Cocaine inhibits GABA release in the VTA through endogenous 5-HT

Donald L. Cameron, John Williams

Research output: Contribution to journalArticle

158 Citations (Scopus)

Abstract

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 A 10 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 μM) inhibited the GABA(B) IPSP in a dose-dependent manner. This effect was observed in the presence of the D2 dopamine receptor antagonists sulpiride (1 μM) and eticlopride (0.1 μM). 5-HT mimicked this effect, as did the selective 5-HT(1D) receptor agonist sumatriptan and the 5-HT-releasing agent fenfluramine. The actions of both 5-HT and cocaine were attenuated by the 5- HT(1C/μ) antagonist metergoline. Pretreatment of slices with the 5-HT- depleting agent p-chloroamphetamine (pCA; 10 μM) abolished the inhibition of the GABA(B) IPSPby 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-HT(1D) 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.

Original languageEnglish (US)
Pages (from-to)6763-6767
Number of pages5
JournalJournal of Neuroscience
Volume14
Issue number11 I
StatePublished - 1994

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Ventral Tegmental Area
Cocaine
gamma-Aminobutyric Acid
Serotonin
Dopaminergic Neurons
Receptor, Serotonin, 5-HT1D
Sumatriptan
eticlopride
antineoplaston A10
Dopamine
p-Chloroamphetamine
Metergoline
Fenfluramine
Autoreceptors
Serotonin Receptor Agonists
Sulpiride
Inhibitory Postsynaptic Potentials
Serotonin Antagonists
Dopamine Plasma Membrane Transport Proteins
Nucleus Accumbens

Keywords

  • 5-HT
  • cocaine
  • dopamine
  • GABA
  • GABA(B)
  • guinea pig
  • ventral tegmental area

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Cocaine inhibits GABA release in the VTA through endogenous 5-HT. / Cameron, Donald L.; Williams, John.

In: Journal of Neuroscience, Vol. 14, No. 11 I, 1994, p. 6763-6767.

Research output: Contribution to journalArticle

Cameron, Donald L. ; Williams, John. / Cocaine inhibits GABA release in the VTA through endogenous 5-HT. In: Journal of Neuroscience. 1994 ; Vol. 14, No. 11 I. pp. 6763-6767.
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