l-DOPA inhibits spontaneous acetylcholine release from the striatum of experimental Parkinson's model rats

doi:10.1016/0006-8993(95)00870-V

Brain Research

Volume 698, Issues 1–2, 6 November 1995, Pages 213-216

https://doi.org/10.1016/0006-8993(95)00870-V Get rights and content

Abstract

Acetylcholine (ACh) release was measured by microdialysis. Addition of 10 nM l-DOPA to the perfusate significantly decreased ACh release, from the striatum of rats lesioned with 6-hydroxydopamine (6-OHDA), but not sham-operated rats. The l-DOPA-induced decrease was not affected by (−)-sulpiride which completely blocked D₂- and D₃-agonist-induced decrease in ACh release in lesioned rats. Neither 10 nM d-DOPA nor 100 nM dopamine caused any change in ACh release. These findings suggest that l-DOPA-sensitive mechanisms are supersensitized in Parkinson's disease model rats.

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Cited by (27)

Expanding the repertoire of L-DOPA's actions: A comprehensive review of its functional neurochemistry
2017, Progress in Neurobiology
Citation Excerpt :
Closer to home, endogenous L-DOPA was found to be released in a partially Ca2+-dependent and TTX-sensitive manner in various brain regions including the striatum (Goshima et al., 1988; Misu and Goshima, 1993; Misu et al., 1990, 1995, 1996; Nakamura et al., 1992). Complementing these studies, it is tempting to argue for the existence of a “L-DOPA receptor” since some responses to L-DOPA are triggered with very low concentrations and independently from DA (Ueda et al., 1995a,b). Though unequivocal evidence is still lacking, the orphan receptor GPR143 (Ocular albinism 1), has been shown to display significant affinity for L-DOPA (approximately 70 μM) and 2 mediates the depressor and bradycardic effects of L-DOPA in the nucleus tractus solitarius (Hiroshima et al., 2014; Lopez et al., 2008).
Though a multi-facetted disorder, Parkinson’s disease is prototypically characterized by neurodegeneration of nigrostriatal dopaminergic neurons of the substantia nigra pars compacta, leading to a severe disruption of motor function. Accordingly, L-DOPA, the metabolic precursor of dopamine (DA), is well-established as a treatment for the motor deficits of Parkinson’s disease despite long-term complications such as dyskinesia and psychiatric side-effects. Paradoxically, however, despite the traditional assumption that L-DOPA is transformed in residual striatal dopaminergic neurons into DA, the mechanism of action of L-DOPA is neither simple nor entirely clear. Herein, focussing on its influence upon extracellular DA and other neuromodulators in intact animals and experimental models of Parkinson’s disease, we highlight effects other than striatal generation of DA in the functional profile of L-DOPA. While not excluding a minor role for glial cells, L-DOPA is principally transformed into DA in neurons yet, interestingly, with a more important role for serotonergic than dopaminergic projections. Moreover, in addition to the striatum, L-DOPA evokes marked increases in extracellular DA in frontal cortex, nucleus accumbens, the subthalamic nucleus and additional extra-striatal regions. In considering its functional profile, it is also important to bear in mind the marked (probably indirect) influence of L-DOPA upon cholinergic, GABAergic and glutamatergic neurons in the basal ganglia and/or cortex, while anomalous serotonergic transmission is incriminated in the emergence of L-DOPA elicited dyskinesia and psychosis. Finally, L-DOPA may exert intrinsic receptor-mediated actions independently of DA neurotransmission and can be processed into bioactive metabolites. In conclusion, L-DOPA exerts a surprisingly complex pattern of neurochemical effects of much greater scope that mere striatal transformation into DA in spared dopaminergic neurons. Their further experimental and clinical clarification should help improve both L-DOPA-based and novel strategies for controlling the motor and other symptoms of Parkinson’s disease.
Dopamine modulates processing speed in the human mesolimbic system
2013, NeuroImage
Citation Excerpt :
Thus, cholinergic agonists have attenuating effects on dopaminergic neurotransmission. Conversely, administration of levodopa decreases striatal acetylcholine release (Tedroff, 1997; Ueda et al., 1995). Furthermore, it has been proposed that the MTL and PFC compete over dominance in processing behaviorally relevant stimuli (Grace et al., 2007).
