Iranian Journal of Basic Medical Sciences

Iranian Journal of Basic Medical Sciences

Linalool restores post-morphine hippocampal-striatal PI3K/Akt and CREB/ΔFosB mRNA expression and LFP power in adult male rats

Articles in Press

Document Type : Original Article

Authors
Mohsen Khanlari Piraliloo
Yaghoob Farbood
Alireza Sarkaki
Neda Yazdanfar
Seyedeh Parisa Navabi
Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
10.22038/ijbms.2026.95517.20584
Abstract
Objective(s): Opioid use disorder (OUD) is a chronic, relapsing condition characterized by compulsive drug seeking and profound abstinence-related disturbances. Opioid receptors are distributed across reward-related regions, including the ventral tegmental area (VTA), the ventral striatum (VS), and the hippocampus. Key mediators—PI3K-Akt in the hippocampus and CREB/ΔFosB in the striatum—modulate opioid addiction along the hippocampal–VS axis.
Materials and Methods: Rats underwent conditioned place preference (CPP) with three phases: pre-conditioning, conditioning, and post-conditioning. During conditioning, animals received morphine (10 mg/kg, IP) for three days, with or without linalool (50 mg/kg, IP, 30 min prior to morphine). This three-day protocol models reward learning rather than chronic dependence. Groups: saline, morphine, and morphine+linalool. Behavioral tests assessed CPP score, passive avoidance memory, anxiety- and depression-like behaviors, and locomotion. Molecular analyses measured PI3K and Akt mRNA expression (real-time PCR) in the hippocampus and CREB/ΔFosB in the VS. Local field potentials (LFPs) were recorded directly from the hippocampal CA1 and the nucleus accumbens (NAc, part of the VS) via implanted electrodes.
Results: Linalool significantly attenuated morphine-induced CPP, improved passive avoidance memory, and reduced anxiety/depressive-like behaviors. Linalool decreased morphine-induced up-regulation of CREB/ΔFosB in VS and PI3K/Akt mRNA in the hippocampus. LFP power in CA1 and NAc was reduced by morphine and restored by linalool.
Conclusion: Linalool attenuates morphine-induced reward, memory deficits, and affective disturbances, which are key features of opioid abstinence-induced behavioral disturbances, and normalizes molecular and electrophysiological alterations in the hippocampal-striatal circuit. Although direct causality is not established, linalool is a promising natural compound for managing opioid-associated behavioral disturbances.
Keywords
&Delta
FosB
Hippocampus
LFP
Linalool
Morphine
PI3K
Ventral striatum
Subjects
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Iranian Journal of Basic Medical Sciences

Articles in Press, Accepted Manuscript
Available Online from 05 August 2026