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Curcumin and two bivalent compounds, namely 17MD and 21MO, both obtained by conjugation of curcumin with a steroid molecule that acts as a membrane anchor, were comparatively studied. When incorporated into 1,2-dipalmitoyl-sn-glycero-3-phosphocholine the compounds showed a very limited solubility in the model membranes. Curcumin and the two bivalent compounds were also incorporated in membranes of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine and quenching the fluorescence of pure curcumin or of the curcumin moiety in the bivalent compounds by acrylamide it was seen that curcumin was accessible to this water soluble quencher but the molecule was somehow located in a hydrophobic environment. This was confirmed by quenching with doxyl-phosphatidylcholines, indicating that the curcumin moieties of 17MD and 21MO were in a more polar environment than pure curcumin itself. 1 H NOESY MAS-NMR analysis supports this notion by showing that the orientation of curcumin was parallel to the plane of the membrane surface close to C2 and C3 of the fatty acyl chains, while the curcumin moiety of 17MD and 21MO positioned close to the polar part of the membrane with the steroid moiety in the centre of the membrane. Molecular dynamics studies were in close agreement with the experimental results with respect to the likely proximity of the protons studied by NMR and show that 17MD and 21MO have a clear tendency to aggregate in a fluid membrane. The anchorage of the bivalent compounds to the membrane leaving the curcumin moiety near the polar part may be very important to facilitate the bioactivity of the curcumin moiety when used as anti-Alzheimer drugs., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Intense associative memories develop between drug-paired contextual cues and the drug withdrawal associated aversive feeling. They have been suggested to contribute to the high rate of relapse. Our study was aimed to elucidate the involvement of hypothalamic-pituitary-adrenocortical (HPA) axis activity in the expression and extinction of aversive memory in Swiss and C57BL/6J (B6) mice. The animals were rendered dependent on morphine by i.p. injection of increasing doses of morphine (10-60 mg/kg). The negative state associated with naloxone (1 mg/kg s.c.) precipitated morphine withdrawal was examined by using conditioned place aversion (CPA) paradigm. B6 mice obtained a higher aversion score and took longer to extinguish the aversive memory than Swiss mice. In addition, corticosterone levels were increased after CPA expression. Moreover, corticosterone levels were decreased during CPA extinction in Swiss mice without changes in B6 mice. Pre-treatment with the selective CRF1 receptor antagonist CP-154,526 before naloxone, impaired morphine-withdrawal aversive memory acquisition and decreased the extinction period. CP-154,526 also antagonized the increased levels of corticosterone observed after CPA expression in Swiss mice, without any changes in B6 mice. These results indicate that HPA axis could be a critical factor governing opioid withdrawal memory storage and retrieval, but in a strain or stock-specific manner. The differences observed between Swiss and B6 mice suggest that the treatment of addictive disorders should consider different individual predisposition to associate the aversive learning with the context., (Copyright © 2021 Elsevier Inc. All rights reserved.)