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 alpha1 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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adrenergic alpha-1 Receptor Agonists
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Adrenergic alpha-1 Receptor Antagonists
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Amphetamine / pharmacology*
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Animals
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Calcium / metabolism
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Calcium Signaling / drug effects
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Calcium Signaling / physiology
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Carrier Proteins / drug effects
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Carrier Proteins / metabolism
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Dopamine / metabolism*
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Dopamine Plasma Membrane Transport Proteins
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Glutamic Acid / metabolism*
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In Vitro Techniques
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Male
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Membrane Glycoproteins*
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Membrane Transport Proteins*
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Nerve Tissue Proteins*
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Neural Inhibition / drug effects*
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Neural Inhibition / physiology
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Neurons / drug effects*
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Neurons / metabolism
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Potassium Channels / drug effects
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Potassium Channels / metabolism
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Rats
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Rats, Wistar
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Receptors, AMPA / drug effects
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Receptors, AMPA / metabolism
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Receptors, Adrenergic, alpha-1 / metabolism
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Receptors, Metabotropic Glutamate / antagonists & inhibitors*
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Receptors, Metabotropic Glutamate / metabolism
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Synaptic Transmission / drug effects*
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Synaptic Transmission / physiology
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Ventral Tegmental Area / drug effects
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Ventral Tegmental Area / metabolism
Substances
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Adrenergic alpha-1 Receptor Agonists
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Adrenergic alpha-1 Receptor Antagonists
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Carrier Proteins
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Dopamine Plasma Membrane Transport Proteins
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Membrane Glycoproteins
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Membrane Transport Proteins
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Nerve Tissue Proteins
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Potassium Channels
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Receptors, AMPA
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Receptors, Adrenergic, alpha-1
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Receptors, Metabotropic Glutamate
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Glutamic Acid
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Amphetamine
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Calcium
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Dopamine