Loss of response to levodopa in Parkinson's disease and co-occurrence with dementia: role of D3 and not D2 receptors

Previous data suggest a relationship between the loss of response to levodopa in Parkinson's disease (PD) patients with the co-occurrence of dementia, but the role of alterations in the dopamine system has not been explored. We measured the extent of striatal DA loss and changes in striatal DA D(2) and D(3) receptors in postmortem striatum of PD patients who historically had or had not lost their clinical response to dopaminergic drugs and/or had an additional diagnosis of dementia. Clinical evaluation and retrospective chart reviews for PD and dementia, and neuropathological diagnoses were obtained. All PD cases (+/-dementia), regardless of response to dopaminergic drugs, exhibited a significant and similar degree and pattern of loss of tyrosine hydroxylase immunocytochemistry and DA transporter binding in striatum, and loss of tyrosine hydroxylase-immunoreactive neurons and brain-derived neurotrophic-immunoreactive neurons from the ventral midbrain. D(2) receptor concentrations were modestly elevated in the rostral striatum of all the PD cases (+/-dementia), whether or not they continued to respond to dopaminergic drugs. In contrast, loss of D(3) receptor concentration correlated with loss of response to dopaminergic drugs, independent of the presence or absence of dementia. A maintained response to dopaminergic drugs correlated with an elevation of D(3) receptors. Dementia with PD was highly correlated with a loss of response to dopaminergic drugs, and was also correlated with reduced D(3) receptors. The alterations in D(3) receptor concentrations were greatest in the nucleus accumbens, caudal striatum, and globus pallidus. Thus, loss of dopamine D(3) receptors may be a more important contributing factor to a loss of response to dopaminergic drugs than changes in the D(2) receptor.     

Is the inhibition of adenosine A(2A) receptors an efficient way of Parkinson's disease treatment?

The authors intended to focus the attention of the medical community on the potential therapeutic usefulness of A(2A) adenosine receptors antagonists in the treatment of Parkinson's disease. Basal ganglia express a big amount of A(2A) adenosine receptors, occurring mainly on the external surfaces of neurons located at indirect pathways between the striatum, globus pallidus and substantia nigra. Experiments with the animal models of Parkinson's disease indicate that A(2A) receptors are strongly involved in the regulation of the central movement system. Co-localization of A(2A) and dopaminergic D2 receptors in the striatum creates a milieu for an antagonistic interaction between adenosine and dopamine. The experimental data prove that the best mobility improvement of patients with Parkinson's disease could be achieved with a simultaneous activation of dopaminergic D2 receptors and inhibition of adenosine A(2A) receptors. In animal models of Parkinson's disease, the use of selective antagonists of A(2A) receptors, such as istradefylline, led to the reversibility of movement dysfunction. These compounds might improve the mobility during both monotherapy and co-administration with L-dopa and the dopamine receptor agonists. The use of these antagonists in the combined therapy enables the reduction of the L-dopa doses, as well as reduction of the side effects. In the adjunctive therapy, the A(2A) antagonists might be used in both moderate and advanced stages of Parkinson's disease. The long-lasting administration of the A(2A) receptor antagonists does not decrease patient's response and does not cause side effects typical of the L-dopa therapy. It was proved on different animal models that inhibition of A(2A) receptors not only decreases the movement disturbance, but also reveals the neuroprotective activity, which might slow down or stop the progress of the disease.     

Endogenous dopaminergic tone and dopamine agonist action.

