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The association between rewarding and drug-related memory is a leading factor for the formation of addiction, yet the neural circuits underlying the association remain unclear. Here, we showed that the interstitial nucleus of the posterior limb of the anterior commissure (IPAC) integrated rewarding and environmental memory information by two different receiving projections from ventral tegmental area (VTA) and nucleus accumbens shell region (NAcSh) to mediate the acquisition of morphine conditioned place preference (CPP). A projection from the VTA GABAergic neurons (VTA GABA ) to the IPAC lateral region GABAergic neurons (IPACL GABA ) mediated the effect of morphine rewarding, whereas the pathway from NAcSh dopamine receptor 1-expressing neurons (NAcSh D1 ) to the IPAC medial region GABAergic neurons (IPACM GABA ) was involved in the acquisition of environmental memory. These findings demonstrated that the distinct IPAC circuits VTA GABA → IPACL GABA and NAcSh D1R were attributable to the rewarding and environmental memory during the acquisition of morphine CPP, respectively, and provided the circuit-based potential targets for preventing and treating opioid addiction.→ IPACM GABA were attributable to the rewarding and environmental memory during the acquisition of morphine CPP, respectively, and provided the circuit-based potential targets for preventing and treating opioid addiction.

Conditioned place preference (CPP) is a learned behavior, in which animals learn to associate environmental contexts with rewarding effects. The formation of CPP is an integrated outcome of multiple learning processes. Although multiple anatomical substrates underlying this contextual learning have been proposed, it remains unknown whether a specific molecular signaling pathway within CA1 mediates context learning associated with morphine conditioning. Here, we showed that repeated context learning associated with morphine conditioning significantly increased CXCL12 levels in hippocampal CA1 neurons, and the inhibition of CXCL12 expression ameliorated the CPP behavior following context exposure with morphine conditioning. Additionally, repeated context exposure with morphine conditioning increased the phosphorylation of STAT3 and the acetylation of histone H4 in CXCL12-expressing neurons in CA1. Immunoprecipitation and chromatin immunoprecipitation assays demonstrated that repeated context exposure with morphine conditioning increased the binding of STAT3 to the CXCL12 gene promoter and the interaction between STAT3 and p300, which contributed to the enhanced transcription of CXCL12 by increasing the acetylation of histone H4 in the CXCL12 gene promoter. The inhibition of STAT3 by intrathecal injection of S3I-201 suppressed the acetylation of histone H4. These data demonstrated the epigenetic upregulation of CXCL12 following repeated context exposure with morphine conditioning, which potentially contributed to the spatial memory consolidation associated with conditioned place preference induced by morphine conditioning., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Addiction-related behaviors, such as conditioned place preference (CPP), require animals to remember an association between environmental cue and drug treatment, and exposure to environmental cue is one of the key contributing factors to relapse. However, how central neural circuit participates in the formation of CPP induced by stimulus of morphine-paired environment remains unknown. In the present study, we found that reexposure to morphine-paired environment significantly increased the activity of hippocampal CA3 neurons, increased the excitability of GABAergic neurons and expression of glutamic acid decarboxylase 65/67 in the caudal lateral septum (LSc) and decreased the activity of GABAergic neurons and GAD65/67 expression in ventral tegmental area (VTA), leading to activation (disinhibition) of dopaminergic neurons. Inactivation of CA3 neurons attenuated GABAergic neurons activity and decreased the upregulation of GAD65/67 in LSc, prevented the dopaminergic neurons activation,and GAD65/67 downregulation in VTA and ameliorated the CPP behavior following exposure to morphine-paired context. Blockade of NMDA receptor in LSc also prevented the upregulation of GAD65/67 in LSc and formation of CPP induced by stimulus of morphine-paired environment. Suppression of GAD activity in LSc also remarkably attenuated the dopaminergic neurons activation and the GAD65/67 downregulation in VTA and prevented the formation of CPP induced by reexposure to morphine-associated context. Collectively, these results, for the first time, illustrated the involvement of neural circuitry of CA3-LSc-VTA, through integration of the contexts and reward information, participated in the reinstatement of CPP induced by exposure to morphine-associated context, which advanced our understanding on neurobiological basis for the context-associated memory and rewarding behavior., (© 2016 Society for the Study of Addiction.)

