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.
The authors declare no competing interests.
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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