatum than after stimulated release locally in the dorsolateral caudate. These results suggest volume transmission of dopamine over large distances is possible and perhaps an important contributor to functional recovery from a large dopamine-depleting lesion. These results may also form the basis for understanding how limited reinnervation of the striatum by grafts or trophic factor therapies may lead to significant functional improvement.

Spontaneous functional recovery from parkinsonism is not due to reinnervation of the dorsal striatum by residual dopaminergic neurons.

Cats exposed to MPTP experience severe motor deficits that spontaneously recover after 4-6 weeks. This recovery occurs despite a persistent deficit (approximately 95%) in dorsal striatal DA levels. To determine whether residual DA neurons that previously did not innervate the dorsal caudate nucleus (CD) have innervated this area in recovered MPTP-treated animals, HRP was injected into the dorsal lateral and dorsal medial CD and the locations of retrogradely labeled neurons in ventral mesencephalon were mapped in normal and recovered MPTP-treated cats. Tyrosine hydroxylase (TH) positive cells were also counted in ventral mesencephalic DA-containing cell groups in normal, symptomatic, and recovered MPTP-treated cats. Results showed no difference in the pattern of HRP labeling in normal and recovered cats except for the loss of labeled substantia-nigra pars compacta (SNc) cells in MPTP-treated cats. Cell counts revealed no significant difference in the degree of TH-positive cell loss in all ventral mesencephalic areas studied in both symptomatic and recovered cats. The results suggest that spontaneous recovery of gross motor function in MPTP-treated cats is most likely not dependent upon reinnervation of the dorsal striatum from residual DAergic neurons.

Response of caudate neurons to stimulation of intrinsic and peripheral afferents in normal, symptomatic, and recovered MPTP-treated cats.

Cat caudate nucleus (CD) neurons were tested for changes in spontaneous activity, response to peripheral sensory stimuli (tactile, auditory, and visual), and electrical stimulation of monosynaptic afferents (pericruciate cortex and nucleus centralis lateralis) in normal cats and in the same cats after induction of and spontaneous recovery from parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). After normal baseline data were collected, cats were given MPTP (7.5 mg/kg, 5-7 d) to induce a parkinsonian syndrome consisting of rigidity, akinesia, and decreased orienting to sensory stimuli. During this symptomatic period, the mean spontaneous activity of CD units increased (6.20 spikes/sec vs 2.25 spikes/sec in normal cats). In these same animals, the percentage of units responding to peripheral sensory stimulation was significantly decreased (compared to normal) while the percentage of units responding to electrical stimulation of monosynaptic afferents increased. By 6 weeks after MPTP administration, cats had recovered gross motor and sensorimotor function and CD unit recordings were reinitiated. In functionally recovered animals, all electrophysiological measures returned to levels resembling those seen in normal animals. These data suggest that the processing of peripheral sensory information is an important part of basal ganglia function and that the sensory responsiveness of the CD may reflect the overall motor condition of the animal. The changes observed in the responsiveness of CD neurons to direct electrical stimulation of monosynaptic afferents may indicate that the defect in the processing of polysynaptic sensory information observed in the striatum in parkinsonian animals may be occurring, at least in part, extrastriatally.

Neurochemical evaluation of the striatum in symptomatic and recovered MPTP-treated cats.

Striatal neurochemistry and motor activity were assessed in cats treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and killed either when symptomatic for a Parkinson-like motor disorder or six weeks later, when showing significant motor recovery. The results of striatal neurochemical analyses showed distinct regional differences in susceptibility to MPTP-induced damage, with dorsal striatal regions generally more severely affected than ventral striatal regions. Symptomatic animals had more severe dopamine loss in all striatal regions than did recovered animals. The dorsal lateral caudate, the cat's sensorimotor striatum, had the largest dopamine depletion in the symptomatic animals (99%) and the least recovery in recovered animals (94% depletion). In contrast, the nucleus accumbens had a 94% dopamine depletion in symptomatic animals and only a 34% depletion in recovered animals. In addition to increases in dopamine levels and dopamine utilization in the striatum in recovered animals, significant increases in serotonin levels and serotonin utilization were also observed. Therefore, motor recovery may have been due to either or both of these neurochemical changes. The fact that the cat develops Parkinson-like motor symptoms but that they are not persistent may make this an interesting model in which to study the role of dopamine in motor function and to study compensatory mechanisms of the damaged dopamine system.