Dopamine receptor agonists provide symptomatic relief in the early stages of Parkinson's disease, but with disease progression, their efficacy decreases. The reason behind this decrease in effectiveness is unknown, but maximal efficacy may be dependent on endogenous dopaminergic tone to provide stimulation of D1 and D2 receptor subtypes. Therefore, we have investigated the effects of the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT) on the actions of D1, D2, and D1/D2 agonists and levodopa (L-dopa) in common marmosets treated with 1 -methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Administration of AMPT alone further increased motor disability and decreased locomotor activity. Administration of L-dopa reversed motor disability and increased locomotor activity, and this reversal was not affected by previous AMPT treatment. The D1 agonist A-77636 and the D2 agonist quinpirole reversed motor deficits, but these effects were markedly inhibited by previous AMPT treatment. Administration of quinpirole with A-77636 produced a reversal of motor deficits that was more resistant to AMPT pretreatment than was the effect produced by quinpirole or A-77636 alone. These data suggest that D1 and D2 receptor stimulation are required for dopamine receptor agonists to produce a maximal antiparkinsonian response. The reversal of motor deficits produced by the mixed D1/D2 agonist apomorphine was more resistant to AMPT treatment than that produced by quinpirole or A-77636. However, the motor effects of A-77636 plus quinpirole and of apomorphine were still affected by AMPT treatment. This suggests that loss of tyrosine hydroxylase activity may also alter motor activity through inhibition of endogenous L-dopa or norepinephrine synthesis, because both are also involved in the genesis of motor activity.     

Antiparkinsonian effects of the novel D3/D2 dopamine receptor agonist, S32504, in MPTP-lesioned marmosets: Mediation by D2, not D3, dopamine receptors.

L-dopa remains the most common treatment for Parkinson's disease. However, there is considerable interest in D3/D2 receptor agonists such as the novel agent S32504, since they exert antiparkinsonian properties in the absence of dyskinesia. An important question concerns the roles of D2 vs. D3 receptors, an issue we addressed with the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned nonhuman primate model of Parkinson's disease. In L-dopa-primed animals, S32504 (0.16-2.5 mg/kg p.o.) dose-dependently enhanced locomotor activity. This action was abolished by the D2 antagonist, L741,626 (2.5 mg/kg), but potentiated by the D3 antagonist, S33084 (0.63 mg/kg). Both antagonists were inactive alone. In drug-naive animals, a maximally effective dose of S32504 (2.5 mg/kg p.o.) displayed pronounced antiparkinsonian properties from the third day of administration, and its actions were expressed rapidly and durably. Thus, on day 33, antiparkinsonian properties of S32504 were apparent within 5 minutes and present for > 4 hours. Moreover, they were associated with neither wearing off nor significant dyskinesia. In conclusion, the novel D3/D2 agonist S32504 may offer advantages over L-dopa in the treatment of newly diagnosed parkinsonian patients. Its actions are expressed primarily by activation of D2, not D3, receptors.     

When a Parkinson's disease patient starts to hallucinate

Visual hallucinations are a typical feature of Lewy body parkinsonism and occur in some 40% of patients with Parkinson's disease. Age and cognitive decline are the most important intrinsic risk factors, but hallucinosis is often triggered by comorbid conditions such as infection and dehydration. The single most important trigger, however, is exposure to CNS drugs, in particular antiparkinsonian agents. While hallucinosis and psychosis can be triggered by amantadine and anticholinergics, they are more commonly experienced after changes in dopaminergic medication. Dopamine agonists have greater potential to induce hallucinosis compared with L-dopa. Attempting to reduce antiparkinsonian drugs is an important part in the management of these patients, but atypical neuroleptics like clozapine or quetiapine are frequently necessary. Visual hallucinations in Parkinson's disease patients with dementia can also be improved by treatment with the cholinesterase inhibitor rivastigmine.     

