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PubMed2006

Role of catechol structure in the adsorption and transformation reactions of L-DOPA in soils.

3-(3',4'-Dihydroxyphenyl)-L-alanine (L-DOPA), which is synthesized in velvet bean (Mucuna pruriens), inhibits plant growth. The concentration of L-DOPA in soil is reduced by adsorption and transformation reactions, which can result in the reduction of its plant-growth-inhibitory activity. To determine which part of the L-DOPA structure is involved in the adsorption and soil transformation reactions, we compared the kinetics of L-DOPA disappearance in a volcanic ash soil with that of L-phenylalanine (3-phenyl-L-alanine) and L-tyrosine (3-(4'-hydroxyphenyl)-L-alanine), compounds that are similar in structure to L-DOPA but do not have a catechol (o-dihydroxybenzene) moiety. L-Phenylalanine and L-tyrosine were not adsorbed and transformed in the soil at equilibrium pH values between 4 and 7. These results suggest that the adsorption and transformation reactions of L-DOPA in the soil involve the catechol moiety and not the amino and carboxylic acid groups, which are common to all three compounds. Like L-DOPA, (+)-catechin, another allelochemical that contains a catechol moiety, underwent adsorption and soil transformation reactions. Thus, we concluded that the concentrations of allelochemicals bearing a catechol moiety in soils will decrease rapidly owing to adsorption and transformation reactions, and this decrease will be faster in soils with a high pH value or high adsorption ability. Owing to this decrease in concentration, allelopathic phenomena may not occur.

Adsorption↗
PubMed1987

Synthesis of 5-S-L-cysteinyl-glycine-L-dopa, a natural substrate for serum and melanocyte dipeptidase.

A method for synthesis of the phaeomelanin pigment intermediate compound 5-S-L-cysteinyl-glycine-L-dopa is presented. This thioether has been suggested as a precursor to 5-S-L-cysteinyl-L-dopa, the key intermediate compound in phaeomelanin pigment formation. 5-S-Glutathione-L-dopa is first synthesized by the tyrosinase-catalyzed reaction between L-dopa and glutathione. The 5-S-glutathione-L-dopa is then converted to 5-S-L-cysteinyl-glycine-L-dopa using the enzyme gamma-glutamyl transpeptidase. The compound thus obtained was suitable as a substrate for melanoma cell and serum dipeptidase which converts the compound into 5-S-L-cysteinyl-L-dopa and glycine. The optimum pH for the dipeptidase from melanoma cells was 7.5 and the Km was 1.2 mM.

Chromatography, High Pressure Liquid↗
PubMed1982

Chronic L-DOPA-pretreatment of rats: an electrophysiological and biochemical study in the basal ganglia.

Treatment of rats with L-DOPA (251.25 mg as the methyl ester HCl/kg) plus benserazide (B, 50 mg/kg) (L-DOPA+B), twice daily (i.p.) for 5 days or 12 days resulted in the dopamine (DA) neurons of the substantia nigra pars compacta becoming subsensitive to the rate-depressing effects of D-amphetamine (i.v.) 16 to 24 h after the last chronic drug dose. In contrast, pretreated rats were significantly less sensitive than control rats to the rate depressant effects of apomorphine (i.v.) after 12, but not 5 days of L-DOPA+B-pretreatment. After 5, but not 12 days of L-DOPA+B-pretreatment, a significant increase in the number of spontaneously active DA neurons was noted in the substantia nigra pars compacta. Caudate tyrosine hydroxylase was examined and a significant increase in apparent Vmax was noted after 5 days of L-DOPA+B, with no apparent change being noted in Km for cofactor. At this time, no change was noted in caudate DA or HVA concentrations. Several distinct processes may be occurring in response to the L-DOPA+B-pretreatment: (1) the DA autoreceptors located on cell bodies in the substantia nigra have become subsensitive after 12 days of L-DOPA+B-pretreatment; (2) the subsensitivity to D-amphetamine seen after both chronic schedules is probably unrelated to the subsensitive DA autoreceptors and may depend upon homeostatic alterations in neurotransmitter systems other than those utilising DA; (3) the activation of tyrosine hydroxylase may be a reflection of the increase in the number of spontaneously active units.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1986

The effects of L-DOPA on regional cerebral glucose utilization in rats with unilateral lesions of the substantia nigra.

