Levo-tetrahydropalmatine attenuates cocaine self-administration under a progressive-ratio schedule and cocaine discrimination in rats.
Levo-tetrahydropalmatine (l-THP) is an alkaloid found in many traditional Chinese herbal preparations and has a unique pharmacological profile that includes dopamine receptor antagonism. Previously we demonstrated that l-THP attenuates fixed-ratio (FR) cocaine self-administration (SA) and cocaine-induced reinstatement in rats at doses that do not alter food-reinforced responding. This study examined the effects of l-THP on cocaine and food SA under progressive-ratio (PR) schedules of reinforcement and the discriminative stimulus effects of cocaine. In adult male Sprague-Dawley rats self-administering cocaine (0.5 or 1.0mg/kg/inf), l-THP significantly reduced breaking points at the 1.875, 3.75 and 7.5mg/kg doses. l-THP also reduced the breaking point and response rate for PR SA of sucrose-sweetened food pellets, although the decrease was significant only at the 7.5mg/kg l-THP dose. In rats trained to discriminate cocaine (10mg/kg, ip) from saline, l-THP (1.875, 3.75 and 7.5mg/kg) produced a rightward shift in the dose-response curve for cocaine generalization. During generalization testing, l-THP reduced response rate, but only at the 7.5mg/kg dose. l-THP also prevented substitution of the dopamine D2/D3 receptor agonist, (±) 7-OH-DPAT, for cocaine suggesting a potential role for antagonism of D2 and/or D3 receptors in the effects of l-THP. These data further demonstrate that l-THP attenuates the reinforcing and subjective effects of cocaine at doses that do not produce marked motor effects and provide additional evidence that l-THP may have utility for the management of cocaine addiction.
Mantsch
John R
JR
Department of Biomedical Sciences, Marquette University, Milwaukee, WI 53201-1881, USA. john.mantsch@marquette.edu
Wisniewski
Samantha
S
Vranjkovic
Oliver
O
Peters
Corey
C
Becker
Amanda
A
Valentine
Abbey
A
Li
Shi-Jiang
SJ
Baker
David A
DA
Yang
Zheng
Z
D018663:Adrenergic Agents / Q000494:pharmacology*; D000818:Animals; D001600:Berberine Alkaloids / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000523:psychology; D003216:Conditioning, Operant / Q000187:drug effects*; D004192:Discrimination, Psychological / Q000187:drug effects*; D018491:Dopamine Agonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists; D050637:Receptors, Dopamine D3 / Q000819:agonists; D012055:Reinforcement Schedule; D012646:Self Administration; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
D018663:Adrenergic Agents; D001600:Berberine Alkaloids; D018491:Dopamine Agonists; D018765:Dopamine Uptake Inhibitors; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D013764:Tetrahydronaphthalenes; C014215:tetrahydropalmatine; D003042:Cocaine; C031349:7-hydroxy-2-N,N-dipropylaminotetralin
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