Evidence that L-dopa-induced rotational behavior is dependent on both striatal and nigral mechanisms

Parkinson's disease results from the death of the dopamine-containing neurons in the substantia nigra pars compacta (SNC). This is accompanied by a loss of dopamine in brain regions, such as the corpus striatum, which receives input from dopaminergic neurons in the substantia nigra (SN). Since the corpus striatum is the primary target for these dopaminergic neurons, it has long been thought that the corpus striatum is the principal region affected. It was, therefore, natural to assume that replenishing dopamine in the striatum might be an effective treatment for Parkinson's disease. In fact, the dopamine precursor L-dihydroxyphenylalanine (L-dopa), the current drug of choice for treatment of Parkinson's disease, is believed to exert its therapeutic effect by replenishing dopamine levels in the corpus striatum via enzymatic decarboxylation within the synaptic terminals of surviving nigrostriatal neurons (Hornykiewicz, 1974). However, dopamine is also synthesized, stored, and released from the dendrites of SNC neurons that arborize in the substantia nigra pars reticulata (SNR) (Cheramy et al., 1981). Using a classic animal model for Parkinson's disease (rats with a unilateral 6-hydroxydopamine lesion of the SN), we show that L-dopa is also converted to dopamine in significant amounts within the 6-OHDA-lesioned SN. Furthermore, in contrast to the situation in the striatum where dopamine levels are only elevated for a short time, dopamine levels in the SN remain elevated until the behavioral effects of L-dopa have subsided. This elevation of nigral dopamine levels produces rotation that can be blocked by injecting a selective D1 dopamine receptor antagonist (SCH 23390, 2 micrograms in 1 microliter) directly into the SN pars reticulata. Infusion of SCH 23390 into the ipsilateral striatum produced only a modest reduction in L-dopa-induced circling behavior. These results suggest that D1 dopamine receptors in the SN may be at least as important as D1 dopamine receptors in the striatum as a site for the effects of L-dopa. This may have important implications for the therapy of Parkinson's disease.     

Loss of D3 receptors in the zitter mutant rat is not reversed by L-dopa treatment

In Parkinson's disease (PD) and animal models of parkinsonism the destruction of nigrostriatal (NSB) system results in a marked loss of the dopamine D(3) receptor and mRNA in the islands of Calleja (ICj) and the nucleus accumbens shell (NAS). In animal models, it has been reported that both measures are elevated by repeated intermittent administration of L-dopa. However, a large proportion of PD cases are resistant to L-dopa-induced elevation of D(3) receptor number. The zitter mutant (Zi/Zi) rat replicates the slow progressive degeneration of the NSB observed in PD and also exhibits a loss of D(3) receptor number in the NAS or ICj. To test if this could be reversed with subchronic L-dopa treatment, injections of carbidopa (10 mg/kg i.p.) were followed an hour later with injection of L-dopa (100 mg/kg i.p.) twice a day for 10 days. In control Sprague-Dawley (SD) and zitter heterozygote (Zi/-) rats that do not show a loss of D(3) receptors with vehicle treatment, L-dopa produced no change in D(3) receptor number or in DA terminal density as measured by dopamine transporter (DAT) binding and tyrosine hydroxylase immunoautoradiography (TH-IR). There was a marked loss of DAT and TH-IR in caudate-putamen (CPu) and NA, as well as D(3) receptors in NAS and ICj in Zi/Zi rats but no further change with L-dopa treatment. To determine if the resistance to L-dopa-induced increase in D(3) receptor was due to a deficiency in expression of cortical BDNF or its receptor, TrkB, in CPu and NAS, we examined BDNF mRNA by ISHH in frontal cortex and TrkB mRNA in frontal cortex, CPu, and NA. The loss of the NSB in the Zi/Zi did not alter levels of BDNF or TrkB mRNA, nor did L-dopa administration alter levels BDNF or TrkB mRNA. Thus, unlike in 6-hydroxydopamine-treated rats, in Zi/Zi rats administered L-dopa does not reverse the loss of BDNF mRNA or lead to an elevation of D(3) receptor number.     

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.     

Antiparkinsonian effect of a new selective adenosine A2A receptor antagonist in MPTP-treated monkeys.

