Orexin A-mediated AKT signaling in the dentate gyrus contributes to the acquisition, expression and reinstatement of morphine-induced conditioned place preference

Abstract

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.

Effects of resveratrol on the acquisition and reinstatement of morphine‑induced conditioned place preference in mice

“…It has been shown that dopaminergic, GABAergic, glutamatergic, serotonergic, adrenergic and orexinergic pathways along with endogen opioid peptides are involved in the reward and reinforcement pathway (4,5,9). One of the most important systems that is involved in the addiction and relapse to drugs of abuse is the dopaminergic system, which begins from the ventral tegmental area (VTA) with projections to nucleus accumbens (NAcc).…”

Image‐guided cranial irradiation‐induced ablation of dentate gyrus neurogenesis impairs extinction of recent morphine reward memories

“…Notably, during CPP testing, entrance to the drug‐paired context is preceded by phase‐locked hippocampal theta rhythm (Takano, Tanaka, Takano, & Hironaka, ), suggesting the involvement of the hippocampus in reward memory retrieval of contextual cues. On a causative level, pharmacological disruptions or lesions of the hippocampus and dentate gyrus interfere with many stages of CPP, including the acquisition and retrieval of the drug/context association (Ebrahimian et al, ; Ferbinteanu & McDonald, ; Guo et al, ; Hernández‐Rabaza et al, ; Hitchcock & Lattal, ; Katebi, Farahimanesh, Fatahi, Zarrabian, & Haghparast, ; Meyers, Zavala, & Neisewander, ; Meyers, Zavala, Speer, & Neisewander, ; Milekic, Brown, Castellini, & Alberini, ; Rezayof, Zatali, Haeri‐Rohani, & Zarrindast, ; Sadeghi, Ezzatpanah, & Haghparast, ; Taubenfeld, Muravieva, Garcia‐Osta, & Alberini, ; Zarrindast, Nouri, & Ahmadi, ), and interfere with other animal models of addiction‐relevant behaviors (Fuchs et al, ; Ramirez et al, ; Paniccia et al, ). Such studies in laboratory animals support that the hippocampus and dentate gyrus play an important role in context‐dependent reward memory (Smith & Bulkin, ).…”

Food deprivation facilitates reinstatement of morphine‐induced conditioned place preference: Role of intra‐accumbal dopamine D2‐like receptors in associating reinstatement of morphine CPP with stress

“…The reinstatement model has been extensively used as animal model of relapse to drug seeking (See et al, ). The conditioned place preference (CPP) paradigm can be used to indicate reinstatement of place preference by stress or a priming drug after an extinction period (Guo et al, ; Lu et al, ; Parker and Mcdonald, ; Sinha, ). Generally, foot shock has been used as stressor to induce behavioral reinstatement in the stress‐reinstatement model (Shaham et al, ).…”