Cocaine and amphetamine depress striatal GABAergic synaptic transmission through D2 dopamine receptors.
The striatum is a brain area implicated in the pharmacological action of drugs of abuse. To test the possible involvement of both cocaine and amphetamine in the modulation of synaptic transmission in this nucleus, we coupled whole-cell patch clamp recordings from striatal spiny neurons to the focal stimulation of glutamatergic or GABAergic nerve terminals. We found that neither cocaine (1-600 microM) nor amphetamine (0.3-300 microM) significantly affected the glutamate-mediated EPSCs recorded from these cells. Conversely, both pharmacological agents depressed GABA-mediated IPSCs in a dose-dependent manner. This effect was mediated by the stimulation of dopamine (DA) D2 receptors since it was prevented by 3 microM L-sulpiride (a DA D2-like receptor antagonist), mimicked by the DA D2-like receptor agonist quinpirole (0.3-30 microM), and absent in mice lacking DA D2 receptors. A presynaptic mechanism was likely involved in this action since both cocaine and amphetamine depress GABAergic transmission by increasing paired-pulse facilitation. Cocaine and amphetamine failed to affect GABAergic IPSCs after 6-OHDA-induced nigral lesion, indicating that both drugs cause their effects through the release of endogenous DA. The modulation of GABAergic synaptic transmission in the striatum might underlie some motor and cognitive effects of psychostimulants in mammalians.
Centonze
Diego
D
Dipartimento di Neuroscienze, Clinica Neurologica, Università "Tor Vergata" and Fondazione Santa Lucia, IRCCS, Rome, Italy.
Picconi
Barbara
B
Baunez
Christelle
C
Borrelli
Emiliana
E
Pisani
Antonio
A
Bernardi
Giorgio
G
Calabresi
Paolo
P
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D003714:Denervation; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D017072:Neostriatum / Q000187:drug effects / Q000502:physiology*; D009434:Neural Pathways / Q000187:drug effects; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000172:deficiency / Q000187:drug effects* / Q000235:genetics; D009435:Synaptic Transmission / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D018765:Dopamine Uptake Inhibitors; D018691:Excitatory Amino Acid Antagonists; D017448:Receptors, Dopamine D2; D005680:gamma-Aminobutyric Acid; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000661:Amphetamine; D003042:Cocaine; D004298:Dopamine