Molecular Neurobiology

, Volume 56, Issue 12, pp 7911–7928 | Cite as

Crucial Role of Dopamine D2 Receptor Signaling in Nicotine-Induced Conditioned Place Preference

  • Gofarana Wilar
  • Yasuharu Shinoda
  • Toshikuni Sasaoka
  • Kohji FukunagaEmail author


Nicotine in tobacco causes psychological dependence through its rewarding effect in the central nervous system (CNS). Although nicotine dependence is explained by dopamine receptor (DR) signaling together with nicotinic acetylcholine receptors (nAChRs), the synaptic molecular mechanism underlying the interaction between dopamine receptor and nAChRs remains unclear. Since reward signaling is mediated by dopamine receptors, we hypothesized that the dopamine D2 receptor (D2R), in part, mediates the synaptic modulation of nicotine-induced conditioned place preference (CPP) in addition to dopamine D1 receptor. To investigate the involvement of D2R, wild-type (WT) and dopamine D2 receptor knockout (D2RKO) mice were assessed using the CPP task after induction of nicotine-induced CPP. As expected, D2RKO mice failed to induce CPP behaviors after repeated nicotine administration (0.5 mg/kg). When kinase signaling was assessed in the nucleus accumbens and hippocampal CA1 region after repeated nicotine administration, both Ca2+/calmodulin-dependent protein kinase (CaMKII) and extracellular signal-regulated kinase (ERK) were upregulated in WT mice but not in D2RKO mice. Likewise, nicotine-induced CPP was associated with elevation of pro- brain-derived neurotropic factor (BDNF) and BDNF protein levels in WT mice, but not in D2RKO mice. Taken together, in addition to dopamine D1 receptor signaling, dopamine D2 receptor signaling is critical for induction of nicotine-induced CPP in mice.


Nicotine dependence Dopamine D2 receptor Conditioned placed preference Brain-derived neurotrophic factor 



Nucleus accumbens shell


Anterior cingulate cortex


Alpha 4 beta 2 nicotinic acetylcholine receptors


Alpha 7 nicotinic acetylcholine receptors


Brain-derived neurotropic factor


Calcium/calmodulin-dependent protein kinase II


Nicotinic acetylcholine receptor (Nachr) Α4 subunit


Conditioned placed preference


cAMP response element binding


Dopamine D2 receptor knockout


Dorsolateral striatum


Dopamine D1 receptors


Dopamine D2 receptors


Extracellular signal-regulated kinase


Long-term potentiation


Medium spiny neurons


Nucleus accumbens


Neurotrophic tyrosine kinase receptor 2


Phosphorylation cAMP response element binding


Phosphokinase C


Polyvinylidene difluoride


Parietal association cortex


Ventral tegmental area


Wild type


Conflict of Interest

The authors declare that they have no conflict of interest.

Authors Contribution

K.F. and G.W. conceived and coordinated the study and wrote the paper. G.W. performed and analyzed the experiment shown in figures. Y.S. provided technical assistance. K.F. and G.W. reviewed the results. All authors approved the final version of the manuscript.

Funding Information

This research was funded by the Grant Indonesia Endowment Fund for Education (LPDP) to G.W. and Indonesia Endowment fund for Education (LPDP) and Smoking Research Foundation and the Project of Translational and Clinical Research Core Centers, AMED, Japan (JP17dm0107071 and JP18dm0107071 to K.F.).

Compliance with Ethical Standards

All experimental animal procedures were approved by the Committee on Animal Experiments at Tohoku University, and studies were conducted in accordance with committee guidelines.


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Authors and Affiliations

  1. 1.Department of Pharmacology, Graduate School of Pharmaceutical SciencesTohoku UniversitySendaiJapan
  2. 2.Department of Pharmacology and Clinical Pharmacy Faculty of PharmacyUniversitas PadjadjaranSumedangIndonesia
  3. 3.Department of Comparative and Experimental Medicine, Brain Research InstituteNiigata UniversityNiigataJapan

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