Neural activity in mesolimbic brain regions scales with stimulus novelty but the mechanistic role of neurotransmitters in this process remains unclear. Here, we used magnetoencephalography together with psychopharmacological stimulation in healthy humans to demonstrate that the neuronal dynamics of novelty processing are temporally adaptive and flexible. In particular, enhanced dopaminergic (150 mg levodopa) – but not cholinergic (8 mg galantamine) – neurotransmission accelerated the onset of novelty signals within the medial temporal lobe (MTL) from ~ 300 to < 100 ms. Cholinergic stimulation, on the other hand, led to a shift in underlying neural substrates from medial temporal to prefrontal brain regions. Our findings indicate a causal role of dopamine in regulating the processing speed of novelty sensitive MTL neurons. Moreover, they suggest that the influence of MTL and prefrontal brain regions in novelty processing is mediated by the balance of dopamine and acetylcholine levels.
L-Amino acid decarboxylase- and tyrosine hydroxylase-immunoreactive cells in the extended olfactory amygdala and elsewhere in the adult prairie vole brain
2012, Journal of Chemical Neuroanatomy
Citation Excerpt :
It also acts on presynaptic β-adrenergic receptors to influence DA release in the striatum and potentiates postsynaptic D2 receptor function in the striatum (Goshima et al., 1991; Hume et al., 1995; Misu et al., 1986). In other neural networks, l-DOPA affects release of norepinephrine, acetylcholine, and glutamate, as well as postsynaptic responses to GABA (Goshima et al., 1986, 1991, 1993; Honjo et al., 1999; Ueda et al., 1995). l-DOPA released by TH-synthesizing terminals may be taken up by neighboring AADC-synthesizing neurons to produce DA (Ugrumov et al., 2002), which may occur for the many TH-ir cells in the male prairie vole pBST and MeApd that terminate in the MPO (Northcutt and Lonstein, 2011) so that the cells can cooperatively produce DA.
Neurons synthesizing dopamine (DA) are widely distributed in the brain and implicated in a tremendous number of physiological and behavioral functions, including socioreproductive behaviors in rodents. We have recently been investigating the possible involvement of sex- and species-specific TH-immunoreactive (TH-ir) cells in the male prairie vole (Microtus ochrogaster) principal bed nucleus of the stria terminalis (pBST) and posterodorsal medial amygdala (MeApd) in the chemosensory control of their monogamous pairbonding and parenting behaviors. These TH-ir cells are not immunoreactive for dopamine-beta-hydroxylase (DBH), suggesting they are not noradrenergic but possibly DAergic. A DAergic phenotype would require them to contain aromatic l-amino acid decarboxylase (AADC) and here we examined the existence of cells immunoreactive for both TH and AADC in the pBST and MeApd of adult virgin male and female prairie voles. We also investigated the presence of TH/AADC cells in the anteroventral periventricular nucleus (AVPV), medial preoptic area (MPO), arcuate nucleus (ARH), zona incerta (ZI), substantia nigra (SN) and ventral tegmental area (VTA). Among our findings were: (1) the pBST and MeApd each contained completely non-overlapping distributions of TH-ir and AADC-ir cells, (2) the AVPV contained surprisingly few AADC-ir cells and almost no TH-ir cells contained AADC-ir, (3) approximately 60% of the TH-ir cells in the MPO, ARH, and ZI also contained AADC-ir, (4) unexpectedly, only about half of TH-ir cells in the SN and VTA contained AADC-ir, and (5) notable populations of AADC-ir cells were found outside traditional monoamine-synthesizing regions, including some sites that do not contain AADC-ir cells in adult laboratory rats or cats (medial septum and cerebral cortex). In the absence of the chemical requirements to produce DA, monoenzymatic TH-ir cells in the virgin adult prairie vole pBST, MeApd, and elsewhere in their brain may instead produce l-DOPA as an end product and use it as a neurotransmitter or neuromodulator, similar to what has been observed for monoenzymatic TH-synthesizing cells in the laboratory rat brain.
Intrastriatal inhibition of aromatic amino acid decarboxylase prevents l-DOPA-induced dyskinesia: A bilateral reverse in vivo microdialysis study in 6-hydroxydopamine lesioned rats
2008, Neurobiology of Disease
Citation Excerpt :
This result was obtained by striatal administration of benserazide blocking the conversion of l-DOPA to DA. Accumulating evidence shows that in addition to being a precursor of DA l-DOPA may be a neurotransmitter in its own right (Hornykiewicz, 2002; Misu et al., 2002, 2003; Ueda et al., 1995). Misu et al. (2003) proposed that l-DOPA itself fulfills the criteria for neurotransmitters (synthesis, metabolism, active transport, presence, physiological release, competitive antagonism, physiological or pharmacological responses).
