Chemogenetic modulation of accumbens direct or indirect pathways bidirectionally alters reinstatement of heroin-seeking in high- but not low-risk rats

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Opioid addiction has been declared a public health emergency, with fatal overdoses following relapse reaching epidemic proportions and disease-associated costs continuing to escalate. Relapse is often triggered by re-exposure to drug-associated cues, and though the neural substrates responsible for relapse in vulnerable individuals remains ambiguous, the nucleus accumbens (NAc) has been shown to play a central role. NAc direct and indirect pathway medium spiny neurons (dMSNs and iMSNs) can have oppositional control over reward-seeking and associative learning and are critically involved in reinstatement of psychostimulant-seeking. However, whether these pathways similarly regulate reinstatement of opioid-seeking remains unknown, as is their role in modulating motivation to take opioids. Here, we describe a method for classifying addiction severity in outbred rats following intermittent-access heroin self-administration that identifies subgroups as addiction-vulnerable (high-risk) or addiction-resistant (low-risk). Using dual viral-mediated gene transfer of DREADDs, we show that transient inactivation of dMSNs or activation of iMSNs is capable of suppressing cue-induced reinstatement of heroin-seeking in high- but not low-risk rats. Surprisingly, however, the motivation to self-administer heroin was unchanged, indicating a divergence in the encoding of heroin-taking and heroin-seeking in rats. We further show that transient activation of dMSNs or inactivation of iMSNs exacerbates cue-induced reinstatement of heroin-seeking in high- but not low-risk rats, again with no effect on motivation. These findings demonstrate a critical role for dMSNs and iMSNs in encoding vulnerability to reinstatement of heroin-seeking and provide insight into the specific neurobiological changes that occur in vulnerable groups following heroin self-administration.

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We thank Dr. John Neumaier and Dr. Michelle Kelly for providing the CAV2-Cre virus for this work, Dr. Scott Ng-Evans for designing MED-PC programs, and Jordyn Richardson and Grayson Baden for assistance with tissue sectioning and immunohistochemistry.

Author information

T.J.O. and S.M.F. conceived experiments, T.J.O., M.N.N. and K.T. performed experiments, T.J.O., M.N.N. and K.T. analyzed data, T.J.O. and S.M.F. wrote the paper and secured funding.

Correspondence to Susan M. Ferguson.

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O’Neal, T.J., Nooney, M.N., Thien, K. et al. Chemogenetic modulation of accumbens direct or indirect pathways bidirectionally alters reinstatement of heroin-seeking in high- but not low-risk rats. Neuropsychopharmacol. (2019) doi:10.1038/s41386-019-0571-9

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