BACKGROUND: Chronic treatment with L-3,4-dihydroxyphenylalanine (L-dopa) is often associated with motor side effects in PD patients. The search for new therapeutic approaches has led to study the role of other neuromodulators including adenosine. Among the four adenosine receptors characterized so far, the A2A subtype is distinctively present on striatopallidal output neurons containing enkephalin and mainly bearing dopamine (DA) D2 receptors (indirect pathway). Studies in DA-denervated rats suggest that blockade of adenosine A2A receptors might be used in PD. OBJECTIVE: To evaluate the antiparkinsonian effect of a new selective adenosine A2A receptor antagonist, KW-6002, in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. METHODS: In the present study, we used six MPTP-exposed cynomolgus monkeys already primed and exhibiting L-dopa-induced dyskinesias to evaluate both the antiparkinsonian and dyskinetic effect upon challenge with two oral doses (60 and 90 mg/kg) of KW-6002 administered alone or in combination with L-dopa/benserazide (50/12.5 mg). RESULTS: KW-6002 administered alone produced a dose-dependent antiparkinsonian response that reached the level of efficacy of L-dopa/benserazide but was less likely to reproduce dyskinesias in these animals. When co-administered, KW-6002 potentiated the effects of L-dopa/benserazide on motor activity (up to 30%) without affecting the dyskinetic response. CONCLUSION: Adenosine A2A receptor antagonists have antiparkinsonian effects of their own with a reduced propensity to elicit dyskinesias. They might therefore be useful agents in the treatment of PD.     

Combined use of the adenosine A(2A) antagonist KW-6002 with L-DOPA or with selective D1 or D2 dopamine agonists increases antiparkinsonian activity but not dyskinesia in MPTP-treated monkeys

The novel selective adenosine A(2A) receptor antagonist KW-6002 improves motor disability in MPTP-treated parkinsonian marmosets without provoking dyskinesia. In this study we have investigated whether KW-6002 in combination with l-DOPA or selective D1 or D2 dopamine receptor agonists enhances antiparkinsonian activity in MPTP-treated common marmosets. Combination of KW-6002 with the selective dopamine D2 receptor agonist quinpirole or the D1 receptor agonist SKF80723 produced an additive improvement in motor disability. Coadministration of KW-6002 with a low dose of L-DOPA also produced an additive improvement in motor disability, and increased locomotor activity. The ability of KW-6002 to enhance antiparkinsonian activity was more marked with L-DOPA and quinpirole than with the D1 agonist. However, despite producing an enhanced antiparkinsonian response KW-6002 did not exacerbate L-DOPA-induced dyskinesia in MPTP-treated common marmosets previously primed to exhibit dyskinesia by prior exposure to L-DOPA. Selective adenosine A(2A) receptor antagonists, such as KW-6002, may be one means of reducing the dosage of L-DOPA used in treating Parkinson's disease and are potentially a novel approach to treating the illness both as monotherapy and in combination with dopaminergic drugs.     

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.     

Glutamate-dopamine interactions in the basal ganglia: relationship to Parkinson's disease

Summary Current antiparkinsonian therapies focus on either replacing dopamine via precursor (L-DOPA) administration, or directly stimulating postsynaptic dopamine receptors with dopamine agonists. Unfortunately, this approach is associated with numerous side effects and these drugs lose efficacy with disease progression. This article reviews recent evidence which suggests that negative modulation of glutamatergic neurotransmission has antiparkinsonian effects in a variety of rodent and primate models of parkinsonism. The pronounced synergism between dopaminergic agents and glutamate receptor antagonists may provide a means of using very low doses of the two drug classes in concert to treat Parkinson's disease effectively and minimize dose-related drug side effects.     

