Role of dopaminergic mechanisms in the stimulatory effects of MK-801 injected into the ventral tegmental area and the nucleus accumbens

Narayanan, S.; Willins, David L.; Dalia, Asad; Wallace, Lane J.; Uretsky, Norman J.

doi:10.1016/0091-3057(95)02220-1

Cited by 57 publications

(32 citation statements)

References 38 publications

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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: 93%

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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Section: Introductionmentioning

confidence: 93%

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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“…It has been suggested that the primary effects of systemic MK-801 injection resemble those displayed in the ACC and VTA (33). In addition to a direct effect, MK-801 could affect the ACC indirectly by modulating dopaminergic activity in the VTA and prefrontal cortex (4).…”

Section: Discussionmentioning

confidence: 99%

“…The activity of MK-801 depends on the availability of free DA D 1 receptors (33,49,50), functional state and integrity of dopaminergic system (6), and the association between DA and excitatory amino acids that occurs postsynaptically in the ACC (5). An intact dopaminergic activity facilitates the stimulatory effects of MK-801 (51,52).…”

Section: Discussionmentioning

confidence: 99%

Role of Dopaminergic System in Core Part of Nucleus Accumbens in Hyperlocomotion and Rearing Induced by MK-801 in Rats: A Behavioral and In Vivo Microdialysis Study

Hatip‐Al‐Khatib

Bolukbasi

Mishima

et al. 2001

Japanese Journal of Pharmacology

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ABSTRACT-We investigated modification of the MK-801 effect on motor activity and extracellular amines concentration by 6-hydroxydopamine (6-OHDA)-induced lesion of core nucleus accumbens (cACC) of rats. In vivo microdialysis-HPLC showed that the concentrations (fmol /ml) of dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and serotonin were 0.738 ± 0.135, 155.34 ± 41.01 and 0.334 ± 0.024, respectively, in the cACC of intact rats. The DOPAC /DA ratio was 264.24 ± 94.01. Unilateral lesion of the cACC with 6-OHDA (8 mg/ml) substantially reduced DA (-93%) and DOPAC (-97%) in desipramine (30 mg /kg, i.p.)-pretreated rats (6-OHDA+DMI rats) as compared to the 65% reduction rate of both amines in salinepretreated rats (6-OHDA+saline rats). Moreover, DOPAC was reduced by 72% in 6-OHDA+DMI rats. MK-801 increased DOPAC (426 -467%) and DOPAC /DA ratio (180 -230%) in intact rats. On the other hand, MK-801 increased DA by 154% and 505% in 6-OHDA+saline and 6-OHDA+DMI rats, respectively. 6-OHDA reduced the effect of MK-801 on DOPAC and DOPAC /DA ratio. In the behavioral studies, MK-801 (0.01 -0.3 mg /kg, i.p.) increased locomotor activity and rearing of intact rats. Bilateral 6-OHDA+DMI lesion of the cACC caused greater reduction in the effect of MK-801 (0.1 mg /kg) than that of the shell nucleus accumbens. These results suggest that increased extracellular DOPAC concentration (but not DA) and DOPAC /DA ratio in the cACC plays an important role in MK-801-hyperactivity.Keywords: MK-801, Core nucleus accumbens (rat), Microdialysis, Motor activityThe nucleus accumbens (ACC) is a part of the mesocortical and mesolimbic dopaminergic system. The ACC receives dopaminergic inputs from the ventral tegmental area (VTA) and glutamatergic inputs that originate from cortical regions (including medial frontal), amygdala and midline thalamus (1). The ACC is involved in a variety of behavioral activities. The dopaminergic system in the ACC plays an important role in control of spontaneous, psychostimulants (2)-and MK-801 (3 -6)-induced locomotor hyperactivity. On the other hand, the allocortical-originated glutamatergic afferents could modulate the psychomotor activation and drug reinforcement (7). Moreover, the glutamatergic and dopaminergic systems not only separately alter the behavioral effects but could also act by interacting and modulating the function of each other. A functional interaction has been reported between the glutamatergic system (via Nmethyl-D-aspartate (NMDA) receptors) and the dopaminergic system at the striatal levels (8) with a negative modulatory effect of the glutamatergic system on the dopaminergic one (9). The consequence of glutamate block depends on which of glutamate receptors are blocked. In the ACC, it is suggested that antagonists that block only NMDA autoreceptors increase synaptic glutamate level and disinhibit dopaminergic terminals. On the other hand, NMDA and non-NMDA antagonists that block both the glutamate autoreceptors and postsynaptic receptors inactivate the dopaminergic terminals (10).Cytoarchite...

