Withdrawal from repeated amphetamine administration reduces NMDAR1 expression in the rat substantia nigra, nucleus accumbens and medial prefrontal cortex

Wenxiao Lu, Lisa M. Monteggia, Marina Wolf

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Glutamate plays a critical role in neuroadaptations induced by drugs of abuse. This study determined whether expression of the NMDAR1 subunit of the NMDA receptor is altered by repeated amphetamine administration. We quantified NMDAR1 mRNA (using in situ hybridization with 35S-labelled oligonucleotide probes) and immunolabelling (using immunocytochemistry with 35S-labelled secondary antibodies) in rat ventral midbrain, nucleus accumbens and prefrontal cortex after 3 or 14 days of withdrawal from five daily injections of saline or amphetamine sulphate (5 mg/kg/day). No changes in NMDAR1 expression were observed after 3 days of withdrawal, whereas significant decreases were observed in all regions after 14 days. NMDAR1 mRNA levels in midbrain were too low for reliable quantification, but immunolabelling was decreased significantly in intermediate and caudal portions of the substantia nigra. This may indicate a reduction in excitatory drive to substantia nigra dopaminergic neurons. In the nucleus accumbens, there were significant decreases in NMDAR1 mRNA levels (74.8 ± 7.7% of control, P < 0.05) and immunolabelling (76.7 ± 4.4%, P < 0.05). This may account for previously-reported decreases in the electrophysiological responsiveness of nucleus accumbens neurons to NMDA after chronic amphetamine treatment, and contribute to dysregulation of goal-directed behaviour. In prefrontal cortex, there was a significant decrease in NMDAR1 mRNA levels (76.1 ± 7.1%, P < 0.05) and a trend towards decreased immunolabelling (89.5 ± 7.0%). This may indicate decreased neuronal excitability within prefrontal cortex. A resultant decrease in activity of excitatory prefrontal cortical projections to nucleus accumbens or midbrain could synergize with local decreases in NMDAR1 to further reduce neuronal excitability in these latter regions.

Original languageEnglish (US)
Pages (from-to)3167-3177
Number of pages11
JournalEuropean Journal of Neuroscience
Volume11
Issue number9
DOIs
StatePublished - Jan 1 1999
Externally publishedYes

Fingerprint

Nucleus Accumbens
Substantia Nigra
Amphetamine
Prefrontal Cortex
Mesencephalon
Messenger RNA
Oligonucleotide Probes
Dopaminergic Neurons
Street Drugs
N-Methylaspartate
NMDA receptor A1
N-Methyl-D-Aspartate Receptors
In Situ Hybridization
Glutamic Acid
Immunohistochemistry
Neurons
Injections
Antibodies

Keywords

  • Behavioural sensitization
  • Dopamine
  • Glutamate receptors
  • Ventral tegmental area

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Withdrawal from repeated amphetamine administration reduces NMDAR1 expression in the rat substantia nigra, nucleus accumbens and medial prefrontal cortex. / Lu, Wenxiao; Monteggia, Lisa M.; Wolf, Marina.

In: European Journal of Neuroscience, Vol. 11, No. 9, 01.01.1999, p. 3167-3177.

Research output: Contribution to journalArticle

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abstract = "Glutamate plays a critical role in neuroadaptations induced by drugs of abuse. This study determined whether expression of the NMDAR1 subunit of the NMDA receptor is altered by repeated amphetamine administration. We quantified NMDAR1 mRNA (using in situ hybridization with 35S-labelled oligonucleotide probes) and immunolabelling (using immunocytochemistry with 35S-labelled secondary antibodies) in rat ventral midbrain, nucleus accumbens and prefrontal cortex after 3 or 14 days of withdrawal from five daily injections of saline or amphetamine sulphate (5 mg/kg/day). No changes in NMDAR1 expression were observed after 3 days of withdrawal, whereas significant decreases were observed in all regions after 14 days. NMDAR1 mRNA levels in midbrain were too low for reliable quantification, but immunolabelling was decreased significantly in intermediate and caudal portions of the substantia nigra. This may indicate a reduction in excitatory drive to substantia nigra dopaminergic neurons. In the nucleus accumbens, there were significant decreases in NMDAR1 mRNA levels (74.8 ± 7.7{\%} of control, P < 0.05) and immunolabelling (76.7 ± 4.4{\%}, P < 0.05). This may account for previously-reported decreases in the electrophysiological responsiveness of nucleus accumbens neurons to NMDA after chronic amphetamine treatment, and contribute to dysregulation of goal-directed behaviour. In prefrontal cortex, there was a significant decrease in NMDAR1 mRNA levels (76.1 ± 7.1{\%}, P < 0.05) and a trend towards decreased immunolabelling (89.5 ± 7.0{\%}). This may indicate decreased neuronal excitability within prefrontal cortex. A resultant decrease in activity of excitatory prefrontal cortical projections to nucleus accumbens or midbrain could synergize with local decreases in NMDAR1 to further reduce neuronal excitability in these latter regions.",
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