A slow-onset, long-duration indanamine monoamine reuptake inhibitor as a potential maintenance pharmacotherapy for psychostimulant abuse: Effects in laboratory rat models relating to addiction

Eliot L. Gardner, Xinhe Liu, William Paredes, Anthony Giordano, Jordan Spector, Marino Lepore, Kuo Ming Wu, Mark Froimowitz

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Slow-onset, long-lasting dopamine reuptake blockers with reduced abuse potential have been suggested as maintenance therapies for cocaine addiction. We have synthesized a series of 3-(3′,4′-dichlorophenyl)-1-indanamine monoamine reuptake inhibitors as candidates for such maintenance pharmacotherapy. The initial lead compound, the N,N-dimethyl analogue 30,640 was then subjected to testing in addiction-relevant animal models. Compound 30,640 (2 mg/kg i.p.) produced a pronounced slow-onset, long-lasting increase (300-400%) in extracellular nucleus accumbens dopamine levels, as measured by in vivo brain microdialysis in awake laboratory rats. Slow-onset, long-lasting decreases (40-80%) in the dopamine metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid, and the serotonin metabolite 5-hydroxyindoleacetic acid were also seen. Compound 30,640 (3 or 5 mg/kg i.p.) also produced a significant (∼30%) slow-onset, long-lasting enhancement of electrical brain-stimulation reward, which was additive with that of cocaine (5 mg/kg i.p.). When given to cocaine-administering rats, 30,640 (2.5, 3, 5, or 10 mg/kg i.p.) significantly inhibited (30-60%) intravenous cocaine self-administration, with a pronounced long-lasting profile. In sum, 30,640 showed cocaine-like effects, but with a marked slow-onset, long-lasting profile. We conclude that the prodrug strategy employed in the design of 30,640 achieved its goal. We suggest that such compounds may be useful as maintenance pharmacotherapies for psychostimulant addiction.

Original languageEnglish (US)
Pages (from-to)993-1003
Number of pages11
JournalNeuropharmacology
Volume51
Issue number5
DOIs
StatePublished - Oct 2006

Fingerprint

Cocaine
Maintenance
Drug Therapy
Dopamine
3,4-Dihydroxyphenylacetic Acid
Cocaine-Related Disorders
Homovanillic Acid
Hydroxyindoleacetic Acid
Deep Brain Stimulation
Self Administration
Dopamine Antagonists
Microdialysis
Nucleus Accumbens
Prodrugs
Reward
Serotonin
Animal Models
Brain
compound 30,640
Therapeutics

Keywords

  • Addiction
  • Cocaine
  • Drug abuse
  • Indanamine
  • Reuptake blockade

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Drug Discovery
  • Pharmacology

Cite this

A slow-onset, long-duration indanamine monoamine reuptake inhibitor as a potential maintenance pharmacotherapy for psychostimulant abuse : Effects in laboratory rat models relating to addiction. / Gardner, Eliot L.; Liu, Xinhe; Paredes, William; Giordano, Anthony; Spector, Jordan; Lepore, Marino; Wu, Kuo Ming; Froimowitz, Mark.

In: Neuropharmacology, Vol. 51, No. 5, 10.2006, p. 993-1003.

Research output: Contribution to journalArticle

Gardner, Eliot L. ; Liu, Xinhe ; Paredes, William ; Giordano, Anthony ; Spector, Jordan ; Lepore, Marino ; Wu, Kuo Ming ; Froimowitz, Mark. / A slow-onset, long-duration indanamine monoamine reuptake inhibitor as a potential maintenance pharmacotherapy for psychostimulant abuse : Effects in laboratory rat models relating to addiction. In: Neuropharmacology. 2006 ; Vol. 51, No. 5. pp. 993-1003.
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abstract = "Slow-onset, long-lasting dopamine reuptake blockers with reduced abuse potential have been suggested as maintenance therapies for cocaine addiction. We have synthesized a series of 3-(3′,4′-dichlorophenyl)-1-indanamine monoamine reuptake inhibitors as candidates for such maintenance pharmacotherapy. The initial lead compound, the N,N-dimethyl analogue 30,640 was then subjected to testing in addiction-relevant animal models. Compound 30,640 (2 mg/kg i.p.) produced a pronounced slow-onset, long-lasting increase (300-400{\%}) in extracellular nucleus accumbens dopamine levels, as measured by in vivo brain microdialysis in awake laboratory rats. Slow-onset, long-lasting decreases (40-80{\%}) in the dopamine metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid, and the serotonin metabolite 5-hydroxyindoleacetic acid were also seen. Compound 30,640 (3 or 5 mg/kg i.p.) also produced a significant (∼30{\%}) slow-onset, long-lasting enhancement of electrical brain-stimulation reward, which was additive with that of cocaine (5 mg/kg i.p.). When given to cocaine-administering rats, 30,640 (2.5, 3, 5, or 10 mg/kg i.p.) significantly inhibited (30-60{\%}) intravenous cocaine self-administration, with a pronounced long-lasting profile. In sum, 30,640 showed cocaine-like effects, but with a marked slow-onset, long-lasting profile. We conclude that the prodrug strategy employed in the design of 30,640 achieved its goal. We suggest that such compounds may be useful as maintenance pharmacotherapies for psychostimulant addiction.",
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AU - Liu, Xinhe

AU - Paredes, William

AU - Giordano, Anthony

AU - Spector, Jordan

AU - Lepore, Marino

AU - Wu, Kuo Ming

AU - Froimowitz, Mark

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