Using [14C]2-deoxyglucose autoradiography, we have studied the effects of systemically administered L-DOPA (10, 25 and 50 mg/kg s.c.) on regional cerebral glucose utilization (RCGU) in rats with unilateral substantia nigra lesions. In comparison with lesioned rats treated with saline, the lesioned-DOPA treated rats demonstrated contralateral turning and RCGU changes in both ipsilateral and contralateral brain regions. L-DOPA treatment markedly increased RCGU in the ipsilateral entopeduncular nucleus (EP) and substantia nigra pars reticulata (SNr), cell groups that receive direct striatal input and function as major outflow pathways of corpus striatal activity. In contrast, L-DOPA did not alter RCGU in the globus pallidus (GP), supporting the thesis that dopamine (DA) has different effects on striatal outflow to the GP compared with outflow to both the EP and SNr. Moderate RCGU increases were observed in the ipsilateral subthalamic nucleus (STN), lateral midbrain reticular formation (LMRF), and deep layers of the superior colliculus (DLSC), all regions which receive direct projections from the GP, EP or SNr. L-DOPA decreased RCGU in the ipsilateral lateral habenular nucleus (LHN) and increased RCGU in the contralateral LHN, changes that we suggest are mediated via altered neuronal activity in the striatum and EP. The results suggest that systemically administered L-DOPA, after conversion to DA in the brain, interacts with supersensitive DA receptors in the DA-depleted striatum to selectively activate efferent pathways. Furthermore, the data suggest that the LMRF and DLSC are functionally activated during L-DOPA induced turning and support the hypothesis that nigroreticular and nigrocollicular projections are of physiologic significance in the expression of striatal activity.

Animals↗
PubMed1989

Progesterone enhances L-dopa-stimulated dopamine release from the caudate nucleus of freely behaving ovariectomized-estrogen-primed rats.

In the present experiment we examined the effect of progesterone upon dopamine (DA) release induced by a direct infusion of unlabeled L-dihydroxyphenylalanine (L-DOPA) into the caudate nucleus of freely behaving rats. Ovariectomized rats were implanted with a push-pull cannula directed at the caudate nucleus and subjected to perfusion under 3 different hormonal conditions: (1) following 4 days of treatment with estradiol benzoate (EB), (2) following 4 days of treatment with estradiol benzoate plus progesterone at 4-6 h prior to perfusion (EB + P-4-6 h) and (3) following 4 days of treatment with estradiol benzoate plus progesterone at 28 h prior to perfusion (EB + P-28 h). During each perfusion session and under each of the 3 hormonal treatment conditions, L-DOPA was infused through the push side of the cannula. Three increasing doses of L-DOPA (10(-6), 10(-5) and 10(-4) M) were infused with a 45-75 min interval between infusions. Regardless of hormonal treatment condition, a clear dose-response increase in DA and 3,4-dihydroxyphenylacetic acid (DOPAC), but not 5-HIAA, output was observed in response to the increasing doses of L-DOPA infusion. For each of the 3 doses of L-DOPA, maximal DA output was observed for animals tested under the EB + P-4-6 h hormonal condition, with statistically significant differences in the areas under the L-DOPA-stimulated DA response curves obtained following the 10(-6) and 10(-5) M doses of L-DOPA infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Preparation and characterization of a specific antibody for the immunohistochemical detection of L-dopa in paraformaldehyde-fixed rodent brains.

A rat polyclonal antiserum has been obtained after coupling of L-3,4-dihydroxyphenylalanine (L-DOPA) to larger proteins using a low concentration of glutaraldehyde. The antiserum was tested for its affinity and specificity using an enzyme-linked-immunosorbent-assay (ELISA). From competition experiments, the most immunoreactive compound was found to be the non-reduced L-DOPA conjugate. Our specific L-DOPA antiserum enables us to visualize L-DOPA molecule on brain of guinea pigs and rats. We examined the immunohistochemical distribution of the polyclonal L-DOPA antiserum after the fixation of brains with a mixture of paraformaldehyde and picric acid. The presence of L-DOPA-immunoreactive (IR) neurons and fibers was described in the posterior, dorsal and periventricular hypothalamic areas and in the arcuate nucleus. Finally, the distribution of L-DOPA-IR cells was compared to that of tyrosine hydroxylase (TH)-IR cells, by means of a double staining procedure. The presence of two populations of TH-IR cells (TH-positive/L-DOPA-negative and TH-positive/L-DOPA-positive cells) was described in the dorsal part of the hypothalamus.