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“…Moreover, the finding that dizocilpine infusion into some brain regions decreases PPI without markedly increasing startle magnitude (DH) and that dizocilpine infusion into other regions increases startle reactivity without disrupting PPI (NAcc) indicates that perhaps different brain regions subserve these two behavioral effects of systemically administered noncompetitive NMDA antagonists (Mansbach and Geyer, 1989). Dizocilpine administration also has been reported to increase locomotor activity, most likely via a dopaminergic mechanism (French, 1986;Tricklebank et al, 1989;Lehmann-Masten and Geyer, 1991;Bubser et al, 1992;Ouagazzal et al, 1993;Ouagazzal and Amalric, 1995;Narayan et al, 1996). Although locomotor activity was not measured in the present study, it should be noted that the doses of dizocilpine required to elicit hyperactivity are generally appreciably higher than those needed to disrupt PPI, either with systemic or central administration (Mansbach and Geyer, 1989;Lehmann-Masten and Geyer, 1991;Ouagazzal and Amalric, 1995;Narayan et al, 1996).…”

Section: Figure 1 Effects On Prepulse Inhibition Of Dizocilpine Micrmentioning

confidence: 99%

“…Dizocilpine administration also has been reported to increase locomotor activity, most likely via a dopaminergic mechanism (French, 1986;Tricklebank et al, 1989;Lehmann-Masten and Geyer, 1991;Bubser et al, 1992;Ouagazzal et al, 1993;Ouagazzal and Amalric, 1995;Narayan et al, 1996). Although locomotor activity was not measured in the present study, it should be noted that the doses of dizocilpine required to elicit hyperactivity are generally appreciably higher than those needed to disrupt PPI, either with systemic or central administration (Mansbach and Geyer, 1989;Lehmann-Masten and Geyer, 1991;Ouagazzal and Amalric, 1995;Narayan et al, 1996). A few studies indicate that dizocilpine infusion into the NAcc increases locomotor activity (Ouagazzal and Amalric, 1995;Narayan et al, 1996); future studies that provide a detailed anatomical mapping of brain regions that mediate dizocilpine-induced hyperactivity will be important in clarifying the degree of homology between the neural substrates underlying dizocilpine-induced PPI deficits and hyperactivity.…”

Section: Figure 1 Effects On Prepulse Inhibition Of Dizocilpine Micrmentioning

confidence: 99%

Multiple Limbic Regions Mediate the Disruption of Prepulse Inhibition Produced in Rats by the Noncompetitive NMDA Antagonist Dizocilpine

Bakshi¹,

Geyer

1998

J. Neurosci.

154

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Prepulse inhibition (PPI), a phenomenon in which a weak prestimulus decreases the startle response to an intense stimulus, provides an operational measure of sensorimotor gating (a process by which an organism filters sensory information) and is diminished in schizophrenia and schizotypal patients. The psychotomimetic phencyclidine and its potent congener dizocilpine are noncompetitive antagonists of the NMDA receptor complex, and they disrupt PPI in rodents, mimicking the clinically observed PPI deficit. The neuroanatomical substrates mediating the PPI-disruptive effects of noncompetitive NMDA antagonists are unknown. The present study sought to identify brain regions subserving the disruption of PPI produced by noncompetitive NMDA antagonists in rats. PPI was measured in startle chambers immediately after bilateral infusion of dizocilpine (0, 0.25, 1.25, and 6.25 g/0.5 l/side) into one of six brain regions: amygdala, dorsal hippocampus, medial prefrontal cortex, nucleus accumbens, ventral hippocampus, and dorsomedial thalamus. Dizocilpine significantly decreased PPI after infusion into the amygdala or dorsal hippocampus. A trend toward PPI disruption was observed with administration into medial prefrontal cortex. In contrast, no change in PPI was produced by dizocilpine infusion into nucleus accumbens, ventral hippocampus, or dorsomedial thalamus. Startle reactivity was increased by dizocilpine infusion into amygdala, dorsal hippocampus, nucleus accumbens, and dorsomedial thalamus, but not medial prefrontal cortex. These findings indicate that multiple limbic forebrain regions mediate the ability of noncompetitive NMDA antagonists to disrupt PPI and that the PPI-disruptive and the startle-increasing effects of dizocilpine are mediated by different central sites.

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Role of dopaminergic mechanisms in the stimulatory effects of MK-801 injected into the ventral tegmental area and the nucleus accumbens

Cited by 57 publications

References 38 publications

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

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

Role of Dopaminergic System in Core Part of Nucleus Accumbens in Hyperlocomotion and Rearing Induced by MK-801 in Rats: A Behavioral and In Vivo Microdialysis Study

Multiple Limbic Regions Mediate the Disruption of Prepulse Inhibition Produced in Rats by the Noncompetitive NMDA Antagonist Dizocilpine

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