Electrophysiological effects of MK-801 on rat nigrostriatal and mesoaccumbal dopaminergic neurons

Zhang, Jing; Chiodo, Louis A.; Freeman, Arthur

doi:10.1016/0006-8993(92)91091-r

Cited by 129 publications

(89 citation statements)

References 48 publications

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“…According to this model, dopaminergic activity may change only when a sufficient number of these receptors are blocked. Indeed, systemic, but not iontophoretic, administration of dizocilpine elevates the overall firing rate of midbrain dopaminergic neurons, and this effect is blocked by a hemitransection of descending forebrain efferents, many of which project to SNR (Zhang et al, 1992). Thus, SNR lesions would be expected to abolish the increase in dopaminergic activity produced by systemic dizocilpine, and to the extent that neostriatal DOPAC parallels dopamine, our results support this view.…”

Section: Discussionsupporting

confidence: 76%

Intraneostriatal administration of glutamate antagonists increases behavioral activation and decreases neostriatal ascorbate via nondopaminergic mechanisms

Pierce

Rebec

1993

J. Neurosci.

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Behavioral findings suggest that the effects of neostriatal glutamate and ascorbate are opposed to those of neostriatal dopamine.Recent evidence also indicates that glutamate and ascorbate are linked via a carrier-mediated heteroexchange process, suggesting that ascorbate may act through the glutamate system to influence behavior. In order to assess glutamate-ascorbate interactions and their influence on the behavioral output of the basal ganglia, glutamate and homocysteic acid (a glutamate reuptake blocker) as well as NMDA antagonists were infused into the neostriatum of freely moving rats while extracellular neostriatal ascorbate was monitored via electrochemically modified carbon-fiber electrodes. Neostriatal 3,4-dihydroxyphenylacetic acid (DO-PAC), a major dopamine metabolite, also was recorded in order to assess the dependency of any drug effect on the nigrostriatal dopamine system. lntraneostriatal infusions of L-glutamate (1 pg/pl), but not L-homocysteic acid (30 rglpl), elevated extracellular neostriatal ascorbate levels. Neither of these drugs had any effect on neostriatal DOPAC or overt behavioral activity. lntraneostriatal infusion of the noncompetitive NMDA antagonist dirocilpine (MK-801; 3 pg/pl) or the competitive NMDA antagonist 3-(2-carboxypiperazin-4-yl)-propyl-1 -phosphonene (CPPene; 5 rg/Al) decreased neostriatal ascorbate but had no effect on neostriatal DO-PAC. Both dizocilpine and CPPene activated behavior in intact and sham-lesioned animals as well as in animals with near-total depletions of neostriatal dopamine following a 6-hydroxydopamine lesion. When administered systemically, however, dizocilpine (1 .O mg/kg) significantly increased neostriatal DOPAC. This effect appears to be regulated via midbrain NMDA receptors, in that this effect was completely abolished by electrolytic lesions of the substantia nigra pars reticulata. In addition, systemic dizocilpine substantially lowered the level of extracellular ascorbate (in both intact/sham and substantia nigra-lesioned animals), but subsequent intraneostriatal infusions of glutamate increased ascorbate levels to the'same extent as that observed in undrugged animals.Taken together, these results suggest that neostriatal NMDA receptors regulate basal, but not glutamate-stimulat-

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Section: Discussionsupporting

confidence: 76%

Intraneostriatal administration of glutamate antagonists increases behavioral activation and decreases neostriatal ascorbate via nondopaminergic mechanisms

Pierce

Rebec

1993

J. Neurosci.

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“…Indeed, ethanol has been reported to stimulate dopamine (DA) release in the nucleus accumbens [103] and electrophysiological studies have demonstrated a concomitant ethanol-induced increase in the activity of ventral tegmental dopaminergic neurons [22,23]. On the other hand, the observations that the NMDAR antagonist MK-801 increased burst firing of dopaminergic neurons [224] and could stimulate the release of DA from dopaminergic terminal areas suggest that glutamate -acting through NMDARs -exerts a tonic inhibitory action on DA release in the nucleus accumbens [83,109]. According to the model of Fadda and Rossetti [53], blockade of the NMDARs by acute ethanol treatment disinhibits dopaminergic neurons via GABAergic interneurons possessing NMDARs.…”