Animals↗
PubMed1995

Sympathectomy does not modify the levels of dopa or dopamine in the rat dorsal root ganglion.

In the present study we report on the levels of dihydroxyphenylalanine (DOPA), dopamine and their metabolites, 3-O-methyl-DOPA, homovanillic acid and dihydroxyphenylacetic acid, in the dorsal root ganglion (DRG) where dopaminergic sensory neurons have recently been identified. HPLC with electrochemical detection was used. Chemical sympathectomy, induced by daily injection of 30 mg/kg/sc of guanethidine over 4 days, did not modify these levels. DOPA, dopamine and their metabolites were also detected in the dorsal root in both intact and sympathectomized rats. The present results show that in the DRG, DOPA and dopamine do not derive from sympathetic nerves, and agree with previous reports suggesting that there is a peripheral dopaminergic sensory innervation. In addition the identification of 3-O-methylDOPA, the extraneuronal metabolite of DOPA is not only the precursor of dopamine in the DRG but may be released from DRG cells. The high 3-O-methyl-DOPA/DOPA ratio found in the DRG and the dorsal root suggests that DOPA could play a role as neurotransmitter or modulator in the peripheral sensory innervation, as it has been proposed for the central nervous system and the sympathetic system.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1995

Aromatic L-amino acid decarboxylase immunoreactive cells in the rat striatum: a possible site for the conversion of exogenous L-DOPA to dopamine.

The efficacy of L-dihydroxyphenylalanine (L-DOPA) in ameliorating the symptoms of Parkinson's disease (PD) is attributed to its conversion to dopamine (DA) by the enzyme aromatic L-amino-acid decarboxylase (AADC) in the striatum. Although the site of this conversion in the DA-denervated striatum has yet to be identified, it has been proposed that L-DOPA could be converted to DA at non-dopaminergic sites containing AADC. In the present study, we used immunocytochemical techniques to examine the localization of AADC and DA in the striatum of rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal dopaminergic projection. In the DA-denervated striatum, we observed AADC-immunoreactive (-IR) cells with morphological characteristics similar to a class of small aspiny interneuron. Although usually obscured by a dense plexus of AADC-IR fibers, these cells could also occasionally be detected in the intact striatum. Acute administration of L-DOPA to DA-denervated animals elicited contralateral rotational behavior as well as a pronounced c-fos protein immunoreactivity in the striatum ipsilateral to the lesion. Following acute administration of L-DOPA, but not after acute saline, DA-IR cells were detected in the denervated striatum. These DA-IR cells are similar in morphology and were found in the same location as the AADC-IR cells. These results strongly suggest the existence of a class of AADC-containing striatal cells that can form DA from exogenous L-DOPA in the rat. In the DA deafferented striatum, DA produced by these cells from exogenous L-DOPA could be released to exert physiological effects on DA receptive tissue. It is possible that similar cells could contribute to the efficacy of L-DOPA in the treatment of Parkinson's disease.

Animals↗
PubMed1996

Elevated striatal dopamine levels following administration of D-DOPA and its alpha-keto acid metabolite DHPPA: behavioral and physiological studies in vivo in the rat.

The D stereoisomer of dihydroxyphenylalanine (D-DOPA) and its alpha-keto acid metabolite 3,4-dihydroxyphenylpyruvic acid (DHPPA) when infused into the striatum, significantly increased in vivo extracellular dopamine levels. Following D-DOPA administration, the cumulative increase in dopamine levels was 30% of the increase following L-DOPA: following DHPPA it was 11% that of L-DOPA. Rats with unilateral 6-hydroxydopamine-induced lesions of the substantia nigra demonstrated brisk contralateral turning following each compound. The turning, however, was delayed by 10-20 min and total turning was 40% less following D-DOPA and 57% less following DHPPA than it was following L-DOPA. These data indicate that exogenously administered D-DOPA can be metabolized in vivo within the brain to dopamine and suggest this may occur via a transamination pathway in which DHPPA is an intermediary metabolite. The possible relevance of these findings to the treatment of Parkinson's disease is discussed.

