Behavioural Brain Research 158 (2005) 79–88 Research report Simultaneous AMPA/kainate receptor blockade and dopamine D 2/3 receptor stimulation in the nucleus accumbens decreases brain stimulation reward in rats Kwang-Ho Choi a , Robert L.H. Clements b,c,∗ , Andrew J. Greenshaw b,c a DepartmentofPsychiatry,NC6.524UniversityofTexas,SouthwesternMedicalCenter,Dallas,TX75390-9070,USA b DepartmentofPsychiatry,1E7.44WalterMackenzieHealthSciencesCentre,UniversityofAlberta,Edmonton,Alta.,CanadaT6G2R7 c CentreforNeuroscience,513HeritageMedicalResearchCentre,UniversityofAlberta,Edmonton,Alta.,CanadaT6G2S2 Received 1 March 2004; received in revised form 16 August 2004; accepted 16 August 2004 Available online 21 September 2004 Abstract Interactions between dopamine (DA) and glutamate (GLU) in the mesocorticolimbic pathway of the brain may influence motivation and reward. Previous work from this laboratory has demonstrated that -amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptor blockade may potentiate decreases in exploratory motor activity induced by the DA D 2/3 receptor agonist 7-OH-DPAT in the nucleus accumbens septi (NAS). This study investigated the interaction of AMPA/kainate receptor antagonists CNQX or NBQX with 7-OH-DPAT on ventral tegmental area (VTA) brain stimulation reward (BSR). Effects of these compounds, alone and combined, were measured in male Sprague–Dawley rats stereotaxically implanted with a unilateral VTA electrode and bilateral guide cannulae in the NAS core or shell subregions. Rate–frequency analysis was used to assess BSR frequency thresholds and maximum response rates of rats trained to lever- press for reinforcing electrical stimulation. When given alone, CNQX (0.5 g), NBQX (0.5 g), or 7-OH-DPAT (5.0 g) did not affect BSR frequency thresholds. Co-administration of CNQX or NBQX with 7-OH-DPAT synergistically increased BSR frequency thresholds, indicative of decreased reward. These data indicate that simultaneous AMPA/kainate receptor blockade and DA D 2/3 receptor stimulation in the NAS may act synergistically to inhibit motivated behaviours such as electrical brain self-stimulation. © 2004 Elsevier B.V. All rights reserved. Keyword: AMPA/kainate; Brain stimulation reward; Dopamine; Electrical self-stimulation; Glutamate; Nucleus accumbens; Ventral tegmental area 1. Introduction Interactions between dopamine (DA) and glutamate (GLU) in the mesocorticolimbic system of the brain are impli- cated in the regulation of motivated behaviour as well as the pathophysiology of psychiatric disorders such as schizophre- nia and drug abuse [16,29]. The nucleus accumbens septi (NAS) is of primary interest in this context as DA-containing cell bodies of the ventral tegmental area (VTA) terminate in the NAS, as do GLU projections from the prefrontal cortex [50,60]. Of the two main groups of DA receptors, D 1 -like ∗ Corresponding author. Tel.: +1 780 492 6550; fax: +1 780 492 6841. E-mailaddress: rob.clements@ualberta.ca (R.L.H. Clements). (D 1 and D 5 ) and D 2 -like (D 2 ,D 3 , and D 4 ), the NAS, in addi- tion to the islands of Calleja and olfactory tubercle, contain a relatively high density of DA D 3 receptors [40]. The NAS is divided into two major subregions, the core and the shell [27,28,67,68,72], that may be functionally distinct based on pharmacological [15,54], electrophysiological [53], and be- havioural observations [37,39]. Glutamate receptors are currently classified into four sub- types: N-methyl-d-aspartate (NMDA), -amino-3-hydroxy- 5-methylisoxazole-4-propionic acid (AMPA), kainate recep- tors, and G-protein coupled metabotropic receptors. Several studies indicate the involvement of excitatory amino acids such as GLU in the physiological regulation of motivation and reward-related behaviour [4,45] and sensorimotor inte- 0166-4328/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2004.08.010