Isoliquiritigenin suppresses cocaine-induced extracellular dopamine release in rat brain through GABA B receptor Eun Young Jang a , Eun Sang Choe c , Meeyul Hwang b , Sang Chan Kim b , Jong Rok Lee b , Sang Geon Kim d , Jae-Pil Jeon e , Russell J. Buono f , Chae Ha Yang a, ⁎ a Department of Physiology, College of Oriental Medicine, Daegu Haany University, Daegu 706-828, South Korea b The Research Center for Biomedical Resource of Oriental Medicine, Daegu Haany University, Daegu, South Korea c Department of Biological Sciences, Pusan National University, Pusan, South Korea d College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea e Division of Genome Resources, National Genome Research Institute, KNIH, Seoul, South Korea f Coatesville Veteran's Affairs Medical Center, Coatesville, PA, USA ABSTRACT ARTICLE INFO Article history: Received 9 October 2007 Received in revised form 28 February 2008 Accepted 13 March 2008 Available online 7 April 2008 Keywords: Isoliquiritigenin Cocaine Nucleus accumbens G. radix (licorice) Glycyrrhizae radix (licorice) comprises a variety of flavonoids as major constituents including isoliquiritigenin, liquiritin, liquiritigenin, and glycyrrihizin. It has shown various biological activities such as anti- inflammatory, anti-carcinogenic and antihistamic. As very little is known in regard to drug addiction, we carried out a study on the effect of G. radix and its active component, isoliquiritigenin, on acute cocaine- induced extracellular dopamine release in moving rats. Male Sprague–Dawley rats were orally administered with methanolic extracts of G. radix or isoliquiritigenin 1 h prior to an injection of cocaine (20 mg/kg, intraperitoneal (i.p.)). Extracellular dopamine was measured by in vivo microdialysis. Extract of G. radix and isoliquiritigenin inhibited cocaine-induced extracellular dopamine level in the nucleus accumbens by dose- dependent manner. Inhibition of dopamine release by isoliquiritigenin resulted in attenuation of the expression of c-Fos, an immediately early gene induced by cocaine. Effect of isoliquiritigenin was completely prevented by a GABA B receptor antagonist. Thus, these results showed that G. radix and isoliquiritigenin inhibit cocaine-induced dopamine release by modulating GABA B receptor, suggesting that isoliquiritigenin might be effective in blocking the reinforcing effects of cocaine. © 2008 Elsevier B.V. All rights reserved. 1. Introduction Psychostimulants such as amphetamine and cocaine are known to stimulate dopamine neurons in the central nervous system (Pierce and Kumaresan, 2006). Dopamine neurons originating from the ventral tegmental area and projecting to the nucleus accumbens and prefrontal cortex appear to be primarily responsible for the reinfor- cing effects of cocaine that contribute to continued drug abuse (Bardo, 1998; Koob et al., 1994) . Specifically, activation of the dopamine system within the shell subregion of the nucleus accumbens appears to play a key role in brain reward mechanisms (McBride et al., 1999). Acute or repeated cocaine administration can lead to an increase in extracellular dopamine levels by preventing reuptake through block- ade of dopamine transport (Kiyatkin, 1994; Kuczenski and Segal, 1999). Elevated dopamine levels cause a dysregulation of dopamine D 1 /D 2 receptor signaling, which in turn leads to the up-regulation of the immediate early genes including c-Fos in nucleus accumbens and striatum (Anderson and Pierce, 2005). Fos family proteins hetero- dimerize with Jun family proteins to form the activator protein-1 (AP- 1) transcription factor complex that binds AP-1 sites (Morgan and Curran, 1995). These Fos family proteins are induced rapidly and transiently and return to basal levels within hours after acute administration of many drugs of abuse (Nestler et al., 2001). GABAergic neurons are known to modulate dopamine neurons via inhibitory GABA B receptors in the mesolimbic dopamine system (Cousins et al., 2002). GABA B receptors are located both pre- and postsynaptically where they modulate, both neurotransmitter release and inhibitory postsynaptic potentials, respectively (Bettler et al., 2004). The GABA B receptor agonist baclofen attenuated cocaine self- administration in rats and there is accumulating evidence from both preclinical and clinical studies that GABA B receptors may play a key role in drug addiction (Brebner et al., 2002; Ling et al., 1998). Glycyrrhizae radix (G. radix, licorice, liquorice) is one of the oldest and most popularly used botanicals in the oriental medicine. G. radix contains flavonoids and pentacyclic triterpene saponin as major constituents, which include liquiritigenin, isoliquiritigenin, liquiritin, liquiritin apioside, glycyrrihizin and glycyrrhizic acid (Kamei et al., 2003). It was reported that licorice extract produced sedative, antitussive and anti-inflammatory effects. In addition, it is reported European Journal of Pharmacology 587 (2008) 124–128 ⁎ Corresponding author. Tel.: +82 53 770 2239; fax: +82 53 768 6340. E-mail address: chyang@dhu.ac.kr (C.H. Yang). 0014-2999/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2008.03.054 Contents lists available at ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar