MK-801 prevents alterations in the mesoaccumbens dopamine system associated with behavioral sensitization to amphetamine

Marina Wolf, Francis J. White, Xiu Ti Hu

Research output: Contribution to journalArticle

182 Citations (Scopus)

Abstract

Behavioral sensitization to psychomotor stimulants has been shown to be accompanied by a number of alterations in the mesoaccumbens dopamine (DA) system, including DA autoreceptor subsensitivity in the ventral tegmental area (VTA), postsynaptic D1 receptor supersensitivity in the nucleus accumbens (NAc), and augmentation of the DA-releasing effects of stimulants in the NAc. The present study examined whether coadministration of the noncompetitive NMDA antagonist MK-801 with amphetamine, which has been shown to prevent the development of behavioral sensitization to amphetamine, would also prevent these changes in mesoaccumbens DA function. Rats were treated for 5 d with amphetamine according to a regimen known to produce lasting sensitization. Extracellular single-unit recordings from VTA DA neurons in amphetamine-treated rats, performed after 1 d of abstinence, revealed robust autoreceptor subsensitivity to DA agonists. This was prevented in rats coadministered MK-801 with amphetamine during the 5 d pretreatment period. Recordings from NAc neurons in amphetamine-treated rats demonstrated supersensitivity of D1 receptors to iontophoretic administration of selective agonists when tested after 7 d of abstinence. This was also prevented by MK-801 coadministration. Microdialysis studies performed in awake rats after 7 d of abstinence failed to demonstrate augmentation of amphetamine-stimulated DA release in amphetamine-treated rats as compared to water controls, despite the fact that behavioral sensitization was evident in the former group during microdialysis experiments. MK-801 coadministration prevented behavioral sensitization in microdialysis rats but did not alter amphetamine-stimulated DA release. These results suggest (1) NMDA receptor stimulation is required for the development of both autoreceptor subsensitivity in the VTA and postsynaptic D1 receptor supersensitivity in the NAc during repeated amphetamine treatment, (2) these functional changes therefore appear to be closely associated with the development of behavioral sensitization, and (3) a dissociation can be demonstrated between the intensity of amphetamine-stimulated behavioral responses and amphetamine- stimulated DA release in the NAc.

Original languageEnglish (US)
Pages (from-to)1735-1745
Number of pages11
JournalJournal of Neuroscience
Volume14
Issue number3 II
StatePublished - Mar 1 1994
Externally publishedYes

Fingerprint

Dizocilpine Maleate
Amphetamine
Dopamine
Nucleus Accumbens
Autoreceptors
Ventral Tegmental Area
Microdialysis
Dopamine Agents
Dextroamphetamine
Dopaminergic Neurons
Dopamine Agonists
N-Methylaspartate
N-Methyl-D-Aspartate Receptors
Neurons

Keywords

  • dopamine autoreceptors
  • dopamine release
  • NMDA receptors
  • nucleus accumbens
  • ventral tegmental area

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

MK-801 prevents alterations in the mesoaccumbens dopamine system associated with behavioral sensitization to amphetamine. / Wolf, Marina; White, Francis J.; Hu, Xiu Ti.

In: Journal of Neuroscience, Vol. 14, No. 3 II, 01.03.1994, p. 1735-1745.

Research output: Contribution to journalArticle

@article{660a9e724b6c4b3db4cf7e1aef6f090f,
title = "MK-801 prevents alterations in the mesoaccumbens dopamine system associated with behavioral sensitization to amphetamine",
abstract = "Behavioral sensitization to psychomotor stimulants has been shown to be accompanied by a number of alterations in the mesoaccumbens dopamine (DA) system, including DA autoreceptor subsensitivity in the ventral tegmental area (VTA), postsynaptic D1 receptor supersensitivity in the nucleus accumbens (NAc), and augmentation of the DA-releasing effects of stimulants in the NAc. The present study examined whether coadministration of the noncompetitive NMDA antagonist MK-801 with amphetamine, which has been shown to prevent the development of behavioral sensitization to amphetamine, would also prevent these changes in mesoaccumbens DA function. Rats were treated for 5 d with amphetamine according to a regimen known to produce lasting sensitization. Extracellular single-unit recordings from VTA DA neurons in amphetamine-treated rats, performed after 1 d of abstinence, revealed robust autoreceptor subsensitivity to DA agonists. This was prevented in rats coadministered MK-801 with amphetamine during the 5 d pretreatment period. Recordings from NAc neurons in amphetamine-treated rats demonstrated supersensitivity of D1 receptors to iontophoretic administration of selective agonists when tested after 7 d of abstinence. This was also prevented by MK-801 coadministration. Microdialysis studies performed in awake rats after 7 d of abstinence failed to demonstrate augmentation of amphetamine-stimulated DA release in amphetamine-treated rats as compared to water controls, despite the fact that behavioral sensitization was evident in the former group during microdialysis experiments. MK-801 coadministration prevented behavioral sensitization in microdialysis rats but did not alter amphetamine-stimulated DA release. These results suggest (1) NMDA receptor stimulation is required for the development of both autoreceptor subsensitivity in the VTA and postsynaptic D1 receptor supersensitivity in the NAc during repeated amphetamine treatment, (2) these functional changes therefore appear to be closely associated with the development of behavioral sensitization, and (3) a dissociation can be demonstrated between the intensity of amphetamine-stimulated behavioral responses and amphetamine- stimulated DA release in the NAc.",
keywords = "dopamine autoreceptors, dopamine release, NMDA receptors, nucleus accumbens, ventral tegmental area",
author = "Marina Wolf and White, {Francis J.} and Hu, {Xiu Ti}",
year = "1994",
month = "3",
day = "1",
language = "English (US)",
volume = "14",
pages = "1735--1745",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "3 II",

}

TY - JOUR

T1 - MK-801 prevents alterations in the mesoaccumbens dopamine system associated with behavioral sensitization to amphetamine

AU - Wolf, Marina

AU - White, Francis J.

