Discrimination of morphine- and haloperidol-induced muscular rigidity and akinesia/catalepsy in simple tests in rats

The present study was conducted to establish a simple method for measuring muscular rigidity in rats, which could be used for screening and is able to discriminate between rigidity and akinesia/catalepsy. Therefore, we treated rats with morphine (30 mg/kg i.p.), since large doses of morphine lead to muscular rigidity and akinesia. We measured muscular rigidity with a new method by determining the resistance of the hindlimb to passive flexion in the 'balance test' and also checked haloperidol (3 mg/kg i.p.) treated rats for muscular rigidity. Furthermore, catalepsy was also tested after administration of each of these drugs. Then, the influence of D(1)-like and D(2)-like dopamine receptor stimulation on muscular rigidity and catalepsy was studied. Therefore, the partial D(1) agonist SKF 38393 (3 and 8 mg/kg s.c.), the D(2)/D(1) agonist pergolide (0.25 and 0.5 mg/kg i.p.) and the dopamine precursor L-DOPA (50 and 100 mg/kg i.p.) were administered up to 30 min before muscular rigidity was measured in morphine-treated rats. The results showed that morphine, but not haloperidol led to muscular rigidity, whereas both drugs led to positive scores in the catalepsy test. The dopaminergic drugs partly antagonized the morphine-induced muscular rigidity in the doses applied, but not the catalepsy. Apparently, rigidity, akinesia/catalepsy produced by morphine can be discriminated from that produced by haloperidol in simple and quick tests.     

Effect of the adenosine A2A receptor antagonist 8-(3-chlorostyryl)caffeine on L-DOPA biotransformation in rat striatum

In the present study, we investigated effects of the new selective adenosine A2A receptor antagonist 8-(3-chlorostyryl)caffeine (CSC) on L-DOPA-induced dopamine (DA) release in the striatum of intact and reserpine-treated rats. CSC given in a pharmacologically effective dose of 5 mg/kg i.p. significantly increased striatal DA release after joint administration of L-DOPA (100 mg/kg, i.p.) and benserazide (50 mg/kg, i.p.) to intact and reserpine (2.5 mg/kg, s.c.)-injected rats. CSC did not change the elevated level of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in intact rats, but raised it in DA-depleted animals. The availability of exogenous L-DOPA in the extracellular space was similar and equally increased by CSC in both intact and reserpinized rats. Our results suggest that the observed effects may be mediated by striatal adenosine A2A receptors, and are probably related to the CSC action on DA metabolism and the increased transport of exogenous L-DOPA into the brain. These observations might be of relevance, considering the use of selective A2A antagonists as potential supplements to L-DOPA therapy of Parkinson's disease.     

Memantine,amantadine, and L-deprenyl potentiate the action of L-DOPA in monoamine-depleted rats

Summary Some treatments used for Parkinson's disease attenuate locomotor depression in rats treated with reserpine and -methyl-p-tyrosine. In the present study memantine (2.5, 5.0mg/kg), amantadine (10, 20mg/kg) (both uncompetitive NMDA antagonists), and L-deprenyl (1.0, 5.0 mg/kg; MAO-B inhibitor) were tested for possible synergistic interactions with the dopamine agonists: bromocriptine (2.5, 5.0mg/kg) and L-DOPA (50, 100mg/kg, + benserazide, 100 mg/kg). At higher doses, memantine (10 mg/kg), amantadine (40 mg/kg), bromocriptine (5 and 10mg/kg) and L-DOPA (100, 200mg/kg) but not L-deprenyl (up to 10 mg/kg) produced a pronounced increase in locomotor activity when given alone. The combination of memantine, amantadine and L-deprenyl with bromocriptine did not result in synergism of action and, at best, an additive effect was seen. On the other hand the combination of these agents with L-DOPA produced a pronounced synergistic effect. Hence, the clinical observation that coadministration of L-DOPA with either memantine or amantadine results in enhancement of their action is also reflected in an animal model of Parkinson's disease. Such a combination therapy should allow the use of lower doses of both drugs which may reduce the occurrence of side effects and may also be predicted to have additional benefits related to the neuroprotective properties of memantine, amantadine, and L-deprenyl.     