Animals↗
PubMed1996

Dopaminergic transplants suppress L-DOPA-induced Fos expression in the dopamine-depleted striatum in a rat model of Parkinson's disease.

We examined the effects of MK-801, a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, and fetal ventral mesencephalic (VM) transplants on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced Fos protein expression in the dopamine (DA)-depleted striatum. Unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway were produced in young adult female rats and grafting was performed 3 weeks later. Methamphetamine-induced rotational behavior recovered significantly on the 4th week after grafting. Immunohistochemical examinations of c-Fos and tyrosine hydroxylase (TH) were performed 3-4 months after grafting. L-DOPA (100 mg/kg, i.p.) markedly induced Fos-like immunoreactivity (FLI) in the DA-depleted striatum. Pretreatment with a large dose of MK-801 (3-4.5 mg/kg, i.p.) dose-dependently suppressed L-DOPA-induced FLI in the striatum. The stimulatory effect of L-DOPA on c-Fos expression observed within the lesioned striatum was suppressed by fetal VM transplants. It seemed that the graft-induced effect on FLI extended over a considerably larger area than that covered by the graft-derived TH-immunoreactive innervation. Taken together, these findings suggest that glutamatergic modulation is involved in the L-DOPA-induced c-Fos expression in the denervated striatum which is normalized by fetal VM transplants. It also seems likely that VM grafts suppress the L-DOPA-induced expression of transcriptional factors which might be involved in the mechanisms underlying various side effects of chronic L-DOPA therapy.

Animals↗
PubMed1989

The effect of L-dopa upon in vitro dopamine release from the corpus striatum of young and old male rats.

In the present experiments, we examined the effects of superfusion of L-DOPA upon in vitro dopamine (DA) release from the corpus striatum (CS) in young (2-4 months) and old (24 months) male rats. In Experiment I, responses to two successive increasing doses of L-DOPA (1.0 and 10 microM) indicated a clear age difference with DA release from CS of young rats significantly greater than that of old rats in response to the 10 microM dose of L-DOPA. Interestingly, CS fragments of young and old male rats responded marginally to the 1.0 microM L-DOPA infusion, and no significant differences between these two age groups were obtained. Since we have previously observed that the addition of naloxone to the superfusion medium restored the potassium stimulated DA release of old rats to that of young rats, in Experiment II, responses of CS tissue fragments of young and old rats superfused in medium with or without naloxone (100 microM) were tested with a single 10 microM L-DOPA infusion. The results of Experiment II indicated that the addition of naloxone to the superfusion medium did not alter the responses of CS tissue to L-DOPA in either young or old rats; however, the overall response of the young rats remained significantly greater than that of the old rats. Taken together, these results demonstrate a significant age-related decrement in the capacity of 10 microM L-DOPA to stimulate DA release from CS fragments.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1988

Transition-state analogues as inhibitors of L-dopa decarboxylase.

1. A series of compounds has been prepared which are analogues of the transition state of the reaction catalysed by L-dopa decarboxylase (EC 4.1.1.28). 2. These compounds are reduced adducts of the substrate (L-dopa) and coenzyme (pyridoxal phosphate), as well as analogues of these substances (D-dopa, pyridoxal and salicaldehyde). 3. Compounds were also prepared with an oxazine link between the 3'-oxygen and the nitrogen attached to the 4'-carbon of the aldehyde moiety. 4. None of the D-dopa adducts produced any significant inhibition, but the L-dopa adducts were all active at millimolar levels, with the oxazine derivatives being more active than their parent compounds. 5. Inhibition was competitive with respect to L-dopa, but was neither competitive nor non-competitive with respect to pyridoxal phosphate. 6. The most active compound tested was the oxazine derivative of the L-dopa/salicaldehyde adduct, with an estimated Ki of 58.0 microM. 7. Increased inhibitory activity was observed when enzyme depleted of pyridoxal phosphate was used.

Animals↗
PubMed1986

Effect of tyrosine administration on dopa accumulation in light- and dark-adapted retinas from normal and diabetic rats.

