Concomitant release of ventral tegmental acetylcholine and accumbal dopamine by ghrelin in rats

PLoS One. 2012;7(11):e49557. doi: 10.1371/journal.pone.0049557. Epub 2012 Nov 14.


Ghrelin, an orexigenic peptide, regulates energy balance specifically via hypothalamic circuits. Growing evidence suggest that ghrelin increases the incentive value of motivated behaviours via activation of the cholinergic-dopaminergic reward link. It encompasses the cholinergic afferent projection from the laterodorsal tegmental area (LDTg) to the dopaminergic cells of the ventral tegmental area (VTA) and the mesolimbic dopamine system projecting from the VTA to nucleus accumbens (N.Acc.). Ghrelin receptors (GHS-R1A) are expressed in these reward nodes and ghrelin administration into the LDTg increases accumbal dopamine, an effect involving nicotinic acetylcholine receptors in the VTA. The present series of experiments were undertaken directly to test this hypothesis. Here we show that ghrelin, administered peripherally or locally into the LDTg concomitantly increases ventral tegmental acetylcholine as well as accumbal dopamine release. A GHS-R1A antagonist blocks this synchronous neurotransmitter release induced by peripheral ghrelin. In addition, local perfusion of the unselective nicotinic antagonist mecamylamine into the VTA blocks the ability of ghrelin (administered into the LDTg) to increase N.Acc.-dopamine, but not VTA-acetylcholine. Collectively our data indicate that ghrelin activates the LDTg causing a release of acetylcholine in the VTA, which in turn activates local nicotinic acetylcholine receptors causing a release of accumbal dopamine. Given that a dysfunction in the cholinergic-dopaminergic reward system is involved in addictive behaviours, including compulsive overeating and alcohol use disorder, and that hyperghrelinemia is associated with such addictive behaviours, ghrelin-responsive circuits may serve as a novel pharmacological target for treatment of alcohol use disorder as well as binge eating.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / metabolism*
  • Animals
  • Dopamine / metabolism*
  • Ghrelin / administration & dosage
  • Ghrelin / pharmacology*
  • Male
  • Nicotinic Antagonists / administration & dosage
  • Nicotinic Antagonists / pharmacology
  • Nucleus Accumbens / drug effects*
  • Nucleus Accumbens / metabolism*
  • Rats
  • Receptors, Ghrelin / antagonists & inhibitors
  • Receptors, Nicotinic
  • Ventral Tegmental Area / drug effects*
  • Ventral Tegmental Area / metabolism*


  • Ghrelin
  • Nicotinic Antagonists
  • Receptors, Ghrelin
  • Receptors, Nicotinic
  • Acetylcholine
  • Dopamine

Grant support

The study was supported by grants from the Swedish Research Council (grant no. K2006-21X-04247-33-3 and 2009-2782), The Swedish brain foundation, LUA/ALF (grant no. 148251) from the Sahlgrenska University Hospital, Alcohol research council of the Swedish alcohol retailing monopoly and the foundations of Adlerbertska, Fredrik and Ingrid Thuring, Tore Nilsson, Längmanska, Torsten and Ragnar Söderberg, Wilhelm and Martina Lundgren, Knut and Alice Wallenberg, Magnus Bergvall, Anérs, Jeansons, Åke Wiberg, NovoNordisk and the Swedish Society of Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.