Adenosine A2A receptor antagonists improve deficits in initiation of movement and sensory motor integration in the unilateral 6-hydroxydopamine rat model of Parkinson's disease

Evidence obtained in rodent and primate models of Parkinson's disease (PD) and preliminary clinical trials, indicates that adenosine A(2A) receptor antagonists might represent a promising nondopaminergic therapeutic tool for the treatment of PD. Those studies demonstrated the ability of adenosine A(2A) receptor antagonists to potentiate l-dopa-mediated motor improvement, whereas very little is known about counteraction of specific motor deficits and on the effects of these compounds when administered alone. To this aim we evaluated the effects of different adenosine A(2A) receptor antagonists on initiation of movement deficits, gait impairment and sensory-motor deficits, induced in rats by a unilateral 6-hydroxydopamine lesion of dopaminergic nigrostriatal neurons. The following tests were used: (1) initiation time of stepping; (2) adjusting step (stepping with forelimb was measured as the forelimb was dragged laterally); (3) vibrissae-elicited forelimb placing (as index of sensory-motor integration deficits). Acute administration of the A(2A) receptor antagonists SCH 58261 (5 mg/kg i.p.) and ST 1535 (20 mg/kg i.p.) similarly to l-dopa (6 mg/kg i.p.) counteracted the impairments in the initiation time of stepping test, in the adjusting step and in the vibrissae-elicited forelimb placing induced by the lesion. The intensity of the effect was l-dopa > SCH 58261 > ST 1535. The results provide the first evidence that blockade of A(2A) receptors is effective in antagonizing specific motor deficit induced by DA neuron degeneration, such as initiation of movement and sensory-motor integration deficits, even without l-dopa combined administration.     

Pharmacological validation of behavioural measures of akinesia and dyskinesia in a rat model of Parkinson's disease

In an attempt to define clinically relevant models of akinesia and dyskinesia in 6-hydroxydopamine (6-OHDA)-lesioned rats, we have examined the effects of drugs with high (L-DOPA) vs. low (bromocriptine) dyskinesiogenic potential in Parkinson's disease on three types of motor performance, namely: (i) abnormal involuntary movements (AIMs) (ii) rotational behaviour, and (iii) spontaneous forelimb use (cylinder test). Rats with unilateral 6-OHDA lesions received single daily i.p. injections of L-DOPA or bromocriptine at therapeutic doses. During 3 weeks of treatment, L-DOPA but not bromocriptine induced increasingly severe AIMs affecting the limb, trunk and orofacial region. Rotational behaviour was induced to a much higher extent by bromocriptine than L-DOPA. In the cylinder test, the two drugs initially improved the performance of the parkinsonian limb to a similar extent. However, L-DOPA-treated animals showed declining levels of performance in this test because the drug-induced AIMs interfered with physiological limb use, and gradually replaced all normal motor activities. L-DOPA-induced axial, limb and orolingual AIM scores were significantly reduced by the acute administration of compounds that have antidyskinetic efficacy in parkinsonian patients and/or nonhuman primates (-91%, yohimbine 10 mg/kg; -19%, naloxone 4-8 mg/kg; -37%, 5-methoxy 5-N,N-dimethyl-tryptamine 2 mg/kg; -30%, clozapine 8 mg/kg; -50%, amantadine 40 mg/kg). L-DOPA-induced rotation was, however, not affected. The present results demonstrate that 6-OHDA-lesioned rats do exhibit motor deficits that share essential functional similarities with parkinsonian akinesia or dyskinesia. Such deficits can be quantified using novel and relatively simple testing procedures, whereas rotometry cannot discriminate between dyskinetic and antiakinetic effects of antiparkinsonian treatments.     

