Optogenetics reveals a role for accumbal medium spiny neurons expressing dopamine D2 receptors in cocaine-induced behavioral sensitization.

Shelly Sooyun Song,Hyo Jin Lee,Tae Hyong Kim,Byeong Jun Kang,Hye-Ri Sim,Bong-June Yoon,Lei Wen,Ja-Hyun Baik,George J Augustine,Sehyoun Yoon

doi:10.3389/fnbeh.2014.00336

Abstract

Long-lasting, drug-induced adaptations within the nucleus accumbens (NAc) have been proposed to contribute to drug-mediated addictive behaviors. Here we have used an optogenetic approach to examine the role of NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2Rs) in cocaine-induced behavioral sensitization. Adeno-associated viral vectors encoding channelrhodopsin-2 (ChR2) were delivered into the NAc of D2R-Cre transgenic mice. This allowed us to selectively photostimulate D2R-MSNs in NAc. D2R-MSNs form local inhibitory circuits, because photostimulation of D2R-MSN evoked inhibitory postsynaptic currents (IPSCs) in neighboring MSNs. Photostimulation of NAc D2R-MSN in vivo affected neither the initiation nor the expression of cocaine-induced behavioral sensitization. However, photostimulation during the drug withdrawal period attenuated expression of cocaine-induced behavioral sensitization. These results show that D2R-MSNs of NAc play a key role in withdrawal-induced plasticity and may contribute to relapse after cessation of drug abuse.

Highlights

Dopamine (DA) signaling is associated with reward expectation and goal-directed behavior (Wise, 2004; Goto and Grace, 2005; Berridge, 2007)
To selectively control the activity of D2 receptors (D2R)-medium spiny neurons (MSNs) in nucleus accumbens (NAc) by light, viral vectors coding AAV-DIOChR2-EYFP were stereotaxically injected into the NAc of D2RCre BAC transgenic mice. 4 weeks after viral injection, robust expression of ChR2-EYFP was observed in the NAc (Figure 1A)
The specificity of ChR2 expression in D2R-MSNs was confirmed by immunofluorescence confocal analysis: expression of YFPtagged ChR2 was co-localized with D2R in NAc (Figure 1B), showing that ChR2 was expressed in D2R-expressing neurons in NAc

Summary

Introduction

Dopamine (DA) signaling is associated with reward expectation and goal-directed behavior (Wise, 2004; Goto and Grace, 2005; Berridge, 2007). It has been suggested that long-lasting drug-induced adaptations in the ventral striatum, better known as the nucleus accumbens (NAc), contribute to the development of addiction as well as drug-seeking and relapse behaviors (Lobo and Nestler, 2011; Smith et al, 2013). MSNs within the NAc can be divided into two major subpopulations: direct pathway MSNs that express D1Rs and project directly to midbrain DA areas, and indirect pathway MSNs that express D2Rs and project to the ventral pallidum (Kreitzer and Malenka, 2008; Sesack and Grace, 2010; Lüscher and Malenka, 2011; Smith et al, 2013). Activation of D1R-MSNs will excite midbrain DA neurons, which contributes to the regulation of reward-related behaviors (Lüscher and Malenka, 2011; Bocklisch et al, 2013)

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Results

Conclusion