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.
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 (approximately 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.
Gardner
Eliot L
EL
Neuropsychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Building C - Room 393, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA. egardner@intra.nida.nih.gov
Liu
Xinhe
X
Paredes
William
W
Giordano
Anthony
A
Spector
Jordan
J
Lepore
Marino
M
Wu
Kuo-Ming
KM
Froimowitz
Mark
M
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D003042:Cocaine / Q000008:administration & dosage*; D003956:Dialysis / Q000379:methods; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D006719:Homovanillic Acid / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007189:Indans / Q000737:chemistry* / Q000627:therapeutic use*; D007192:Indenes / Q000737:chemistry / Q000627:therapeutic use; D008297:Male; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration / Q000379:methods; D019966:Substance-Related Disorders / Q000188:drug therapy* / Q000209:etiology*; D013997:Time Factors
D007189:Indans; D007192:Indenes; D014179:Neurotransmitter Uptake Inhibitors; C516053:compound 30,640; D015102:3,4-Dihydroxyphenylacetic Acid; D006897:Hydroxyindoleacetic Acid; D003042:Cocaine; D004298:Dopamine; D006719:Homovanillic Acid