Homocysteinemia and schizophrenia as a case of methylation deficiency

Summary MK-801, a non-competitive antagonist of NMDA receptors, is known to exhibit a beneficial action in many animal models of Parkinson's disease. The aim of this study was to examine the influence of MK-801 on the reserpine-induced muscle rigidity. The rigidity was estimated by a direct mechanomyographic method. This method consists in successive bending and traightening of a rat's hind foot in the ankle joint and measuring the resistance of the foot to passive movements. Reserpine in doses of 5–10 mg/kg ip, given alone or in combination with -methyl-p-tyrosine (MT, 250 mg/kg ip), induced rigidity. The strongest muscle rigidity was induced by 10 mg/kg of reserpine 1 hour after administration. MK-801 (0.32–1.28 mg/kg sc) injected 70 min after reserpine (10 mg/kg ip) decreased the rigidity induced by the latter compound. Similarly, MK-801 (1.28 mg/kg sc), administered 27 h 40 after joint treatment with reserpine (10 mg/kg ip) and MT (250 mg/kg ip), strongly inhibited the reserpine-induced muscle rigidity. The obtained results show that the glutamatergic hyperactivity plays a significant role in the reserpine-induced rigidity. As the reserpine-induced motor disturbances are commonly accepted to be an animal model of parkinsonian symptoms, it may be assumed that the NMDA receptor blocking component may contribute substantially to the therapeutic action of antiparkinsonian drugs.     

D2 receptor stimulation, but not D1, restores striatal equilibrium in a rat model of Parkinsonism

In Parkinson's disease dopamine depletion imbalances the two major output pathways of the striatum. L-DOPA replacement therapy is believed to correct this imbalance by providing effective D1 and D2 receptor stimulation to striatonigral and striatopallidal neurons, respectively. Here we tested this assumption in the rat model of Parkinsonism by monitoring the spike response of identified striatal neurons to cortical stimulation. As predicted, in 6-hydroxydopamine lesioned rats we observed that L-DOPA (6 mg/kg + benserazide), apomorphine and the D2 agonist quinpirole (0.5 mg/kg i.p.) counteract the enhanced responsiveness of striatopallidal neurons. Unexpectedly, the depressed responsiveness of striatonigral neurons was corrected by quinpirole whereas D1 stimulation exerted no (apomorphine, cPB) or worsening effects (L-DOPA, SKF38393 10 mg/kg). Therefore, quinpirole, but not D1 stimulation, restores functional equilibrium between the two striatal output pathways. Our results might explain the therapeutic effect of D2-based medications in Parkinson's disease.     

MDMA and fenfluramine reduce L-DOPA-induced dyskinesia via indirect 5-HT1A receptor stimulation

Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) pharmacotherapy in Parkinson's disease is often accompanied by the development of abnormal and excessive movements known as dyskinesia. Clinical and experimental studies indicate that indirect serotonin agonists can suppress dyskinesia without affecting the efficacy of L-DOPA. While the mechanism by which these effects occur is not clear, recent research suggests that serotonin 5-HT1A receptors may play a pivotal role. To test this, male Sprague-Dawley rats with unilateral 6-hydroxydopamine medial forebrain bundle lesions received 1 week of daily treatment with L-DOPA (12 mg/kg, i.p.) plus benserazide (15 mg/kg, i.p.). Beginning on the 8th day of treatment and every 3rd or 4th day thereafter, rats were pretreated with vehicle (0.9% NaCl), the serotonin and dopamine releaser 3,4-methylenedioxymethamphetamine (MDMA; 0.25 or 2.5 mg/kg, i.p.) or the serotonin releaser fenfluramine (FEN; 0.25 or 2.5 mg/kg, i.p.) 5 min prior to L-DOPA, after which abnormal involuntary movements (AIMs) and rotations were quantified every 20th minute for 2 h. Pretreatment with 2.5 mg/kg of either MDMA or FEN reduced AIMs. To determine the contribution of the 5-HT1A receptor to these effects, another group of L-DOPA-primed 6-hydroxydopamine-lesioned rats were pretreated with the 5-HT1A antagonist WAY100635 (0.5 mg/kg, i.p.), MDMA + WAY100635 (2.5 + 0.5 mg/kg, i.p.) or FEN + WAY100635 (2.5 + 0.5 mg/kg, i.p.) 5 min prior to L-DOPA and subsequent AIMs and rotation tests. The antidyskinetic effects of MDMA and FEN were reversed by cotreatment with WAY100635. These results suggest that 5-HT-augmenting compounds such as MDMA and FEN probably convey antidyskinetic properties in part via stimulation of 5-HT1A receptors.     