The interaction of tyrosine concentration and lighting on in vivo dihydroxyphenylalanine (dopa) accumulation rate was studied in retinas of normal and diabetic rats. In both groups of rats, dopa accumulation and in vitro hydroxylase activity were higher in retinas exposed to light than in those adapted to darkness. In light-adapted diabetic rats, though, retinal tyrosine level, dopa accumulation, and in vitro tyrosine hydroxylase activity were all below normal. In both normal and diabetic rats exposed to light, tyrosine injection raised retinal tyrosine concentrations and stimulated dopa accumulation. Injection of tyrosine into dark-adapted rats raised retinal tyrosine level but did not enhance dopa accumulation. Together, these results suggest that in vivo retinal amacrine cells will vary their dopa accumulation rate as a function of substrate supply, but only in the light, when tyrosine hydroxylase is activated. They further indicate that dopa accumulation rate remains sensitive to tyrosine supply in the light-activated diabetic retina.

Adaptation, Ocular↗
PubMed1992

L-dopa is protective against indomethacin-induced small intestinal ulceration in the rat: possible role of an alpha-2-adrenergic mechanism.

Dopaminergic agents ameliorate experimentally induced gastroduodenal mucosal injury, but there is no information about their effect on small intestinal mucosa. We studied the effect of L-dopa and related substances on indomethacin-induced intestinal ulceration in the rat. Ulceration was produced by s.c. injection of 30 mg/kg indomethacin, 30 min after refeeding fasted rats. Total ulcer area was measured 24 hrs after indomethacin administration. L-dopa, 5 mg/kg given in two divided doses 5 h apart, starting 30 minutes before administration of indomethacin, was found to protect the small bowel mucosa against indomethacin- induced damage (ulcer area 122 +/- 5.5 vs 224.2 +/- 5.4 mm2, mean +/- SEM, p less than 0.006). Administration of 5 mg/kg haloperidol, a dopa antagonist, did not abolish the protective effect of L-dopa. On the other hand, yohimbine, an alpha-2-adrenoreceptor antagonist, almost completely abolished the protective effect (180.4 +/- 5.3 vs 122 +/- 5.5, p less than 0.004). Clonidine 20 micrograms/kg, an alpha-2-adrenoreceptor agonist, closely mimicked the protective effect of L-dopa (141.5 +/- 10.9 vs 224.2 +/- 5.4, p less than 0.006). All drugs were give i.p. in two divided doses, at the same schedule as described for L-dopa. The results demonstrate that L-dopa has a protective effect on indomethacin-induced small bowel injury in the rat. The protective effect is probably mediated through stimulation of alpha-2-adrenoreceptors.

Animals↗
PubMed1988

Evidence that the substantia nigra is a site of action for L-DOPA.

Rats with unilateral 6-hydroxydopamine lesions of the substantia nigra (SN) were challenged with L-DOPA (25 mg/kg, i.p.). One hour later, during the peak of rotational behavior, the animals were killed and the striatum and the SN were dissected and assayed for dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) content. While L-DOPA treatment elevated DA levels in the lesioned striatum by only 10%, DA levels in the lesioned SN were completely restored to normal levels. DOPAC levels showed similar changes. In order to establish whether the large DA increase in the lesioned SN contributed to L-DOPA-induced contralateral circling, animals were implanted with chronic in-dwelling cannulas in the lesioned SN. Infusion of the DOPA decarboxylase inhibitor carbidopa (5 micrograms in 1 microliter) 30 min prior to peripheral L-DOPA injection not only reduced contralateral circling but reversed the direction of turning 20 min after the L-DOPA injection. The results are discussed in terms of dopaminergic regulation of the striatonigral pathway, their clinical relevance to Parkinson's disease and the suggestion that the SN is an important site for the action of L-DOPA.

Animals↗
PubMed1995

Chronic L-DOPA treatment differentially regulates gene expression of glutamate decarboxylase, preproenkephalin and preprotachykinin in the striatum of 6-hydroxydopamine-lesioned rat.

