Amphetamine selectively blocks inhibitory glutamate transmission in dopamine neurons

Carlos A. Paladini; Christopher D. Fiorillo; Hitoshi Morikawa; John T. Williams

doi:10.1038/85124

Amphetamine selectively blocks inhibitory glutamate transmission in dopamine neurons

Carlos A. Paladini, Christopher D. Fiorillo, Hitoshi Morikawa, John T. Williams

Vollum Institute

Research output: Contribution to journal › Article › peer-review

107 Scopus citations

Abstract

Amphetamine is a highly addictive psychostimulant that promotes the release of the catecholamines dopamine and norepinephrine. Amphetamine-induced release of dopamine in the midbrain inhibits the activity of dopamine neurons through activation of D² dopamine autoreceptors. Here we show that amphetamine may also excite dopamine neurons through modulation of glutamate neurotransmission. Amphetamine potently inhibits metabotropic glutamate receptor (mGluR)-mediated IPSPs in dopamine neurons, but has no effect on ionotropic glutamate receptor-mediated EPSCs. Amphetamine desensitizes the mGluR-mediated hyperpolarization through release of dopamine, activation of postsynaptic α¹ adrenergic receptors, and suppression of InsP₃-induced calcium release from internal stores. By selectively suppressing the inhibitory component of glutamate-mediated transmission, amphetamine may promote burst firing of dopamine neurons. Through this mechanism, amphetamine may enhance phasic release of dopamine, which is important in the neural processing of reward.

Original language	English (US)
Pages (from-to)	275-281
Number of pages	7
Journal	Nature Neuroscience
Volume	4
Issue number	3
DOIs	https://doi.org/10.1038/85124
State	Published - 2001

ASJC Scopus subject areas

General Neuroscience

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title = "Amphetamine selectively blocks inhibitory glutamate transmission in dopamine neurons",

abstract = "Amphetamine is a highly addictive psychostimulant that promotes the release of the catecholamines dopamine and norepinephrine. Amphetamine-induced release of dopamine in the midbrain inhibits the activity of dopamine neurons through activation of D2 dopamine autoreceptors. Here we show that amphetamine may also excite dopamine neurons through modulation of glutamate neurotransmission. Amphetamine potently inhibits metabotropic glutamate receptor (mGluR)-mediated IPSPs in dopamine neurons, but has no effect on ionotropic glutamate receptor-mediated EPSCs. Amphetamine desensitizes the mGluR-mediated hyperpolarization through release of dopamine, activation of postsynaptic α1 adrenergic receptors, and suppression of InsP3-induced calcium release from internal stores. By selectively suppressing the inhibitory component of glutamate-mediated transmission, amphetamine may promote burst firing of dopamine neurons. Through this mechanism, amphetamine may enhance phasic release of dopamine, which is important in the neural processing of reward.",

author = "Paladini, {Carlos A.} and Fiorillo, {Christopher D.} and Hitoshi Morikawa and Williams, {John T.}",

note = "Funding Information: We thank K. Khodakhah for instruction and guidance in the flash photolysis experiments, and O. Manzoni for comments on the work and manuscript. This work was supported by NIH grants DA04523 (J.T.W.), DA05793 (C.D.F.) and DA07262 (C.A.P.).",

year = "2001",

doi = "10.1038/85124",

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AU - Fiorillo, Christopher D.

AU - Morikawa, Hitoshi

AU - Williams, John T.

N1 - Funding Information: We thank K. Khodakhah for instruction and guidance in the flash photolysis experiments, and O. Manzoni for comments on the work and manuscript. This work was supported by NIH grants DA04523 (J.T.W.), DA05793 (C.D.F.) and DA07262 (C.A.P.).

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N2 - Amphetamine is a highly addictive psychostimulant that promotes the release of the catecholamines dopamine and norepinephrine. Amphetamine-induced release of dopamine in the midbrain inhibits the activity of dopamine neurons through activation of D2 dopamine autoreceptors. Here we show that amphetamine may also excite dopamine neurons through modulation of glutamate neurotransmission. Amphetamine potently inhibits metabotropic glutamate receptor (mGluR)-mediated IPSPs in dopamine neurons, but has no effect on ionotropic glutamate receptor-mediated EPSCs. Amphetamine desensitizes the mGluR-mediated hyperpolarization through release of dopamine, activation of postsynaptic α1 adrenergic receptors, and suppression of InsP3-induced calcium release from internal stores. By selectively suppressing the inhibitory component of glutamate-mediated transmission, amphetamine may promote burst firing of dopamine neurons. Through this mechanism, amphetamine may enhance phasic release of dopamine, which is important in the neural processing of reward.

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Amphetamine selectively blocks inhibitory glutamate transmission in dopamine neurons

Abstract

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