The effects of desipramine (DMI) and alpha-2 adrenoceptor agonists on flexor reflex activity (FRA) in the spinalized and decerebrate rat

Summary In the spinalized and decerebrate rat, electrically evoked flexor reflex activity (FRA) of the right anterior tibialis muscle was facilitated by DMI (0.1–3 mg/kg i.v.). DMI (3 mg/kg i.v.) had not effect on twitches of the left ant. tib. muscle evoked by electrical stimulation of the distal stump of the severed sciatic nerve (directly evoked twitches). The alpha-1 adrenoceptor antagonist prazosin (300 g/kg i.v.) and the alpha-2 adrenoceptor agonists clonidine (5 and 10 g/kg i.v.) and BHT-920 (100 g/kg i.v.) all suppressed FRA facilitated by DMI (3 mg/kg i.V.). The alpha-2 adrenoceptor antagonists yohimbine (100 g/kg i.v.) and mianserin (30 g/kg i.v.) antagonized the suppressant effect of clonidine (5 g/kg i.v.) on DMI-facilitated FRA. Clonidine (10 g/kg i.v.) had no effect on directly evoked twitches, and at 3–300 g/kg i.v. had no effect on FRA facilitated by L-DOPA (100 mg/kg i.p.). It is suggested that DMI-facilitated FRA can be used as a test for alpha-2 adrenoceptor agonists which may act at presynaptic alpha-2 adrenoceptors in the spinal cord.     

Microdialysis study of the effects of the antiparkinsonian drug budipine on L-DOPA-induced release of dopamine and 5-hydroxytryptamine by rat substantia nigra and corpus striatum.

The purpose of this study was to determine if systemic treatment with the antiparkinsonian drug budipine was capable of influencing the release of dopamine newly synthesised from L-DOPA in the substantia nigra and corpus striatum of the monoamine-depleted rat. Dual probe microdialysis was therefore employed in freely moving animals pretreated with reserpine (4 mg/kg i.p. 18-20 h earlier) and alpha-methyl-p-tyrosine (200 mg/kg i.p. 45 min earlier). Budipine (10 mg/kg i.p.) alone evoked a small but significant increase in basal dopamine efflux in nigra, though not in striatum, but did not affect the spontaneous outputs of DOPAC, 5-HT, or 5-HIAA in either structure. A threshold amount of L-DOPA (25 mg/kg i.p.) stimulated the release of dopamine, DOPAC, and 5-HT (but not 5-HIAA), both in nigra and striatum. The L-DOPA-induced releases of dopamine and DOPAC were greatly accentuated by pretreatment with budipine (10 mg/kg i.p. 45 min earlier), which delayed rather than potentiated the nigral and striatal effluxes of 5-HT. A higher dose of L-DOPA (100 mg/kg i.p.) did not significantly raise the outputs of dopamine or 5-HT, but greatly magnified that of DOPAC. In these experiments, pretreatment with budipine (10 mg/kg i.p.) facilitated the formation of DOPAC from L-DOPA, without increasing the extracellular concentration of dopamine. We conclude from these findings that budipine, at a therapeutically relevant dose, potentiates the release of dopamine newly synthesised from L-DOPA from either end of the nigrostriatal dopamine axis. This effect of budipine could be related to the drug's recently described ability to increase the activity of the converting enzyme, aromatic L-amino acid decarboxylase, and could explain the clinical efficacy of budipine as an adjunct to L-DOPA therapy of Parkinson's disease in man. The significance of 5-HT release to the antiparkinsonian L-DOPA, and the delay in this release caused by budipine, remain to be established.     

Effect of pergolide on endogenous and exogenous L-DOPA metabolism in the rat striatum: a microdialysis study

Summary We used a model of intrastriatal microdialysis in freely moving rats to study the effect of pergolide, a mixed D₁/D₂ dopamine (DA) receptor agonist with predominant D₂ action in vivo, on the biotransformation of endogenous and exogenous L-DOPA.Levels of L-DOPA, DA, DOPAC, HVA and 5-HIAA were measured by high performance liquid chromatography. Pergolide (50 g/kg, i.p.) caused a 47%, 65% and 70% decrease in basal striatal extracellular (EC) levels of DOPAC, HVA and DA, respectively. L-DOPA (100 mg/kg, i.p.), injected 2 hours after carbidopa, produced significant increase in EC levels of L-DOPA, DOPAC, HVA and DA in rats with and without local perfusion of 10^-4 M pergolide. The DOPAC peak value was lower and was reached 60 minutes later in the group with pergolide.This study demonstrated inhibitory effects of pergolide on endogenous DA release and influence of pergolide on exogenous L-DOPA biotransformation.     

