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, 53 (6), 771-82

Levo-tetrahydropalmatine Inhibits Cocaine's Rewarding Effects: Experiments With Self-Administration and Brain-Stimulation Reward in Rats

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Levo-tetrahydropalmatine Inhibits Cocaine's Rewarding Effects: Experiments With Self-Administration and Brain-Stimulation Reward in Rats

Zheng-Xiong Xi et al. Neuropharmacology.

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.

Conflict of interest statement

Disclosure/Conflict of Interest: All authors hereby declare that, except for income received from their respective primary employers, no financial support or compensation has been received from any individual or corporate entity over the past three years for research or professional services. There are no personal financial holdings that could be perceived as constituting a potential conflict of interest.

Figures

Figure 1
Figure 1
Effects of l-THP on cocaine self-administration under FR2 reinforcement. Panel A shows representative cocaine self-administration records illustrating that systemic administration of 3 or 10 mg/kg of l-THP increased, while 20 mg/kg inhibited cocaine self-administration. Each vertical line represents a cocaine infusion (0.5 mg/kg/infusion). Panel B shows the mean time courses of cocaine self-administration for the maximal 50 infusions after each dose of l-THP administration. Panel C shows the total numbers of cocaine infusions during the 1st hr of cocaine self-administration. The arrows (↑) indicate the last cocaine infusion. *p<0.05, **p<0.01, ***p<0.001, when compared with the same time point in the vehicle control group (Panel B) or the vehicle (0 mg/kg l-THP) control group (Panel C).
Figure 2
Figure 2
Effect of l-THP on cocaine self-administration under PR reinforcement. Panel A shows representative records of an individual animal illustrating a reduction in the PR break-point for cocaine self-administration from 62 after vehicle (1 ml sterile water, i.p.; upper trace) to 32 after l-THP (3 mg/kg i.p., 30 min prior to test; lower trace) pretreatment. Each vertical line indicates a cocaine infusion (0.5 mg/kg/infusion). The number between the vertical lines indicates the work demand (progressively increased PR ratio, i.e., number of lever presses) for a subsequent cocaine infusion. The PR breakpoint was defined as the highest completed work requirement (lever-presses) to receive the last cocaine infusion. Panel B depicts the percent changes in break-point for cocaine self-administration after each dose of l-THP pretreatment. *p<0.05, ** p<0.01, *** p<0.001, when compared to the vehicle (0 mg/kg l-THP) pretreatment group.
Figure 3
Figure 3
Effects of l-THP on oral sucrose self-administration under FR2 reinforcement, demonstrating that 10 mg/kg, but not 1 mg/kg or 3 mg/kg, l-THP inhibited sucrose self-administration behavior. ***p<0.001, when compared with the vehicle (0 mg/kg l-THP) control group.
Figure 4
Figure 4
Effects of cocaine and/or l-THP on electrical brain stimulation reward (BSR). Panel A shows a representative rate-frequency function for BSR, indicating the BSR threshold (θ0) and Ymax. Cocaine (2 mg/kg, i.p.) shifted the rate-frequency function to the left, lowering the BSR θ0 threshold. Pretreatment with l-THP (3 mg/kg, i.p.) significantly attenuated the cocaine-induced decrease in BSR threshold (θ0). Panel B shows the effects of l-THP alone on BSR, indicating that 10 mg/kg, but not 3 mg/kg, l-THP significantly increased the threshold (θ0) (i.e., shifted the rate-response function to the right) and also lowered Ymax levels. Panel C shows the mean percentage changes in BSR threshold (θ0), indicating that l-THP (1-10 mg/kg, i.p.) dose-dependently inhibited 2 mg/kg cocaine-enhanced BSR. Panel D shows the mean percentage changes in BSR threshold (θ0) produced by l-THP alone, indicating that 10 mg/kg, but not 1 mg/kg or 3 mg/kg, l-THP inhibited BSR. Panel E shows the effects of l-THP and cocaine on BSR Ymax levels, indicating that 2 mg/kg cocaine had no effect on Ymax levels, but l-THP, at 10 mg/kg, but not 1 or 3 mg/kg, significantly lowered Ymax in the presence of cocaine. Panel F shows the effects of l-THP alone on BSR Ymax levels, indicating that l-THP, at 1 or 3 mg/kg, i.p. failed to, but 10 mg/kg of l-THP significantly lowered BSR Ymax levels. *p<0.05, ***p<0.001, when compared with the vehicle control group in each panel. # p<0.05, ### p<0.001, when compared with the cocaine only group in Panel C.
Figure 5
Figure 5
Effects of l-THP on locomotor activity in rats. L-THP, at 10 mg/kg, but not 3 mg/kg, significantly inhibited basal levels of locomotion. ***p<0.001, when compared with the vehicle control group.
Figure 6
Figure 6
Effects of cocaine and/or l-THP on extracellular DA in the NAc. L-THP (1, 3, 10 mg/kg) slightly elevated extracellular NAc DA. Pretreatment with l-THP dose-dependently augmented cocaine-enhanced DA in the NAc. *p<0.05, **p<0.01, ***p<0.001, when compared with baselines before l-THP administration (C) or the vehicle (for cocaine) treatment group (D). #p<0.05, when compared with the vehicle (0 mg/kg l-THP) plus cocaine treatment group (C, D).
Figure 7
Figure 7
Diagram illustrating the placements of microdialysis probes within the NAc. The active microdialysis membrane portions were located within both the shell and core of the NAc.

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