Pharmacological recruitment of the GABAergic tail of the ventral tegmental area by acute drug exposure

Br J Pharmacol. 2010 Dec;161(8):1677-91. doi: 10.1111/j.1476-5381.2010.00984.x.


Background and purpose: The tail of the ventral tegmental area (tVTA), also called the rostromedial tegmental nucleus, is a newly defined brain structure and a potential control centre for dopaminergic activity. It was identified by the induction of DeltaFosB following chronic cocaine exposure. In this work, we screened 20 drugs for their ability to induce FosB/DeltaFosB in the tVTA.

Experimental approach: Immunohistochemistry following systemic drug administration was used to study FosB/DeltaFosB induction in the tVTA of adult rats. Double-staining was used to determine whether dopamine or GABA neurones are involved in this induction.

Key results: The acute injection of the psychostimulant drugs cocaine, D-amphetamine, (+/-)-3,4-methylenedioxymethamphetamine (MDMA), methylphenidate or caffeine, induced the expression of FosB/DeltaFosB in the tVTA GABAergic cells. No induction was observed following exposure to ethanol, diazepam, γ-hydroxybutyric acid (GHB), morphine, ketamine, phencyclidine (PCP), Δ(9)-tetrahydrocannabinol (THC), sodium valproic acid or gabapentin. To evaluate the role of monoamine transporters in the psychostimulant-induced expression of FosB/DeltaFosB, we tested the antidepressant drugs reboxetine, nortriptyline, fluoxetine and venlafaxine (which target the noradrenaline and/or the 5-hydroxytryptamine transporters), the 5-hydroxytryptamine releasing agent dexfenfluramine, and the dopamine transporter inhibitor GBR12909. Only GBR12909 was able to induce FosB/DeltaFosB expression in the tVTA, showing that this induction is mediated by dopamine.

Conclusions and implications: Newly described brain structures may help to increase our knowledge of brain function, pathology and targets for treatments. FosB/DeltaFosB induction in the tVTA is a common feature of drugs sharing psychostimulant properties but not of drugs sharing risk of abuse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Central Nervous System Stimulants / pharmacology*
  • Dopamine / metabolism
  • Dopamine Plasma Membrane Transport Proteins / antagonists & inhibitors
  • Dose-Response Relationship, Drug
  • Male
  • Neurons / metabolism
  • Piperazines / pharmacology
  • Proto-Oncogene Proteins c-fos / metabolism
  • Psychotropic Drugs / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Ventral Tegmental Area / drug effects*
  • Ventral Tegmental Area / metabolism*
  • gamma-Aminobutyric Acid / metabolism*


  • (1-(2-(bis(4-fluorophenyl)methoxy)ethyl)-4-(3-hydroxy-3-phenylpropyl) piperazinyl decanoate)
  • Central Nervous System Stimulants
  • Dopamine Plasma Membrane Transport Proteins
  • Fosb protein, rat
  • Piperazines
  • Proto-Oncogene Proteins c-fos
  • Psychotropic Drugs
  • gamma-Aminobutyric Acid
  • Dopamine