The effect of a unilateral 6-hydroxydopamine lesion of the medial forebrain bundle in rats and subsequent L-DOPA treatment for eight weeks on preproenkephalin, preprotachykinin and glutamate decarboxylase (M(r) 67,000) gene expression in the striatum was investigated by in situ hybridization. A 6-hydroxydopamine lesion of the medial forebrain bundle markedly increased the level of preproenkephalin messenger RNA (+66%) and modestly elevated the level of glutamate decarboxylase (M(r) 67,000) messenger RNA (+36%) in the denervated striatum, but caused a decrease in the level of preprotachykinin messenger RNA (-54%) relative to the intact striatum and to sham-lesioned control animals. Treatment with L-DOPA (200 mg/kg/24 h) for eight weeks reduced but did not abolish the 6-hydroxydopamine lesion-induced elevation of preproenkephalin messenger RNA and slightly reduced the elevation of glutamate decarboxylase (M(r) 67,000) messenger RNA in denervated striatum relative to intact side and control groups. However, L-DOPA treatment almost completely reversed the decrease in preprotachykinin messenger RNA caused by 6-hydroxydopamine lesioning when compared to intact side and control groups. The effect of L-DOPA on the gene expression of preproenkephalin and glutamate decarboxylase (M(r) 67,000) differs from the increase in striatal enkephalin content and glutamate decarboxylase activity previously found following L-DOPA treatment. In contrast, L-DOPA reversed the changes in preprotachykinin messenger RNA, reflecting previously reported increases in substance P content. The findings provide new evidence that chronic L-DOPA treatment differentially affects direct striatonigral and indirect striatopallidal pathways at the molecular level.

Animals↗
PubMed2005

Enhanced cortical dopamine output and antipsychotic-like effect of raclopride with adjunctive low-dose L-dopa.

BACKGROUND: Clozapine shows superior efficacy in schizophrenia and enhances prefrontal dopamine (DA) output like other atypical, but not typical, antipsychotic drugs (APDs). Clinical data also suggest an improved effect of typical APDs in schizophrenia by adjunctive treatment with low doses of 3,4-dihydroxyphenylalanine (L-dopa), but experimental support is scarce, and the underlying mechanisms are poorly understood. METHODS: Antipsychotic efficacy of the D2 antagonist raclopride with or without adjunctive treatment with a low dose of L-dopa was assessed with the conditioned avoidance response paradigm. Extrapyramidal side effects were scored by the catalepsy test. Finally, in vivo microdialysis was used to measure DA efflux in the prefrontal cortex and the nucleus accumbens. RESULTS: A low dose of L-dopa (3 mg/kg) combined with benserazide, an inhibitor of peripheral DOPA decarboxylase, significantly enhanced the antipsychotic-like effect of raclopride without any associated catalepsy. L-dopa/benserazide alone had no effect. In contrast to raclopride alone, combined L-dopa/raclopride also produced a much larger increase in DA output in the prefrontal cortex than in the nucleus accumbens. CONCLUSIONS: These data support the clinical observation that low-dose L-dopa might improve the effect of typical APDs in schizophrenia and indicate that increased prefrontal DA output per se enhances the antipsychotic effect of typical APDs.

Analysis of Variance↗
PubMed2005

ERK phosphorylation and FosB expression are associated with L-DOPA-induced dyskinesia in hemiparkinsonian mice.

BACKGROUND: The dopamine precursor 3,4-dihydroxyphenyl-L-alanine (L-DOPA) is currently the most efficacious noninvasive therapy for Parkinson's disease. A major complication of this therapy, however, is the appearance of the abnormal involuntary movements known as dyskinesias. We have developed a model of L-DOPA-induced dyskinesias in mice that reproduces the main clinical features of dyskinesia in humans. METHODS: Dyskinetic symptoms were triggered by repetitive administration of a constant dose of L-DOPA (25 mg/kg, twice a day, for 25 days) in unilaterally 6-hydroxydopamine (6-OHDA) lesioned mice. Mice were examined for behavior, expression of FosB, neuropeptides, and externally regulated kinase (ERK) phosphorylation. RESULTS: Dyskinetic symptoms appear toward the end of the first week of treatment and are associated with L-DOPA-induced changes in DeltaFosB and prodynorphin expression. L-DOPA also induces activation of ERK1/2 in the dopamine-depleted striatum. Interestingly, elevated FosB/DeltaFosB expression occurs exclusively within completely lesioned regions of the striatum, displaying an inverse correlation with remaining dopaminergic terminals. Following acute L-DOPA treatment, FosB expression occurs in direct striatal output neurons, whereas chronic L-DOPA also induces FosB expression in nitric oxide synthase-positive striatal interneurons. CONCLUSIONS: This model provides a system in which genetic manipulation of individual genes can be used to elucidate the molecular mechanisms responsible for the development and expression of dyskinesia.

Animals↗