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 1.0 mg/kg/inf), l-THP significantly reduced breaking points at the 1.875, 3.75 and 7.5 mg/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 7.5 mg/kg l-THP dose. In rats trained to discriminate cocaine (10 mg/kg, ip) from saline, l-THP (1.875, 3.75 and 7.5 mg/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 7.5 mg/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.

Research Highlights
► The tetrahydroprotoberberine compound, levo-tetrahydropalmatine (l-THP), found in many Chinese herbal preparations, has a unique pharmacological profile that includes dopamine receptor antagonism and may have utility for the treatment of cocaine addiction.
► l-THP attenuated breaking points in rats self-administering cocaine under a progressive-ratio schedule at doses that did not affect self-administration of sucrose-sweetened food pellets under an identical schedule.
► l-THP, at doses that did not attenuate response rate, produced a rightward shift in the dose–response curve for cocaine generalization in rats trained to discriminate cocaine from saline.
► l-THP attenuated substitution of the dopamine D2/D3 receptor agonist, (±) 7-OH-DPAT, for cocaine in rats trained to discriminate cocaine from saline, suggesting a role for D2 and/or D3 receptor antagonism in the effects of l-THP.