l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia consists of involuntary choreiform and dystonic movements. Here we report whether intrastriatal l-DOPA itself is able to trigger dyskinetic behavior and which role the neurotransmitter dopamine (DA) and its metabolites play.
Intrastriatal l-DOPA as well as DA administration at the 6-hydroxydopamine (6-OHDA) lesioned side led to a significant appearance of dyskinetic behavior, whereas DA metabolites were ineffective. Intrastriatal inhibition of the enzyme aromatic amino acid decarboxylase (AADC) by benserazide prevented the appearance of l-DOPA-induced dyskinetic movements at the lesioned side. Principle component analysis of DA and DA metabolite levels with dyskinesia scores after l-DOPA/benserazide (6/15 mg/kg) administration indicated a significant correlation only for DA, whereas DA metabolites did not show any significant correlation with the occurrence of dyskinetic behavior.
We conclude that intrastriatal l-DOPA itself is not able to induce dyskinetic movements, whereas the increase of intrastriatal DA levels is instrumental for l-DOPA- and DA-induced dyskinetic behavior.
L-3,4-dihydroxyphenylalanine as a neurotransmitter candidate in the central nervous system
2003, Pharmacology and Therapeutics
Citation Excerpt :
Thus, we have to find potent, peripherally or orally effective, and stable antagonists of levodopa and released DOPA. Rats given a nigrostriatal dopaminergic hemilesion with 6-hydroxydopamine prior to local injection of levodopa (10–100 nM) into the medial forebrain bundle, in the absence of NSD-1015, experienced an inhibition of the basal release of ACh during striatal microdialysis compared with sham-operated rats (Ueda et al., 1995) (Fig. 5B). This inhibition elicited by levodopa is independent of the conversion of dopamine from levodopa because dopamine (100 nM) administered at the same dose to the highest dose of levodopa elicits no inhibition.
Historically, 3,4-dihydroxyphenylalanine (DOPA) has been believed to be an inert amino acid that alleviates the symptoms of Parkinson's disease by its conversion to dopamine via the enzyme aromatic l-amino acid decarboxylase. In contrast to this generally accepted idea, we propose that DOPA itself is a neurotransmitter and/or neuromodulator, in addition to being a precursor of dopamine. Several criteria, such as synthesis, metabolism, active transport, existence, physiological release, competitive antagonism, and physiological or pharmacological responses, must be satisfied before a compound is accepted as a neurotransmitter. Recent evidence suggests that DOPA fulfills these criteria in its involvement mainly in baroreflex neurotransmission in the lower brainstem and in delayed neuronal death by transient ischemia in the striatum and the hippocampal CA1 region of rats.
DOPA causes glutamate release and delayed neuron death by brain ischemia in rats
2002, Neurotoxicology and Teratology
DOPA seems to be a neuromodulator in striata and hippocampal CA1 and a neurotransmitter of the primary baroreceptor afferents terminating in the nucleus tractus solitarii (NTS) and baroreflex pathways in the caudal ventrolateral medulla and rostral ventrolateral medulla in the brainstem of rats. DOPA recognition sites differ from dopamine (DA) D₁ and D₂ and ionotropic glutamate receptors. Via DOPA sites, DOPA stereoselectively releases by itself neuronal glutamate from in vitro and in vivo striata. In the cultured neurons, DOPA and DA cause neuron death via autoxidation. In addition, DOPA causes autoxidation-irrelevant neuron death via glutamate release. Furthermore, DOPA released by four-vessel occlusion seems to be an upstream causal factor for glutamate release and resultant delayed neuron death by brain ischemia in striata and hippocampal CA1. Glutamate has been regarded as a neurotransmitter of baroreflex pathways. Herein, we propose a new pathway that DOPA is a neurotransmitter of the primary aortic depressor nerve and glutamate is that of secondary neurons in neuronal microcircuits of depressor sites in the NTS. DOPA seems to release unmeasurable, but functioning, endogenous glutamate from the secondary neurons via DOPA sites. A common following pathway may be ionotropic glutamate receptors–nNOS activation–NO production–baroreflex neurotransmission and delayed neuron death. However, we are concerned that DOPA therapy may accelerate neuronal degeneration process especially at progressive stages of Parkinson's disease.

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l-DOPA inhibits spontaneous acetylcholine release from the striatum of experimental Parkinson's model rats

Abstract

Neurosci. Lett.

Trends Neurosci.

Neurosci. Lett.

Life Sci.

Neurosci. Lett.

Neurosci. Lett.

Brain Res.

Semin. Neurosci.

Trends Pharmacol. Sci.