Skip to main content

Modulation of dopamine release by α7-type nicotinic acetylcholine receptors

Disentangling receptor kinetics and network dynamics is a prerequisite for understanding and predicting the systemic effects of pharmacological compounds. These effects may result from a complex balance between activation and desensitization of various receptor subtypes that can be located on excitatory or inhibitory neurons or their afferent fibres. We therefore combined receptor and network modelling [1] to explain the suppressive effect that TC-7020 [2, 3], a partial agonist of α7-type nicotinic acetylcholine receptors (nAChRs), was observed to exert on the release of dopamine (DA) in the nucleus accumbens of anesthetized rats. As nAChRs are ion channels permeating Na+ and Ca2+, and as i.v. injection of nicotine itself enhanced DA release, partial agonists would rather be expected to enhance DA release as well.

Using the model, we evaluated several potential effects of TC-7020 on DA-ergic and GABA-ergic neurons in the ventral tegmental area (VTA) and its glutamatergic afferents from neocortex. Potential effects of TC-7020 included on the one hand a reduced nAChR channel conductance on DA neurons through competitive or non-competitive inhibition, or through receptor desensitization. On the other hand, enhancing the nAChR conductance on GABA-neurons (through direct activation of nAChRs, or through priming of their response to background ACh [4]) could have produced, through inhibition of DA neurons, a similar suppressive effect on DA release. The model showed that rapid desensitization of the α7 nAChRs on DA neurons explained both the sign and time-course of the voltammetric DA response, provided that a background cholinergic tone was present that contributed, by activating α7 nAChRs without desensitizing them, to the baseline level of DA release.

Another surprising finding of the voltammetric DA recordings was that PNU-120596, a positive allosteric modulator of α7 nAChRs, prevented and abolished the effect of TC-7020 on DA release, instead of amplifying it. The model proposes two possible but contrasting mechanisms: a well-established relieve of α7 nAChRs from the weak state of desensitization into which they were brought by TC-7020, or, in contrast, the induction of a strong desensitization in α7 nAChRs due to channel over-excitation by background ACh under the amplifying effect of PNU-120596 [5].

These results show that tonic levels of neurotransmitters and neuromodulators like acetylcholine and dopamine may profoundly affect the dynamics, and hence the systemic effect, of pharmacological compounds. As these background levels may be altered in in-vitro preparations, circuit modelling may become an indispensible tool in drug development.


  1. Graupner M, Gutkin B: Modeling nicotinic neuromodulation from global functional and network levels to nAChR based mechanisms. Acta Pharmacol Sin. 2009, 30: 681-693. 10.1038/aps.2009.87.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Marrero MB, Lucas R, Salet C, Hauser TA, Mazurov A, Lippiello PM, Bencherif M: An α7 nicotinic acetylcholine receptor-selective agonist reduces weight gain and metabolic changes in a mouse model of diabetes. J Pharmacol Exp Ther. 2010, 332: 173-180. 10.1124/jpet.109.154633.

    Article  CAS  PubMed  Google Scholar 

  3. Kucinski A, Syposs C, Wersinger S, Bencherif M, Stachowiak MK, Stachowiak EK: α7 neuronal nicotinic receptor agonist (TC-7020) reverses increased striatal dopamine release during acoustic PPI testing in a transgenic mouse model of schizophrenia. Schizophr Res. 2012, 136: 82-87. 10.1016/j.schres.2012.01.005.

    Article  CAS  PubMed  Google Scholar 

  4. Zwart R, Vijverberg HP: Potentiation and inhibition of neuronal nicotinic receptors by atropine: competitive and noncompetitive effects. Mol Pharmacol. 1997, 52: 886-895.

    Article  CAS  PubMed  Google Scholar 

  5. Williams DK, Wang J, Papke RL: Investigation of the molecular mechanism of the α7 nicotinic acetylcholine receptor positive allosteric modulator PNU-120596 provides evidence for two distinct desensitized states. Mol Pharmacol. 2011, 80: 1013-1032. 10.1124/mol.111.074302.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Reinoud Maex.

Rights and permissions

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and Permissions

About this article

Cite this article

Maex, R., Grinevich, V., Budygin, E. et al. Modulation of dopamine release by α7-type nicotinic acetylcholine receptors. BMC Neurosci 14 (Suppl 1), P155 (2013).

Download citation

  • Published:

  • DOI:


  • Dopamine
  • Nicotine
  • Ventral Tegmental Area
  • Partial Agonist
  • Allosteric Modulator