Selective increase of dopamine D3 receptor gene expression as a common effect of chronic antidepressant treatments

The mesolimbic dopaminergic system is a neuroanatomical key structure for reward and motivation upon which previous studies indicated that antidepressant drugs exert a stimulatory influence, via still unknown neurobiological mechanisms. Here we examined the effects of chronic administration of antidepressants of several classes (amitriptyline, desipramine, imipramine, fluoxetine and tranylcypromine) and repeated electroconvulsive shock treatments (ECT) on dopamine D3 receptor expression in the shell of the nucleus accumbens, a major projection area of the mesolimbic dopaminergic system. Short-term drug treatments had variable effects on D3 receptor mRNA expression. In contrast, treatments for 21 days (with all drugs except fluoxetine) significantly increased D3 receptor mRNA expression in the shell of nucleus accumbens; D3 receptor binding was also significantly increased by amitriptyline or fluoxetine after a 42-day treatment. ECT for 10 days increased D3 receptor mRNA and binding in the shell of nucleus accumbens. D1 receptor and D2 receptor mRNAs were increased by imipramine and amitriptyline, but not by the other treatments. The time-course of altered D3 receptor expression, in line with the delayed clinical efficiency of antidepressant treatment, and the fact that various antidepressant drugs and ECT treatments eventually produced the same effects, suggest that increased expression of the D3 receptor in the shell of nucleus accumbens is a common neurobiological mechanism of antidepressant treatments, resulting in enhanced responsiveness to the mesolimbic dopaminergic system.     

Parkinsonism or Parkinson's disease unmasked by pentoxifylline?

Pentoxifylline is a synthetic derivative of xantine which stimulates adenosine receptors, inhibit phosphodiesterase and increases cyclic monophosphate adenosine. It is also considered a dopaminergic D1 receptor agonist. Worsening of patients with Parkinson's disease when taking this product has been reported. On the other hand, it is considered that adenosine A2A receptors antagonists have antiparkinsonian properties. Four cases of patients with a mean age of 77 years who developed a rigid akinetic syndrome following therapy with a mean dose of 1100 mg/day of pentoxifylline over a mean period of 32 days are presented. Two of these patients presented clinical characteristics of drug-induced parkinsonism and the other two showed Parkinson's disease. The possibility of pentoxifylline causing an imbalance between D1 and D2 receptor stimulation and producing pharmacologic parkinsonism, or rather, the possibility of pentoxifylline unmasking subclinical Parkinson's disease are discussed.     

Continuous transdermal dopaminergic stimulation in advanced Parkinson's disease

The objective of the study was to determine the safety and efficacy of increasing doses of Rotigotine CDS in patients with advanced Parkinson's disease. The development of motor complications in Parkinson's disease has been linked to intermittent stimulation of dopamine receptors. Continuous, noninvasive, dopaminergic stimulation has not been available to date. Rotigotine CDS is a lipid-soluble D2 dopamine agonist in a transdermal delivery system that could fill this void. This inpatient study consisted of a 2-week dose escalation phase followed by a 2-week dose maintenance phase at the highest dose (80 cm2). Each individual's L-Dopa dose was back-titrated as feasible. The primary outcome measure was L-Dopa dose, and secondary outcome measures included early morning "off"-L-Dopa Unified Parkinson's Disease Rating Scale motor scores by a blinded evaluator and motor fluctuation data obtained from patient diaries ("on" without dyskinesia, "on" with dyskinesia, and "off"). Seven of 10 subjects provided data that could be evaluated. There were two administrative dropouts, and one individual was eliminated from the study because of recrudescence of hallucinations. The median daily L-Dopa dose decreased from 1,400 to 400 mg (p = 0.018, Wilcoxon test). Unified Parkinson's Disease Rating Scale motor scores were unchanged. Although diary variables improved in most individuals, only the reduction in "off" time attained statistical significance. Adverse effects were mild and consisted mainly of dopaminergic side effects and local skin reactions. The data suggest that Rotigotine CDS is an effective treatment for advanced Parkinson's disease and permits patients to substantially lower L-Dopa doses without loss of antiparkinsonian efficacy. Full-scale controlled clinical trials are warranted. In addition to potential therapeutic benefits, this drug can be used to test the hypothesis that continuous dopaminergic stimulation from the initiation of Parkinson's disease therapy will limit the development of motor complications.     

