Levo-tetrahydropalmatine Inhibits Methamphetamine Self-administration And Reinstatement

Objective :Addictive drugs can activate the brain’s reward system and produce rewarding effects. Drug seeking behavior became to be forced by brain neuroplasticity and adaptability changing in the effect of rewarding. In humans, relapsed to drug use can be triggered by adventitious drug administration, exposure to environmental stimuli previously associated with drug use, or stress. In experimental animals, relapse to drug use can be similarly modeled with the reinstatement paradigm triggered by addictive drugs, drug associated cues or stress. Drug craving and relapse to illicit drug use is a core feature of drug addiction. Our lab previous findings suggest that levo-tetrahydropalmatine(l-THP) which is the primary active constituent of the traditional Chinese herbs stephania and corydalis attenuates herion self-administration and reinstatement. Whether l-THP has simlar impact on the rewarding effects of methamphetamine and relapse behavior has not been reported. Therefore, in this study we observed the effects of administration of l-THP on methamphetamine self-administration 、 cue-induced and methamphetamine-induced reinstatement of drug seeking, which could provide a useful data support for the development of l-THP treatment for methamphetamine addiction.Methods: 1. Methamphetamine self-administration test. Rats were trained to self-administer methamphetamine under fixed ratio 1(FR1) scheduler until stable responding was established. Then rats randomly were divided into four groups. The four groups received one of four l-THP doses(0.00, 1.25, 2.50, 5.00 mg/kg, i.p.) 30 min prior to the test session. During the FR1 self-administration training session, inactive nose pokes and active nose poke were recorded. During the progressive ratio(PR) self-administration training session, the breakpoint of each rats was recorded.2. Extinction and reinstatement test. After rats established stable responding, extinction(daily 2h) sessions were conducted until responding was less than 10% of the responses maintained by methamphetamine self administration. Following extinction, rats randomly divided into four groups. Each group received one doses of l-THP treatment(0, 1.25, 2.5, 5.0 mg/kg, i.p.) 30 min prior to the test session respectively. Cues-induced and single methamphetamine priming dose(1 mg/kg) induced methamphetamine seeking behavior were tested respectively. During the reinstatement test, active nose pokes and inactive nose pokes were recorded.3. Locomotor activity test. Rats move freely in automated photocell system chamber. activities within 1h of the rats were recorded. Then, rats randomly divided into four groups. Each group received one dose of l-THP(0.00, 1.25, 2.50, 5.00 mg/kg, i.p.) 30 min before methamphetamine injection(1 mg/kg). Rats were transported to the automated photocell system chambers for a 2 h locomotor activity test. The locomotor activity of each rat was expressed as the total distance traveled(in millimeters).Result1. Effects of l-THP on the reinforcing effects of methamphetamineIn the methamphetamine self-administration under the FR schedule experiment, the 2.50 and 5.00 mg/kg l-THP pretreatment groups had significantly fewer active nose pokes(P<0.01) compared to the 0.00 mg/kg l-THP group. In contrast, inactive nose pokes were not significantly different(F3.24=0.535, P>0.05). In the methamphetamine self-administration under the PR schedule experiment, the 2.50 and 5.00 mg/kg l-THP pretreatment groups can significantly reduced methamphetamine self-administration breakpoint(F3.12=15.12, P<0.01) compared with 0.00 mg/kg l-THP group.2. Effects of l-THP treatment on methamphetamine seeking induced by cues and methamphetamine primingIn the cues-induced methamphetamine reinstatement test, As compared with 0 mg/kg l-THP pretreatment group, l-THP(1.25, 2.5, 5.0 mg/kg, i.p.) pretreatment group significantly decreased the number of active nose poke(F3.28=20.289,P<0.01). Also in the methamphetamine priming reinstatement test, pretreatment with l-THP(1.25, 2.50 and 5.00 mg/kg) significantly decreased the number of active nose pokes(F3.28=18.798, P<0.05). In contrast, inactive nose pokes were not significantly different(F3.28=0.421, P>0.05).3. Effects of l-THP on locomotor activityPretreatment with 1.25 and 2.50 mg/kg l-THP had not influences on the total distance travelled(cm) compared to rats pretreated with 0.00 mg/kg l-THP(F3.28=2.389, P>0.05).Conclusion1. l-THP(2.5mg/kg and 5.0 mg/kg, i.p.) attenuated methamphetamine self-administration behavior under the FR schedule and reduced the breakpoint under the PR schedule in rats, suggesting that l-THP attenuates the reinforcing effects of methamphetamine.2. l-THP(1.25mg/kg、2.5mg/kg and 5.0mg/kg, i.p.) attenuated methamphetamine seeking behaviors induced by cues and methamphetamine in rats, which suggested that l-THP may be useful for the treatment of methamphetamine relapse.3. 1.25 and 2.50 mg/kg l-THP had no influences on rat’s locomotor activity, suggeting that l-THP at the concentrations of 1.25 and 2.50 mg/kg affects methamphetamine self-administration and reinstatement probablely not through l-THP’s sedative effects on rat’s locomotor activity.