Morphine, commonly used to relieve the acute or chronic pain, has a high potential for addiction and exerts rewarding effects via a critical role for mesolimbic dopamine system. Studies suggest that addiction-related behavior is highly associated with inflammatory immune response, but the mechanisms are poorly understood. The present study showed that intra-VTA microinjection of TLR4 antagonist LPS-RS prevented the acquisition and maintenance, but not the expression, of morphine-induced CPP in rats. In addition, chronic morphine treatment significantly activated STAT3 on day 6 and 11 in VTA, and bilateral microinjection of STAT3 inhibitor S3I-201 into the VTA suppressed the acquisition and maintenance of morphine-induced CPP in rats. Furthermore, local knockout of STAT3 by injection of the AAV-Cre-GFP into the VTA area of STAT3 flox/flox mice also significantly impaired the acquisition of morphine CPP. Importantly, the TLR4 expression is colocalized with p-STAT3-positive cell in VTA, and repeated injection of LPS-RS significantly attenuated the STAT3 activation in VTA induced by chronic morphine treatment. Collectively, these data suggest that TLR4/STAT3 signaling pathway in VTA might play a critical role in the acquisition and maintenance of morphine CPP, and provides new evidence that TLR4/STAT3 signaling pathway might be a potential target for treatment of morphine addiction., (Copyright © 2017. Published by Elsevier B.V.)

Accumulating evidence indicates that the hippocampal dentate gyrus (DG), a critical brain region contributing to learning and memory, is involved in the addiction and relapse to abused drugs. Emerging studies also suggest the role of orexin signaling in the rewarding behavior induced by repeated exposure to opiates. In the present study, we investigated the dynamic adaptation of orexin signaling in the DG and its functional significance in the acquisition, expression, maintenance of and relapse to rewarding behavior induced by morphine. Repeated place conditioning with morphine significantly increased the orexin A content released from the lateral hypothalamic area projecting neurons into the DG. Local infusions of orexin A into the DG sensitized the acquisition of and relapse to the conditioned place preference induced by morphine. The application of the orexin receptor type 1 (OXR1) antagonist SB334867 significantly abolished the acquisition, expression and maintenance of the conditioned place preference induced by repeated exposure to morphine. Furthermore, the significant increase of the phosphorylation of AKT in the DG was associated with preference for the morphine-paired chamber in rats, which was reversed by the local administration of an OXR1 antagonist. Thus, these findings suggested that the dynamic upregulation of orexin A signaling, via the AKT pathway in the DG, may promote the acquisition and maintenance of opioid-induced craving behaviors and may increase sensitivity to the rewarding effect of subsequent opioids., (© 2015 Society for the Study of Addiction.)

Several lines of evidence have suggested that activated glia contributes to morphine-induced reward (conditioned place preference, CPP). Compared to well-defined roles of astrocyte in morphine CPP, the role of microglia in the nucleus accumbens (NAc) remains poorly characterized. The aim of the present study was to investigate the distinct role of microglia in morphine-induced CPP. Systemic administration of morphine (7.5 mg/kg for 5 days) induced significant preference for the morphine-paired compartment in rats, which lasted for at least 6 days after cessation of morphine treatment. Immunohistochemistry results showed that activation of p38 in the NAc microglia induced by chronic morphine treatment maintained on day 11. Bilateral intra-NAc injection of minocycline, a putative microglia inhibitor, or SB203580, an inhibitor of p38, prior to morphine administration not only inhibited p38 activation in the microglia but impaired the acquisition of CPP. On the day following the acquisition of morphine CPP, a single injection of minocycline or SB203580 failed to block the expression of CPP. Notably, pretreatment with minocycline or SB203580 for 5 days following the acquisition of morphine CPP significantly suppressed the activation of p38 and attenuated the maintenance of morphine CPP. Collectively, our present study indicates that the p38 signaling in the NAc microglia may play an important role in the acquisition and maintenance but not the expression of morphine CPP, and provides new evidence that microglia might be a potential target for the therapy of morphine addiction., (Copyright © 2011 Elsevier Inc. All rights reserved.)