Levo-tetrahydropalmatine inhibits cocaine's rewarding effects: Experiments with self-administration and brain-stimulation reward in rats

Abstract

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.

Introduction

Cocaine addiction is a persistent social and health problem worldwide, with no effective medications currently available for treatment. In light of the important role of the mesolimbic dopamine (DA) system in drug abuse (Wise, 1996, Wise, 2005), much attention has focused on various DA receptor antagonists as potential treatments (Rothman and Glowa, 1995, Platt et al., 2002). However, clinical trials with D₁ or D₂ receptor antagonists for cocaine addiction have failed due to ineffectiveness, surmountability by increased drug intake, and/or unfavorable side effects such as dysphoria, extrapyramidal movements or inhibition of natural reward (Sherer et al., 1989, Nann-Vernotica et al., 2001, Haney et al., 2001, Newton et al., 2001; see reviews by Platt et al., 2002, Gorelick et al., 2004).

Alternatively, a number of research groups have investigated novel compounds that target other DA receptors, such as D₃ receptors (Heidbreder et al., 2005, Xi and Gardner, 2007) or drug cocktails that target multiple DA receptors. The rationale for the development of D₃ receptor antagonists is largely based on the highly restricted distribution of D₃ receptors in brain reward circuits (Sokoloff et al., 2006), suggesting that D₃ receptor antagonists may have anti-cocaine actions but without significant side effects. The drug cocktail medications are based on the presumption that multiple DA receptor blockade may produce additive or synergistic therapeutic effects, but have fewer unwanted side effects due to lower doses of each component in the cocktails (Soyka and De Vry, 2000, Platt et al., 2002, Gorelick et al., 2004).

Levo-tetrahydropalmatine (l-THP) is a purified active ingredient from the Chinese herb Stephanie (Jin, 1987, Jin et al., 2002). l-THP, as a traditional sedative-analgesic agent, has been used for more than 40 years in China for the treatment of chronic pain and anxious insomnia (Jin, 1987, Jin et al., 2002). Recent studies have demonstrated that l-THP is a non-selective D₁ and D₂ (and possibly D₃) receptor antagonist (Xu et al., 1989, Guo et al., 1997, Mantsch et al., 2007). In addition, it also has high binding affinity for α₁- and α₂-adrenergic receptors and several serotonin (5-hydroxytryptamine; 5-HT) receptors (5-HT_1A, 5-HT₄ and 5-HT₇) (Mantsch et al., 2007; Shijiang Li at the Medical College of Wisconsin, unpublished data). Given that cocaine is also a non-selective monoamine (DA, norepinephrine and 5-HT) reuptake inhibitor (Wise, 2005), the similar binding properties of l-THP for monoamine receptors suggest that l-THP may act as a natural cocktail-like cocaine antagonist. Recent studies have shown that l-THP significantly inhibits cocaine- or methamphetamine-induced conditioned place preference (Ren et al., 2000, Luo et al., 2003), cocaine self-administration under fixed-ratio (FR) reinforcement and cocaine-triggered reinstatement of drug-seeking behavior in rats (Mantsch et al., 2007). In addition, l-THP also inhibits opiate tolerance and withdrawal syndromes in rats (Jin et al., 1998, Ge et al., 1999), as well as locomotor sensitization to oxycodone, an opioid receptor agonist, in mice (Liu et al., 2005). Further, it was recently reported that l-THP significantly attenuates opiate craving and relapse in heroin addicts (Yang et al., 2006). However, it remains unclear whether l-THP inhibits the acute rewarding effects of cocaine, or whether such an inhibition is due to a direct action on brain reward function or to non-specific sedation and locomotor inhibition. Therefore, in the present study, we investigated: (1) whether l-THP inhibits cocaine self-administration under both FR and progressive-ratio (PR) reinforcement, and cocaine-enhanced brain stimulation reward (BSR)—both PR self-administration and BSR are thought to be sensitive and reliable paradigms to evaluate a drug's rewarding effects (Gardner, 2000, Wise, 2005); (2) whether the same doses of l-THP inhibit locomotion or sucrose self-administration; (3) whether l-THP itself has rewarding or aversive effects in the BSR paradigm; and finally, (4) whether a presynaptic or postsynaptic DA receptor mechanism underlies l-THP's potential therapeutic actions by measuring brain DA responses to cocaine in the presence or absence of l-THP using in vivo brain microdialysis.