AU - Hu, Xiu Ti

PY - 1994/3/1

Y1 - 1994/3/1

N2 - Behavioral sensitization to psychomotor stimulants has been shown to be accompanied by a number of alterations in the mesoaccumbens dopamine (DA) system, including DA autoreceptor subsensitivity in the ventral tegmental area (VTA), postsynaptic D1 receptor supersensitivity in the nucleus accumbens (NAc), and augmentation of the DA-releasing effects of stimulants in the NAc. The present study examined whether coadministration of the noncompetitive NMDA antagonist MK-801 with amphetamine, which has been shown to prevent the development of behavioral sensitization to amphetamine, would also prevent these changes in mesoaccumbens DA function. Rats were treated for 5 d with amphetamine according to a regimen known to produce lasting sensitization. Extracellular single-unit recordings from VTA DA neurons in amphetamine-treated rats, performed after 1 d of abstinence, revealed robust autoreceptor subsensitivity to DA agonists. This was prevented in rats coadministered MK-801 with amphetamine during the 5 d pretreatment period. Recordings from NAc neurons in amphetamine-treated rats demonstrated supersensitivity of D1 receptors to iontophoretic administration of selective agonists when tested after 7 d of abstinence. This was also prevented by MK-801 coadministration. Microdialysis studies performed in awake rats after 7 d of abstinence failed to demonstrate augmentation of amphetamine-stimulated DA release in amphetamine-treated rats as compared to water controls, despite the fact that behavioral sensitization was evident in the former group during microdialysis experiments. MK-801 coadministration prevented behavioral sensitization in microdialysis rats but did not alter amphetamine-stimulated DA release. These results suggest (1) NMDA receptor stimulation is required for the development of both autoreceptor subsensitivity in the VTA and postsynaptic D1 receptor supersensitivity in the NAc during repeated amphetamine treatment, (2) these functional changes therefore appear to be closely associated with the development of behavioral sensitization, and (3) a dissociation can be demonstrated between the intensity of amphetamine-stimulated behavioral responses and amphetamine- stimulated DA release in the NAc.

AB - Behavioral sensitization to psychomotor stimulants has been shown to be accompanied by a number of alterations in the mesoaccumbens dopamine (DA) system, including DA autoreceptor subsensitivity in the ventral tegmental area (VTA), postsynaptic D1 receptor supersensitivity in the nucleus accumbens (NAc), and augmentation of the DA-releasing effects of stimulants in the NAc. The present study examined whether coadministration of the noncompetitive NMDA antagonist MK-801 with amphetamine, which has been shown to prevent the development of behavioral sensitization to amphetamine, would also prevent these changes in mesoaccumbens DA function. Rats were treated for 5 d with amphetamine according to a regimen known to produce lasting sensitization. Extracellular single-unit recordings from VTA DA neurons in amphetamine-treated rats, performed after 1 d of abstinence, revealed robust autoreceptor subsensitivity to DA agonists. This was prevented in rats coadministered MK-801 with amphetamine during the 5 d pretreatment period. Recordings from NAc neurons in amphetamine-treated rats demonstrated supersensitivity of D1 receptors to iontophoretic administration of selective agonists when tested after 7 d of abstinence. This was also prevented by MK-801 coadministration. Microdialysis studies performed in awake rats after 7 d of abstinence failed to demonstrate augmentation of amphetamine-stimulated DA release in amphetamine-treated rats as compared to water controls, despite the fact that behavioral sensitization was evident in the former group during microdialysis experiments. MK-801 coadministration prevented behavioral sensitization in microdialysis rats but did not alter amphetamine-stimulated DA release. These results suggest (1) NMDA receptor stimulation is required for the development of both autoreceptor subsensitivity in the VTA and postsynaptic D1 receptor supersensitivity in the NAc during repeated amphetamine treatment, (2) these functional changes therefore appear to be closely associated with the development of behavioral sensitization, and (3) a dissociation can be demonstrated between the intensity of amphetamine-stimulated behavioral responses and amphetamine- stimulated DA release in the NAc.

KW - dopamine autoreceptors

KW - dopamine release

KW - NMDA receptors

KW - nucleus accumbens

KW - ventral tegmental area

UR - http://www.scopus.com/inward/record.url?scp=0028273730&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028273730&partnerID=8YFLogxK

M3 - Article

C2 - 8126567

AN - SCOPUS:0028273730

VL - 14

SP - 1735

EP - 1745

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 3 II

ER -