Combined Use of the Adenosine A2A Antagonist KW-6002 with -DOPA or with Selective D1 or D2 Dopamine Agonists Increases Antiparkinsonian Activity but Not Dyskinesia in MPTP-Treated Monkeys

The novel selective adenosine A_2A receptor antagonist KW-6002 improves motor disability in MPTP-treated parkinsonian marmosets without provoking dyskinesia. In this study we have investigated whether KW-6002 in combination with -DOPA or selective D1 or D2 dopamine receptor agonists enhances antiparkinsonian activity in MPTP-treated common marmosets. Combination of KW-6002 with the selective dopamine D2 receptor agonist quinpirole or the D1 receptor agonist SKF80723 produced an additive improvement in motor disability. Coadministration of KW-6002 with a low dose of -DOPA also produced an additive improvement in motor disability, and increased locomotor activity. The ability of KW-6002 to enhance antiparkinsonian activity was more marked with -DOPA and quinpirole than with the D1 agonist. However, despite producing an enhanced antiparkinsonian response KW-6002 did not exacerbate -DOPA-induced dyskinesia in MPTP-treated common marmosets previously primed to exhibit dyskinesia by prior exposure to -DOPA. Selective adenosine A_2A receptor antagonists, such as KW-6002, may be one means of reducing the dosage of -DOPA used in treating Parkinson's disease and are potentially a novel approach to treating the illness both as monotherapy and in combination with dopaminergic drugs.     

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.     

Localization of dopamine D2 receptors on cholinergic interneurons of the dorsal striatum and nucleus accumbens of the rat

Striatal cholinergic interneurons located in the dorsal striatum and nucleus accumbens are amenable to influences of the dopaminergic mesolimbic pathway, which is a pathway involved in reward and reinforcement and targeted by several drugs of abuse. Dopamine and acetylcholine neurotransmission and their interactions are essential to striatal function, and disruptions to these systems lead to a variety of clinical disorders. Dopamine regulates acetylcholine release through dopamine receptors that are localized directly on striatal cholinergic interneurons. The dopamine D2 receptor, which attenuates acetylcholine release, has been implicated in drug relapse and is targeted by therapeutic drugs that are used to treat a variety of neurological disorders including Tourette Syndrome, Parkinson's disease and schizophrenia. The present study provides the first direct evidence for the localization of dopamine D2 receptors on striatal cholinergic interneurons of the rat brain using dual labeling immunocytochemistry procedures. Using light microscopy, dopamine D2 receptors were localized on the cell somata and dendritic and axonal processes of striatal cholinergic interneurons in the dorsal striatum and nucleus accumbens of the rat brain. These findings provide a foundation for understanding the specific roles that cholinergic neuronal network systems and interacting dopaminergic signaling pathways play in striatal function and in a variety of clinical disorders including drug abuse and addiction.     

Neuroleptic malignant syndrome-like state following a withdrawal of antiparkinsonian drugs

A 63-year-old woman with diagnosis of Parkinson's disease developed an unusual symptom complex which consisted of extrapyramidal symptoms, disturbances of consciousness, diaphoresis, fever, and increased serum creatine phosphokinase following the discontinuation of large doses of combined antiparkinsonian drugs. After the patient's condition did not improve with the first 14 days of treatment consisting of intravenous fluids and antibiotics, a trial administration of L-dopa and carbidopa brought about definite clinical improvement. The symptoms strongly resembled neuroleptic malignant syndrome which is often a serious complication of antipsychotic drugs. The symptoms and the treatment of the present case suggest that dopaminergic hypoactivity in the brain may be an important factor in antiparkinsonian drug withdrawal syndrome and that similar neurochemical mechanisms may exist in neuroleptic malignant syndrome.