Levo-tetrahydropalmatine attenuates cocaine self-administration and cocaine-induced reinstatement in rats
- 372 Downloads
Levo-tetrahydropalmatine (l-THP) is an alkaloid constituent of plants from the botanical genera Corydalis and Stephania and is contained in many traditional Chinese herbal preparations. In addition to its low-affinity antagonism of D2 dopamine (DA) receptors, we report that l-THP functions as a higher-affinity antagonist at D1 DA receptors and interacts with D3 DA receptors, suggesting that it may be effective for the treatment of drug addiction. Accordingly, l-THP has been reported to reduce heroin craving and relapse in recovering addicts.
This study investigated the effects of l-THP (3.75, 7.5, and 15.0 mg/kg, i.p.) on cocaine self-administration (SA) and cocaine-induced reinstatement.
Materials and methods
Rats were trained to self-administer cocaine and food by pressing separate response levers during sessions consisting of a multiple schedule of alternating 30-min FR4 cocaine and 15-min FR4 food reinforcement. During the cocaine components of each session, the available cocaine dose varied such that rats had access to low and high dose ranges in varying sequence on alternating days. After SA, cocaine-reinforced responding was extinguished, and effects of l-THP on cocaine-induced reinstatement (10 mg/kg, i.p.) were examined.
l-THP produced a rightward and downward shift in the dose–response curve for cocaine SA and attenuated cocaine-induced reinstatement. l-THP also reduced food-reinforced responding and locomotor activity. However, reductions in cocaine SA were found at doses that failed to alter food-reinforced responding, and significant effects were not observed on food responding during reinstatement.
These findings suggest that l-THP is potentially useful for treating cocaine addiction.
KeywordsAddiction Relapse Dopamine Antagonist Dopamine receptor Drug abuse D1 D2 Cocaine Self-administration
This work was supported by NIH grant numbers DA15758 to JRM and EB01820 to SJL and by Chinese Ministry of Science and Technology grant number 2003CB51540 to ZY. The authors would like to thank Joseph Serge and Michael Hoks for their technical assistance.
- Huang KX , Jin GZ (1992) The antagonistic effects of tetrahydroprotoberberines on dopamine receptors: electrophysiological studies. Scientia Sinica Series B 35:688–696Google Scholar
- Jin GZ, Wang XL, Shi WX (1986) Tetrahydroprotoberberine - a new chemical type of antagonist of dopamine receptors. Scientia Sinica Series B 29:527–534Google Scholar
- Levesque D, Diaz J, Pilon C, Martres MP, Giros B, Souil E, Schott D, Morgat JL, Schwartz JC, Sokoloff P (1992) Identification, characterization, and localization of the dopamine D3 receptor in brain using 7-[3H]hydroxyl-N, N-di-n-propyl-2-aminotetralin. Proc Natl Acad Sci USA 89:8155–8159PubMedCrossRefGoogle Scholar
- Mantsch JR, Yuferov V, Mathieu-Kia AM, Ho A, Kreek MJ (2004) Effects of extended access to high versus low cocaine doses on self-administration, cocaine-induced reinstatement and brain mRNA levels in rats. Psychopharmacology (Berl) 175:26–36Google Scholar
- Xi ZX, Newman AH, Gilbert JG, Pak AC, Peng XQ, Ashby CR Jr, Gitajn L, Gardner EL (2005a) The novel dopamine D3 receptor antagonist NGB 2904 inhibits cocaine’s rewarding effects and cocaine-induced reinstatement of drug-seeking behavior in rats. Neuropsychopharmacology 31:1393–1405PubMedCrossRefGoogle Scholar
- Xi ZX, Gilbert JG, Pak AC, Ashby CR Jr, Heidbreder CA, Gardner EL (2005b) Selective dopamine D3 receptor antagonism by SB-277011A attenuates cocaine reinforcement as assessed by progressive-ratio and variable-cost-variable-payoff fixed-ratio cocaine self-administration in rats. Eur J Neurosci 21:3427–3438PubMedCrossRefGoogle Scholar
- Yang Z, Chen H, Hao W, Jin GZ, Li SJ (2006) Medication of l-tetrahydropalmatine increased the abstinence rate in heroin addicts. In: College on Problems of Drug Dependence 2006 Meeting Abstracts, Scottsdale, AZ, Available at http://biopsych.com:81/CPDD06_Web/MeetProgAbSearch_06.html