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Pharmacologically-mediated reactivation and reconsolidation blockade of the psychostimulant-abuse circuit: a novel treatment strategy.

Publication ,  Journal Article
Lee, TH; Szabo, ST; Fowler, JC; Mannelli, P; Mangum, OB; Beyer, WF; Patkar, A; Wetsel, WC
Published in: Drug Alcohol Depend
July 1, 2012

Psychostimulant abuse continues to present legal, socioeconomic and medical challenges as a primary psychiatric disorder, and represents a significant comorbid factor in major psychiatric and medical illnesses. To date, monotherapeutic drug treatments have not proven effective in promoting long-term abstinence in psychostimulant abusers. In contrast to clinical trials utilizing monotherapies, combinations of dopamine (DA) agonists and selective 5-HT(3), 5HT(2A/2C), or NK(1) antagonists have shown robust efficacy in reversing behavioral and neurobiological alterations in animal models of psychostimulant abuse. One important temporal requirement for these treatments is that the 5-HT or NK(1) receptor antagonist be given at a critical time window after DA agonist administration. This requirement may reflect a necessary dosing regimen towards normalizing underlying dysfunctional neural circuits and "addiction memory" states. Indeed, chronic psychostimulant abuse can be conceptualized as a consolidated form of dysfunctional memory maintained by repeated drug- or cue-induced reactivation of neural circuit and subsequent reconsolidation. According to this concept, the DA agonist given first may reactivate this memory circuit, thereby rendering it transiently labile. The subsequent antagonist is hypothesized to disrupt reconsolidation necessary for restabilization, thus leading progressively to a therapeutically-mediated abolishment of dysfunctional synaptic plasticity. We propose that long-term abstinence in psychostimulant abusers may be achieved not only by targeting putative mechanistic pathways, but also by optimizing drug treatment regimens designed to disrupt the neural processes underlying the addicted state.

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Published In

Drug Alcohol Depend

DOI

EISSN

1879-0046

Publication Date

July 1, 2012

Volume

124

Issue

1-2

Start / End Page

11 / 18

Location

Ireland

Related Subject Headings

  • Substance-Related Disorders
  • Substance Abuse
  • Serotonin Antagonists
  • Self Administration
  • Rats
  • Ondansetron
  • Humans
  • Central Nervous System Stimulants
  • Central Nervous System Sensitization
  • Behavior Therapy
 

Citation

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Lee, T. H., Szabo, S. T., Fowler, J. C., Mannelli, P., Mangum, O. B., Beyer, W. F., … Wetsel, W. C. (2012). Pharmacologically-mediated reactivation and reconsolidation blockade of the psychostimulant-abuse circuit: a novel treatment strategy. Drug Alcohol Depend, 124(1–2), 11–18. https://doi.org/10.1016/j.drugalcdep.2012.01.021
Lee, Tong H., Steven T. Szabo, J Corey Fowler, Paolo Mannelli, O Barry Mangum, Wayne F. Beyer, Ashwin Patkar, and William C. Wetsel. “Pharmacologically-mediated reactivation and reconsolidation blockade of the psychostimulant-abuse circuit: a novel treatment strategy.Drug Alcohol Depend 124, no. 1–2 (July 1, 2012): 11–18. https://doi.org/10.1016/j.drugalcdep.2012.01.021.
Lee TH, Szabo ST, Fowler JC, Mannelli P, Mangum OB, Beyer WF, et al. Pharmacologically-mediated reactivation and reconsolidation blockade of the psychostimulant-abuse circuit: a novel treatment strategy. Drug Alcohol Depend. 2012 Jul 1;124(1–2):11–8.
Lee, Tong H., et al. “Pharmacologically-mediated reactivation and reconsolidation blockade of the psychostimulant-abuse circuit: a novel treatment strategy.Drug Alcohol Depend, vol. 124, no. 1–2, July 2012, pp. 11–18. Pubmed, doi:10.1016/j.drugalcdep.2012.01.021.
Lee TH, Szabo ST, Fowler JC, Mannelli P, Mangum OB, Beyer WF, Patkar A, Wetsel WC. Pharmacologically-mediated reactivation and reconsolidation blockade of the psychostimulant-abuse circuit: a novel treatment strategy. Drug Alcohol Depend. 2012 Jul 1;124(1–2):11–18.
Journal cover image

Published In

Drug Alcohol Depend

DOI

EISSN

1879-0046

Publication Date

July 1, 2012

Volume

124

Issue

1-2

Start / End Page

11 / 18

Location

Ireland

Related Subject Headings

  • Substance-Related Disorders
  • Substance Abuse
  • Serotonin Antagonists
  • Self Administration
  • Rats
  • Ondansetron
  • Humans
  • Central Nervous System Stimulants
  • Central Nervous System Sensitization
  • Behavior Therapy