Neuroscience Letters 541 (2013) 120–125 Contents lists available at SciVerse ScienceDirect Neuroscience Letters j our nal ho me p ag e: www.elsevier.com/locate/neulet Protein kinase G linked to dopamine D3 receptors in the dorsal striatum controls dopamine release, FosB expression and locomotor activity after repeated cocaine administration Dong Kun Lee a,1 , Jeong Hwan Oh a,1 , Ju Hwan Yang a , BuHyun Youn a , Yoon-Bo Shim b , Insop Shim c , John Q. Wang d , Eun Sang Choe a,∗ a Department of Biological Sciences, Pusan National University, 63-2 Pusandaehak-ro, Kumjeong-gu, Pusan 609-735, Republic of Korea b Department of Chemistry, Pusan National University, 63-2 Pusandaehak-ro, Kumjeong-gu, Pusan 609-735, Republic of Korea c Lab of Neuroscience, AMSRC, Kyung Hee University, 26 Kyunghee-daero, Dongdaemun-gu, Seoul 130-701, Republic of Korea d Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA h i g h l i g h t s ◮ Repeated cocaine activates PKG in rat dorsal striatum in vivo. ◮ PKG activation controls dopamine releases by interacting with dopamine D3 receptors. ◮ PKG-D3 receptor interaction results in behavioral sensitization. a r t i c l e i n f o Article history: Received 10 November 2012 Received in revised form 29 January 2013 Accepted 4 February 2013 Keywords: Behavioral change Dopamine receptor Fos-related antigen Protein kinase Psychostimulant Striatum a b s t r a c t Protein kinase G (PKG) has been implicated in a variety of physiological functions including synaptic plasticity in the brain. This study investigated the involvement of dopamine D3 (D3) receptors in PKG- regulated dopamine release, long-term changes in gene expression and behavioral sensitization after repeated cocaine administration. Repeated systemic injections of cocaine (20 mg/kg), once a day for seven consecutive days, increased extracellular dopamine concentrations in the dorsal striatum. Inhibition of neuronal nitric oxide synthase, cGMP or PKG, stimulation of D3 receptors, and simultaneous inhibition of each of them with D3 receptor stimulation decreased the repeated cocaine-induced increase in dopamine concentrations and locomotor activity. Similarly, inhibition of PKG and simultaneous inhibition of PKG with D3 receptor stimulation decreased FosB immunoreactivity elevated by repeated cocaine adminis- tration, however stimulation of D3 receptors alone did not. These findings suggest that activation of PKG after repeated cocaine administration is more sensitive to interact with D3 receptors in the dopamine ter- minals than those in medium spiny neurons. This interaction may result in the development of behavioral sensitization by the upregulation of dopamine releases in the dorsal striatum. © 2013 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Cocaine increases synaptic dopamine concentrations by block- ing dopamine reuptake, playing a crucial role in the addictive properties of cocaine [12]. Increase in dopamine releases, in response to cocaine exposure, modulates dopamine D2 receptors in the dopamine terminals of the forebrain [3,4]. Like dopamine D2 receptors, dopamine D3 (D3) receptors coupled to inhibitory Gi proteins are densely expressed in the shell of the nucleus ∗ Corresponding author. Tel.: +82 51 510 2272; fax: +82 51 581 2962. E-mail address: eschoe@pusan.ac.kr (E.S. Choe). 1 These authors are equal contributors. accumbens [4]. Stimulation of D3 receptors downregulates dopamine releases in the striatum [18]. Phosphorylation and feedback control of metabotropic recep- tors by protein kinases play an important role in the regulation of cocaine-induced synaptic and behavioral plasticity. For instance, phosphorylation of D3 receptors in the nucleus accumbens by the activation of Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) potentiates cocaine-induced motor activity [17]. C- GMP-dependent protein kinase (PKG), a serine/threonine-specific protein kinase, is widely expressed in the brain. Two types of PKG genes have been biochemically characterized: a cytosolic 76 kDa homodimer (PKGI) and a membrane-bound 86 kDa homodimer (PKGII) [11]. Previous studies have demonstrated that repeated cocaine administration increases nitric oxide (NO) efflux in the 0304-3940/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neulet.2013.02.014