Section: Consequences Of Increased Nmdar Functionmentioning

confidence: 87%

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

Nagy

Kolok²,

Boros³

et al. 2005

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Long-term alcohol exposure gives rise to development of physical dependence on alcohol in consequence of changes in certain neurotransmitter functions. Accumulating evidence suggests that the glutamatergic neurotransmitter system, especially the N-methyl-D-aspartate (NMDA) type of glutamate receptors is a particularly important site of ethanol's action, since ethanol is a potent inhibitor of the NMDA receptors (NMDARs) and prolonged ethanol exposition leads to a compensatory "upregulation" of NMDAR mediated functions supposedly contributing to the occurrence of ethanol tolerance, dependence as well as the acute and delayed signs of ethanol withdrawal.Recently, expression of different types of NMDAR subunits was found altered after long-term ethanol exposure. Especially, the expression of the NR2B and certain splice variant forms of the NR1 subunits were increased in primary neuronal cultures treated intermittently with ethanol. Since NMDA ion channels with such an altered subunit composition have increased permeability for calcium ions, increased agonist sensitivity, and relatively slow closing kinetics, the abovementioned alterations may underlie the enhanced NMDAR activation observed after long-term ethanol exposure. In accordance with these changes, the inhibitory potential of NR2B subunit-selective NMDAR antagonists is also increased, demonstrating excellent potency against alcohol withdrawal-induced in vitro cytotoxicity. Although in vivo data are few with these compounds, according to the effectiveness of the classic NMDAR antagonists in attenuation, not only the physical symptoms,but also some affective and motivational components of alcohol withdrawal, novel NR2B subunit selective NMDAR antagonists may offer a preferable alternative in the pharmacotherapy of alcohol dependence.

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“…Notably, NMDA agonists produce excitatory responses in cerebellar Purkinje cells and persistent inflammatory hyperalgesia and administration of progesterone attenuates these effects by reducing NMDAR activity (Ren et al, 2000;Smith, 1991). Finally, NMDARs have been localized to the ventral tegmental area (Paquet and Smith, 2000) and pharmacological manipulations of NMDARs in the ventral tegmental area elicit electrophysiological and behavioral changes in rats (Narayanan et al, 1996;Willick and Kokkinidis, 1995;Zhang et al, 1992). Together these findings suggest progestins are capable of mediating changes in NMDAR function that produce alterations in behavior and leave open the possibility that, in the ventral tegmental area, progestins may modulate NMDARs, directly or indirectly, to produce changes in lordosis of rodents.…”

Section: Introductionmentioning

confidence: 94%

MK-801 infusions to the ventral tegmental area and ventromedial hypothalamus produce opposite effects on lordosis of hormone-primed rats

Petralia¹,

DeBold²,

Frye³

2007

Pharmacology Biochemistry and Behavior

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Progesterone initiates female sexual behavior of rodents (lordosis) through actions at intracellular progestin receptors in the ventromedial hypothalamus. Progesterone's metabolite, 5α-pregnan-3α-ol-20-one, mediates the intensity and duration of lordosis through its actions at GABA A receptors in the ventral tegmental area. Whether progestins can influence sexual behavior through actions that involve N-methyl-D-aspartate receptors (NMDARs) in the ventromedial hypothalamus and ventral tegmental area was investigated. The current study examines the effect of bilateral ventral tegmental area or ventromedial hypothalamus infusions of the non-competitive NMDAR antagonist (+)-MK-801 hydrogen maleate (MK-801; 0, 20, or 200 ng) on lordosis, motor activity, and NMDA R1 subtype (NMDAR1) immunoreactivity in estradiol benzoate (10 μg)+ progesterone (50 μg)-and estradiol benzoate+vehicle primed rats. Compared to vehicle infusions, infusions of MK-801 to the ventral tegmental area facilitated lordosis of estradiol benzoate (10 μg)+progesterone (50 μg)-and estradiol benzoate+vehicle primed rats. Infusions of MK-801 to the ventromedial hypothalamus inhibited lordosis of estradiol benzoate (10 μg)+progesterone (50 μg)-and estradiol benzoate+vehicle primed rats, compared to vehicle. There was no effect of MK-801 infusions to the ventral tegmental area or the ventromedial hypothalamus on motor behavior. Immunocytochemistry for NMDAR1 revealed MK-801 (200 ng) infusions to the ventral tegmental area or ventromedial hypothalamus of estradiol benzoate (10 μg)+progesterone (50 μg)-or estradiol benzoate+vehicle primed rats significantly reduced the number of darkly stained NMDAR1-immunoreactive cells, compared to vehicle infusions. These data suggest NMDARs may be important in the mediation of hormonal actions in both the ventral tegmental area and the ventromedial hypothalamus for sexual receptivity of rodents, but in different ways.

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Electrophysiological effects of MK-801 on rat nigrostriatal and mesoaccumbal dopaminergic neurons

Cited by 129 publications

References 48 publications

Intraneostriatal administration of glutamate antagonists increases behavioral activation and decreases neostriatal ascorbate via nondopaminergic mechanisms

Intraneostriatal administration of glutamate antagonists increases behavioral activation and decreases neostriatal ascorbate via nondopaminergic mechanisms

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

MK-801 infusions to the ventral tegmental area and ventromedial hypothalamus produce opposite effects on lordosis of hormone-primed rats

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