Subchronic administration of L-DOPA to adult rats with a unilateral 6-hydroxydopamine lesion of dopamine neurons results in a sensitization of enhanced GABA release in the substantia nigra, pars reticulata

L-DOPA is the most effective pharmacological agent used for the symptomatic treatment of Parkinson's disease but long-term L-DOPA treatment induces involuntary abnormal movements such as dyskinesias. The present study, using in vivo microdialysis, investigated the effects of a single or subchronic administration of L-DOPA to adult rats with a unilateral 6-OHDA lesion of dopamine neurons on GABA release in the substantia nigra, pars reticulata (SNr). The results indicate that a challenge injection of L-DOPA (50 mg/kg, i.p.) significantly increases GABA levels in the SNr of rats treated with a daily repeated administration of L-DOPA (50 mg/kg, i.p.). Further statistical analysis between groups also showed that extracellular GABA levels were significantly higher in the subchronic L-DOPA group than in the group receiving only one injection of L-DOPA. These results show that the subchronic administration of L-DOPA results in a sensitization of enhanced extracellular GABA levels in the SNr.     

Comparison of the effects of dopamine D 1 and D 2 receptor antagonists on rat striatal,limbic and nigral dopamine synthesis and utilisation

Summary The effects of dopamine (DA) antagonists upon DA synthesis and utilisation in the rat striatum, olfactory tubercle and substantia nigra have been studied. The concentrations of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), the rate of depletion of DA afterin vivo inhibition of tyrosine hydroxylase by H 44/68, and the accumulation of L-DOPA afterin vivo inhibition of 1-aromatic amino acid decarboxylase by NSD 1015 were measured in the study. Haloperidol (0.23mol/kg i. p.), sulpiride (293mol/kg i. p.) and remoxipride (5.6mol/kg i. p.) increased both DA synthesis and utilisation in the striatum and olfactory tubercle. A lower dose of sulpiride (45mol/kg i. p.) increased DA synthesis and utilisation in the olfactory tubercle alone. None of the compounds, at the doses used, affected either DOPAC and HVA concentrations or the rate of utilisation of DA in the substantia nigra. Sulpiride (293mol/kg i. p.) and remoxipride, however, produced a modest rise in nigral DA synthesis. The dopamine D 1-selective antagonist SCH 23390 had only modest effects on striatal, limbic and nigral DA synthesis and utilisation at the doses tested (0.078 and 0.36mol/kg i. p.).     

Antiparkinsonian activity of CY 208-243, a partial D-1 dopamine receptor agonist, in MPTP-treated marmosets and patients with Parkinson's disease

The effect of stimulation of cerebral dopamine D-1 receptors by CY 208-243 on motor disability was tested in MPTP-treated parkinsonian marmosets and patients with Parkinson's disease. CY 208-243 (0.5-1.25 mg/kg s.c.) produced a dose-related reversal of akinesia and rigidity in the marmosets, lasting some 2 h. Single morning doses of CY 208-243 (5-40 mg) were compared with the usual morning dose of levodopa in eight patients with Parkinson's disease on long-term levodopa therapy who had developed motor fluctuations from immobility with akinesia and rigidity (off) to mobility often with dyskinesias (on). CY 208-243 alone was capable of switching such patients from off to on; five of the eight patients responded to the highest dose (40 mg), sometimes with dyskinesias. The response to CY 208-243 was comparable to that produced by levodopa in these cases. Drugs designed to stimulate both dopamine D1 and D2 receptors in the brain may improve the therapy of Parkinson's disease.     

Histamine H3 receptor ligands modulate L-dopa-evoked behavioral responses and L-dopa-derived extracellular dopamine in dopamine-denervated rat striatum

