Levo-tetrahydropalmatine inhibits cocaine's rewarding effects: experiments with self-administration and brain-stimulation reward in rats.
It was recently reported that levo-tetrahydropalmatine (l-THP), a dopamine (DA) D1 and D2 receptor antagonist purified from the Chinese herb Stephanie, appears to be effective in attenuating cocaine self-administration, cocaine-triggered reinstatement and cocaine-induced conditioned place preference in preclinical animal models. The present study was designed to contrast l-THP's effects on cocaine self-administration under fixed-ratio (FR) and progressive-ratio (PR) reinforcement, and to study l-THP's effects on cocaine-enhanced brain stimulation reward (BSR). Systemic administration of l-THP produced dose-dependent, biphasic effects, i.e., low-to-moderate doses (1, 3, 10 mg/kg) increased, while a high dose (20 mg/kg) inhibited cocaine self-administration behavior under FR2 reinforcement. The increased cocaine self-administration is likely a compensatory response to a reduction in cocaine's rewarding effects, because the same low doses of l-THP dose-dependently attenuated cocaine self-administration under PR reinforcement and also attenuated cocaine-enhanced BSR. These attenuations of PR cocaine self-administration and cocaine-enhanced BSR are unlikely due to l-THP-induced sedation or locomotor inhibition, because only 10 mg/kg, but not 1-3 mg/kg, of l-THP inhibited locomotion, sucrose self-administration and asymptotic operant performance in the BSR paradigm. In vivo microdialysis demonstrated that l-THP slightly elevates extracellular nucleus accumbens DA by itself, but dose-dependently potentiates cocaine-augmented DA, suggesting that a postsynaptic, rather than presynaptic, DA receptor antagonism underlies l-THP's actions on cocaine reward. Together, the present data, combined with previous findings, support the potential use of l-THP for treatment of cocaine addiction.
Xi
Zheng-Xiong
ZX
Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA. zxi@intra.nida.nih.gov
Yang
Zheng
Z
Li
Shi-Jiang
SJ
Li
Xia
X
Dillon
Christopher
C
Peng
Xiao-Qing
XQ
Spiller
Krista
K
Gardner
Eliot L
EL
D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D001600:Berberine Alkaloids / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects*; D003042:Cocaine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000188:drug therapy*; D003216:Conditioning, Operant / Q000187:drug effects; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D008297:Male; D017551:Microdialysis; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D012055:Reinforcement Schedule; D012201:Reward; D012646:Self Administration; D013237:Stereoisomerism
D014150:Antipsychotic Agents; D001600:Berberine Alkaloids; C014215:tetrahydropalmatine; D003042:Cocaine; D004298:Dopamine