The effects of an irreversible dopamine receptor antagonist, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), on the regulation of muscle tone in the rat: the role of the substantia nigra

doi:10.1016/S0304-3940(98)00463-7

Neuroscience Letters

Volume 251, Issue 2, 24 July 1998, Pages 77-80

https://doi.org/10.1016/S0304-3940(98)00463-7 Get rights and content

Abstract

Recent evidence has questioned the view that the increased muscle tone of Parkinson's disease results solely from reduced release of dopamine in the striatum, by emphasising the important role of the substantia nigra. The aim of the current study was to compare the effects on muscle tone of inactivating D₁ and D₂ dopamine receptors throughout the brain with those seen following their inactivation only in the substantia nigra. Inactivation of dopamine receptors by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline injected either intraperitoneally, or bilaterally into the substantia nigra, resulted in similar increases in muscle tone, measured as changes in tonic electromyographic (EMG) activity. The magnitude and onset of EMG increases was related to the level of dopamine receptor inactivation. The results are consistent with the hypothesis that nigral dopamine mechanisms play a key role in the maintenance of muscle tone.

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2017, Experimental Neurology
Citation Excerpt :
Behavioral studies modulating dopaminergic receptors in rodents SNr has shown that, generally, activation of DA receptors in SNr augment movement (Meloni and Davis, 2004). In contrast, infusions of DA antagonist or DA blockade result in a series of shortfall motor behaviors such as decreased lever-pressing (Trevitt et al., 2001), contralateral circling (Asin and Montana, 1988) or rigidity (Hemsley and Crocker, 1998). Another potential compensatory mechanism is the glutamatergic projection from STN to the SNc (Bezard et al., 1997a), which could stimulate the remaining dopaminergic neurons.
The motor features of Parkinson's disease (PD) are well known to manifest only when striatal dopaminergic deficit reaches 60–70%. Thus, PD has a long pre-symptomatic and pre-motor evolution during which compensatory mechanisms take place to delay the clinical onset of disabling manifestations. Classic compensatory mechanisms have been attributed to changes and adjustments in the nigro-striatal system, such as increased neuronal activity in the substantia nigra pars compacta and enhanced dopamine synthesis and release in the striatum. However, it is not so clear currently that such changes occur early enough to account for the pre-symptomatic period. Other possible mechanisms relate to changes in basal ganglia and motor cortical circuits including the cerebellum. However, data from early PD patients are difficult to obtain as most studies have been carried out once the diagnosis and treatments have been established. Likewise, putative compensatory mechanisms taking place throughout disease evolution are nearly impossible to distinguish by themselves. Here, we review the evidence for the role of the best known and other possible compensatory mechanisms in PD. We also discuss the possibility that, although beneficial in practical terms, compensation could also play a deleterious role in disease progression.
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Thus it is possible to test whether the effects of EEDQ treatment are caused by selective inactivation of a given receptor by comparing its effects in preparations with and without protection of the receptor with its antagonist. Our EEDQ treatment is based on the protocol of Hemsley and Crocker (1998). All animals were injected intraperitoneally with 60 μmol/kg of EEDQ 2 h before sacrifice.
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Contribution of the serotonin 5-HT<inf>1A</inf> receptor agonism of 8-OH-DPAT and EMD 128130 to the regulation of haloperidol-induced muscle rigidity in rats
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The aim of the present study was to find out whether (±)-8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT), a prototypical 5-HT_1A agonist, and (R)-(−)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane HCl (EMD 128130), a compound with serotonin 5-HT_1A-agonist and dopamine D₂-like antagonist properties, are able to attenuate the haloperidol-induced (1 mg/kg) muscle rigidity in rats. Muscle tone was examined using a combined mechano- and electromyographic (EMG) method that simultaneously measured the mechanical muscle resistance (MMG) of the rat’s hind foot to passive movements in the ankle joint, and the EMG activity of two antagonist muscles. Both 8-OH-DPAT (0.125–0.5 mg/kg i.p.) and EMD 128130 (1–10 mg/kg i.p.) dose-dependently decreased the haloperidol-enhanced MMG to passive movements, as well as the tonic and the long-latency reflex EMG activities.
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While muscarinic receptor antagonists are used to reduce motor side effects associated with the use of antipsychotic drugs, their site of action remains unclear. The study investigated the site of action of the non-selective muscarinic receptor antagonist atropine on catalepsy induced by the selective dopamine D2 receptor antagonist, raclopride. Initially, catalepsy and striatal muscarinic receptor occupancy was assessed 2 h following subcutaneous injection of raclopride and either atropine or vehicle. Catalepsy was significantly reduced by doses of atropine that occupied more than 69% of muscarinic receptors. Next, atropine was injected bilaterally into the ventral striatum, which produced a significant reduction in catalepsy, while injections into the dorsal striatum and substantia nigra had no effect. The site of atropine's action was localised to a discrete area of the ventral striatum through the use of quantitative autoradiographic techniques. These findings provide further evidence for the importance of the ventral striatum in the expression of behaviours.

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The effects of an irreversible dopamine receptor antagonist, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), on the regulation of muscle tone in the rat: the role of the substantia nigra

Abstract

Trends Neurosci.

Brain Res.

Neurosci Lett.

Neurosci. Lett.

Quantitative autoradiographic localisation of the D1 and D2 subtypes of dopamine receptors in rat brain

J Neurosci.

Dendritic release of dopamine in the substantia nigra

Nature

Quantitative autoradiographic localisation of the D₁ and D₂ subtypes of dopamine receptors in rat brain