To explore a recently established association between histaminergic and dopaminergic neuronal phenotypic systems in brain, we determined the effect of the respective histaminergic H(3) receptor agonist and antagonist/inverse agonist, imetit and thioperamide, on L-DOPA - derived tissue and extracellular DA and metabolite levels in the striatum of 6-hydroxydopamine (6-OHDA) - lesioned rats (i.e., parkinsonian rats). We also examined the influence of histamine H(3) ligands on L-DOPA evoked behavioral responses (locomotor activity, number of rearings, stereotyped behavior and motor coordination). Using HPLC/ED and in vivo microdialysis technique imetit (5 mg/kg, i.p.) but not thioperamide (5 mg/kg, i.p.) was shown to attenuate an L-DOPA-evoked (15 mg/kg, i.p.; carbidopa, 30 min pretreatment) increase in extracellular DA in the neostriatum of 6-OHDA-lesioned rats. However, both imetit and thioperamide increased microdialysate levels of DOPAC and HVA, probably by enhancing intraneuronal DA utilization. As indicated by neurochemical analysis of the striatum imetit produced a decrease in tissue DA content. These findings support the hypothesis that central H(3) histaminergic receptors have a modulatory role in the storage, metabolism and release of DA derived from exogenous L-DOPA challenge. Furthermore, evidence from behavioral studies indicate that histamine H3 receptor blockade markedly improved motor coordination. Conversely, histamine H(3) receptor stimulation, being without effect on motor coordination, enhanced vertical activity in rats. From the above we conclude that the histamine H(3) agonism may augment motor dyskinesia in Parkinson's disease (PD) patients and presumably worsen L-DOPA therapy. Consequently, the histaminergic system represents a viable target for modulating the effectiveness of L-DOPA therapy in Parkinson's disease.     

SCH 58261, a selective adenosine A2A receptor antagonist,decreases the haloperidol-enhanced proenkephalin mRNA expression in the rat striatum

In the striatum, dopamine D(2) receptors are co-localized with adenosine A(2A) receptors on the GABAergic neurons of the striopallidal pathway. Moreover, blockade of A(2A) receptors has been previously shown to suppress parkinsonian-like symptoms (catalepsy, akinesia, muscle rigidity) in rodent and primate models of Parkinson's disease (PD). Since it is believed that main motor symptoms of PD are due to the overactivity of the GABAergic striopallidal pathway, the aim of the present study was to find out whether SCH 58261, a selective antagonist of the adenosine A(2A) receptors, is capable of counteracting both the catalepsy and the enhancement of proenkephalin (PENK) mRNA expression in the rat striatum, induced by haloperidol administered at 1.5 mg/kg s.c. 3 times, every 3 h. Systemic administration of SCH 58261 (5 mg/kg i.p., 3 times, every 3 h, 10 min before haloperidol), partially decreased the haloperidol-induced catalepsy and the increase in the PENK mRNA expression in both dorsolateral and ventrolateral parts of the striatum at all three examined levels. No such changes were seen in the medial striatum and in the nucleus accumbens. Moreover, SCH 58261 given alone did not influence the level of PENK mRNA in any examined part of the striatum. The present results suggest that similarly to other A(2A) receptor antagonists, SCH 58261 normalizes activity of the striopallidal pathway, enhanced by blockade of dopamine D(2) receptors with haloperidol, which may result in recovery of motor functions.     

Pramipexole, a nonergot dopamine agonist, is effective against rest tremor in intermediate to advanced Parkinson's disease.

We evaluated the efficacy of the nonergot dopamine receptor agonist pramipexole in 16 patients with advanced Parkinson's disease and marked rest tremor during an "on" period. The patients were drawn from a larger placebo-controlled, double-blind, randomized trial, which was not originally designed to investigate the effect of pramipexole on tremor. Eleven patients received pramipexole. The first effects were seen with a pramipexole dose of 0.75 mg/d with a reduction of the tremor item A of Unified Parkinson's Disease Rating Scale (UPDRS III, "on" state) by 25% and of rigidity and akinesia by 22%. Under the highest dose, 4.5 mg/d, the tremor score was improved by 61% over baseline (p < 0.0056, Wilcoxon signed rank) and the sum of rigidity and akinesia items by 66% (p < 0.0038, Wilcoxon signed rank). Five patients received placebo and did not improve. Based on this sample of patients, the nonergot dopamine receptor agonist pramipexole appears to have a potent anti-rest tremor action while being effective against akinesia and rigidity.     

