TY - JOUR
T1 - A slow-onset, long-duration indanamine monoamine reuptake inhibitor as a potential maintenance pharmacotherapy for psychostimulant abuse
T2 - Effects in laboratory rat models relating to addiction
AU - Gardner, Eliot L.
AU - Liu, Xinhe
AU - Paredes, William
AU - Giordano, Anthony
AU - Spector, Jordan
AU - Lepore, Marino
AU - Wu, Kuo Ming
AU - Froimowitz, Mark
N1 - Funding Information:
These experiments were supported by NIDA research contract N01 DA-4-8313 and NIDA research grant R01 DA-15795 (M.F.), by research grant (E.L.G.) and postdoctoral research fellowship (M.L.) support from the Aaron Diamond Foundation of New York, by research grant support from the Julia Sullivan Medical Research Fund and the Old Stones Foundation (E.L.G.), by equipment support from National Science Foundation grant BNS-86-09351 and from the Medical Department of Brookhaven National Laboratories, and by salary and stipend support from the New York State Office of Alcoholism and Substance Abuse Services. The authors thank Dr Joyce Lowinson for financial support from the Albert Einstein College of Medicine Division of Substance Abuse, Dr Robert Hayes for technical help as these studies were being initiated, Sharon Buie for administrative assistance with accessing stored data, and Arlene C. Pak for assistance with the figures. Manuscript preparation was supported by the Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health. Some of the present data were previously presented, in preliminary abstract form, at annual scientific meetings of the College on Problems of Drug Dependence and the Society for Neuroscience.
PY - 2006/10
Y1 - 2006/10
N2 - 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.
AB - 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.
KW - Addiction
KW - Cocaine
KW - Drug abuse
KW - Indanamine
KW - Reuptake blockade
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U2 - 10.1016/j.neuropharm.2006.06.009
DO - 10.1016/j.neuropharm.2006.06.009
M3 - Article
C2 - 16901516
AN - SCOPUS:33749633480
SN - 0028-3908
VL - 51
SP - 993
EP - 1003
JO - Neuropharmacology
JF - Neuropharmacology
IS - 5
ER -