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Journal of Neuroscience, Vol 14, 6763-6767, Copyright © 1994 by Society for Neuroscience
Cocaine inhibits GABA release in the VTA through endogenous 5-HT
DL Cameron and JT Williams
Vollum Institute for Advanced Biomedical Research, Oregon Health Sciences University, Portland 97201.
The ventral tegmental area (VTA) is thought to be involved in the addictive
properties of many drugs, including cocaine. It has been hypothesized that
cocaine exerts its actions in the VTA by blocking the reuptake of dopamine
released from the dendrites of the A10 dopamine neurons, thus prolonging
the actions of dopamine at D2 autoreceptors. However, cocaine also blocks
the reuptake of the other monoamines, including serotonin (5-HT). Using
intracellular recordings from midbrain dopamine neurons in a brain slice
preparation, we have found that cocaine (0.1-10 microM) inhibited the GABAB
IPSP in a dose- dependent manner. This effect was observed in the presence
of the D2 dopamine receptor antagonists sulpiride (1 microM) and
eticlopride (0.1 microM). 5-HT mimicked this effect, as did the selective
5-HT1D receptor agonist sumatriptan and the 5-HT-releasing agent
fenfluramine. The actions of both 5-HT and cocaine were attenuated by the
5-HT1C/D antagonist metergoline. Pretreatment of slices with the
5-HT-depleting agent p-chloroamphetamine (pCA; 10 microM) abolished the
inhibition of the GABAB IPSP by cocaine but failed to affect the actions of
sumatriptan. We conclude that cocaine acts to modulate the GABA input to
A10 dopamine neurons via inhibition of the 5-HT transporter, increasing the
concentration of 5-HT at presynaptic 5-HT1D receptors. These actions of
cocaine were apparent at lower concentrations than those required to act
via inhibition of the dopamine transporter. This reduction of inhibitory
synaptic input into the VTA would be expected to attenuate the
GABA-mediated feedback inhibition from the nucleus accumbens, thus leading
to increased activation of dopamine neurons.
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