Deuterium substitutions in the L-DOPA molecule improve its anti-akinetic potency without increasing dyskinesias

Treatment of Parkinson's disease is complicated by a high incidence of L-DOPA-induced dyskinesias (LID). Strategies to prevent the development of LID aim at providing more stable dopaminergic stimulation. We have previously shown that deuterium substitutions in the L-DOPA molecule (D3-L-DOPA) yield dopamine that appears more resistant to enzymatic breakdown. We here investigated the effects of D3-L-DOPA on motor performance and development of dyskinesias in a rodent model of Parkinson's disease. Through acute experiments, monitoring rotational behavior, dose–effect curves were established for D3-L-DOPA and L-DOPA. The equipotent dose of D3-L-DOPA was estimated to be 60% of L-DOPA. Subsequently, animals were treated with either the equipotent dose of D3-L-DOPA (5 mg/kg), the equivalent dose of D3-L-DOPA (8 mg/kg), L-DOPA (8 mg/kg) or vehicle. The equivalent dose of D3-L-DOPA produced superior anti-akinetic effects compared to L-DOPA in the cylinder test (p < 0.05), whereas the equipotent dose of D3-L-DOPA produced an anti-akinetic effect similar to L-DOPA. Dyskinesias developed to the same degree in the groups treated with equivalent doses of D3-L-DOPA and L-DOPA. The equipotent dose of D3-L-DOPA induced fewer dyskinesias than L-DOPA (p < 0.05). In conclusion, our study provides evidence for improved potency and reduced side-effects of L-DOPA by deuterium substitutions in the molecule. These results are of clinical interest since the occurrence of LID is related to the total L-DOPA dose administered. D3-L-DOPA may thus represent a novel strategy to reduce the total dose requirement and yet achieve an effective control of parkinsonian symptoms.     

Ethanol behaves as an NMDA antagonist with respect to locomotor stimulation in monoamine-depleted mice

Summary Previous studies have shown that administration of NMDA antagonists in combination with the ₂-adrenoceptor agonist clonidine results in a marked locomotor stimulation in monoamine-depleted mice, albeit the pattern of movement produced is highly stereotyped and primitive. Ethanol has recently been suggested to display NMDA antagonistic properties; hence, in the present study the ability of ethanol to produce locomotor activation in monoamine-depleted mice with a movement pattern similar to that produced by NMDA antagonists was investigated. It was found that neither ethanol nor clonidine given alone reversed the akinesia induced by pretreatment with reserpine (10 mg/ kg; 18 h) and -methyl-para-tyrosine (500 mg/kg; 2 h). However, when the drugs were combined a marked stimulatory effect was observed and, indeed, the animals displayed the same primitive locomotor pattern previously observed following treatment with NMDA antagonists in conjunction with clonidine. The locomotor response was effectively blocked by pretreatment with the selective ₂-adrenoceptor antagonists yohimbine (10 mg/kg) or idazoxan (10 mg/ kg) but not with the selective ₁-adrenoceptor antagonist prazosin (1 mg/kg). The present results suggest that ethanol in conjunction with ₂-adrenoceptor stimulation induces locomotion in monoamine-depleted mice via a mechanism that may involve interference with glutamate receptor-mediated neurotransmission.     

The effects of chronic L-DOPA therapy on pharmacodynamic parameters in a rat model of motor response fluctuations

Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) therapy in Parkinson's disease (PD) is complicated by motor response fluctuations and dyskinesia. The relative contributions of disease severity and chronic L-DOPA therapy to the development of motor fluctuation are not well defined clinically. Experimental studies have been limited partly because models for the antiparkinsonian effects on akinesia have not been employed. Therefore, we employed a model of akinesia using forepaw adjusting steps that have been well characterized to reflect the effect of lesions and the antiparkinsonian effect of dopaminergic drugs and transplants. We administered L-DOPA (12.5 mg/kg) intermittently for 4 weeks to rats with severe nigrostriatal lesions produced by injecting 6-hydroxydopamine into the medial forebrain bundle. The peak magnitude responses to L-DOPA increased after treatment compared to the pretreatment baseline. The latency to peak response to L-DOPA became shorter and reversed after the discontinuation of treatment. The duration of response showed minor changes. The pattern of changes in response to apomorphine was similar to that of L-DOPA except that the peak magnitude did not increase despite chronic L-DOPA treatment. The changes in D1 and D2 receptor binding did not correlate with behavioral changes. In summary, long-term intermittent L-DOPA treatment resulted in priming of antiparkinsonian effects on improving akinesia in a rat model of severe PD. These observed changes do not mirror all aspects of motor response fluctuations in advanced PD patients and suggest differential contributions of dopaminergic treatment and lesion severity to motor complication patterns.