Chronic Dizocilpine Maleate (MK‐801) Treatment Suppresses the Effects of Nigrostriatal Dopamine Deafferentation on Enkephalin but not on Substance P Expression in the Rat Striatum

Abstract

The present study examined the effects of chronic treatment with dizocilpine maleate (0.2 mg/kg i.p., twice a day for 8 days) alone or in combination with unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal dopaminergic neurons on substance P and enkephalin expression in the rat striatum. This was done by means of quantitative in situ hybridization histochemistry and immunocytochemistry. As reported previously, the unilateral dopaminergic lesion resulted in marked decreases in substance P mRNA expression and immunoreactivity in the ipsilateral striatum while enkephalin mRNA expression and Met-enkephalin immunoreactivity were considerably increased in this structure. Blockade of NMDA receptors by chronic dizocilpine maleate treatment alone resulted in decreased levels of striatal substance P mRNA without significant change in substance P immunoreactivity versus controls. Enkephalin mRNA levels were also decreased in the striatum, matched by parallel reductions in Met-enkephalin immunoreactivity. These observations indicate that NMDA receptor activity may exert tonic excitatory effects on substance P and enkephalin expression in the striatum. The same chronic treatment with dizocilpine maleate started 12 days after the 6-hydroxydopamine injection suppressed the lesion-induced up-regulation of enkephalin expression without significantly affecting the down-regulation of substance P expression. These data provide evidence that NMDA receptor-mediated mechanisms contribute to the alteration of striatal enkephalin expression associated with dopaminergic depletion in hemiparkinsonian rat models.

Treadmill running induces striatal Fos expression via NMDA glutamate and dopamine receptors

“…now et al 1990) or neutralization of the inhibitory effects of DA influence via D 2 receptors on striatopallidal neurons (Gerfen 1992;Hajji et al 1996). Our results showing increased Fos expression in the lateral striatum after administration of eticlopride, and decreased Fos expression in the medial striatum but not in the lateral striatum after administration of SCH-23390 plus eticlopride are in accordance with these previous reports of the effects of D 2 antagonists.…”

High-Frequency Stimulation of the Subthalamic Nucleus Potentiates l-DOPA-Induced Neurochemical Changes in the Striatum in a Rat Model of Parkinson's Disease

“…For instance, dopamine lesion is known to induce an increase in striatal glutamate transmission, and we recently provided evidence for an additional increase in L-DOPAtreated dyskinetic rats (Gubellini et al, 2006). Consistently, treatments with glutamate antagonists reduce both the increase in striatal PPE induced by dopamine lesion (Hajji et al, 1996) and the additional increase elicited by L-DOPA (Perier et al, 2002) as well as LID. However, striatal glutamate synaptic transmission is unlikely to mediate the cellular effects of STN-HFS reported here.…”

Fenfluramine-induced increase in preproenkephalin mRNA levels in the striatum: Interaction between the serotonergic, glutamatergic, and dopaminergic systems

“…This is in agreement with previous data showing that striatal DA depletion (i.e., 6-OHDA lesion) resulted in increased expression of PPE mRNA (Cenci et al, 1993;Gerfen et al, 1991;Voorn et al, 1987). The increase in levels of PPE mRNA observed in 6-OHDA-lesioned striata after removing the inhibitory effect of DA on D 2 receptors is blocked by administra-tion of MK-801 or by corticostriatal deafferentation (Campbell and Björklund, 1994;Hajji et al, 1996). These results could be related to the observation that lack of stimulation of D 1 DA receptors decreases the conductance of NMDA-receptor-associated channels, while lack of stimulation of D 2 receptors increases the conductance of these channels (Cepeda et al, 1993).…”

“…Given that administration of FE in experimental conditions similar to those of the present study has been reported to induce release of DA in the striatum, and DA is usually considered to exert tonic inhibitory control over enkephalinergic neurons (see above), one would expect to find PPE mRNA levels decreased or unchanged after FE administration (Hurd and Herkehnham, 1992;Smith and McGinty, 1994). However, there is a great deal of evidence indicating that striatal neuropeptide gene expression is regulated not only by dopaminergic afferents but also by the glutamatergic corticostriatal system and the serotonergic system (Bath and Baraban, 1993;Campbell and Björklund, 1994;Hajji et al, 1996;Morris et al, 1988a). Similarly, it has been suggested that the striatal Fos expression induced by a dose of FE similar to that used in the present study is due to DA release, and specifically to dopaminergic stimulation of D 1 -receptor containing neurons (Hanson et al, 1991;Torres and Rivier, 1994;Torres, 1995); however, we have recently demonstrated that FE-induced Fos expression in striatal neurons involves interaction between the serotonergic, dopaminergic, and glutamatergic systems .…”

“…After removing the intense inhibitory control that DA exerts over enkephalinergic striatopallidal neurons, the increase in levels of PPE mRNA is blocked by administration of MK-801 or by corticostriatal deafferentation (Campbell and Björk-lund, 1994;Hajji et al, 1996) but only reduced by 5-HT depletion. After DA denervation, the increase in striatal levels of PPE mRNA could be mostly related to the increase in the excitatory effect of glutamate (see above), but also related to some compensatory changes in the serotonergic system that would be eliminated in animals subjected to simultaneous lesion of the DA system and the 5-HT system.…”