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Rottlerin impairs the formation and maintenance of psychostimulant-supported memory

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Abstract

Rationale and objective

Since brain proteins such as protein kinase C (PKC), brain-derived neurotrophic factor (BDNF), and mammalian target of rapamycin (mTOR) are involved in the establishment and maintenance of psychostimulant memory, we sought to determine if systemic treatment with rottlerin, a natural compound affecting all these proteins, may modulate stimulant-supported memory.

Materials and methods

Stimulant-induced conditioned place preference (CPP) was used in modeling stimulant-supported memory.

Results

Three cocaine (10 mg/kg; COC) or three methamphetamine (1 mg/kg; MA) conditioning trials reliably established the drug-induced CPP in male C57BL/6 mice. An intra-peritoneal rottlerin injection (5 mg/kg) at least 24 h prior to the first COC or first MA conditioning trial prevented the establishment of CPP. Following the establishment of the COC- or MA-induced CPP, saline conditioning trial was used to extinguish the CPP. Rottlerin (5 mg/kg, intra-peritoneal (i.p.)) administered 20 h prior to the first saline conditioning trial diminished subsequent drug- and stressor-primed reinstatement of the extinguished CPP. Rottlerin (5 mg/kg, i.p.) produced a fast-onset and long-lasting increase in hippocampal BDNF levels. However, treatment with a BDNF tropomyosin receptor kinase B (TrkB) receptor antagonist, K252a (5 μg/kg), did not affect rottlerin’s suppressing effect on COC-induced CPP and treatment with 7,8-dihydroxyflavone (10 mg/kg x 6, 7,8-DHF), a selective TrkB agonist, prior to each conditioning trial did not affect COC-induced CPP.

Conclusion

These results suggest that systemic rottlerin treatment may impair the formation of COC- and MA-supported memory. Importantly, such a treatment may advance our understanding of the underlying mechanism through which extinction training resulted in the “forgetting” of the COC- and MA-supported memory.

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Abbreviations

COC:

Cocaine

MA:

Methamphetamine

CPP:

Conditioned place preference

mTOR:

Mammalian target of rapamycin

mTORC1:

Mammalian target of rapamycin complex 1

PKC:

Protein kinase C

BDNF:

Brain-derived neurotrophic factor

TrkB:

Tropomyosin receptor kinase B

7,8-DHF:

7,8-Dihydroxyflavone

DMSO:

Dimethyl sulfoxide

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Acknowledgments

This research is supported by ROC Ministry of Science and Technology (MOST) grant 103-2410-H-006 -028 -MY3 to L.Y.

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    Authors and Affiliations

    1. Institute of Behavioral Medicine, National Cheng Kung University College of Medicine, 1 University Rd., Tainan, 70101, Taiwan, ROC

      Tien You Liao, Wen-Yu Tzeng, Hsin-Hua Wu & Lung Yu

    2. Department of Health Psychology, Chang Jung Christian University, Tainan, 71101, Taiwan, ROC

      Chianfang G. Cherng

    3. Institute of Basic Medical Sciences, National Cheng Kung University College of Medicine, Tainan, 70101, Taiwan, ROC

      Ching-Yi Wang & Lung Yu

    4. Department of Psychology, National Cheng Kung University, Tainan, 70101, Taiwan, ROC

      Sherry S-J. Hu

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    1. Tien You Liao
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    Correspondence to Lung Yu.

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    Tien You Liao and Wen-Yu Tzeng contributed equally to this work.

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    Liao, T.Y., Tzeng, WY., Wu, HH. et al. Rottlerin impairs the formation and maintenance of psychostimulant-supported memory. Psychopharmacology 233, 1455–1465 (2016). https://doi.org/10.1007/s00213-016-4251-8

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    • DOI: https://doi.org/10.1007/s00213-016-4251-8

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