INVOLVEMENT OF DOPAMINE D 2 RECEPTORS IN COMPLEX MAZE LEARNING AND ACETYLCHOLINE RELEASE IN VENTRAL HIPPOCAMPUS OF RATS H. UMEGAKI, a * J. MUNOZ, b R. C. MEYER, b E. L. SPANGLER, b J. YOSHIMURA, a H. IKARI, c A. IGUCHI a and D. K. INGRAM b a Department of Geriatrics, University of Nagoya Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan b Molecular Physiology and Genetics Section, Laboratory of Cellular and Molecular Biology, Gerontology Research Center, National Institute on Aging, 5600 Nathan Shock Lane, Baltimore, MD 21042, USA c Fukushimura Hospital, 19-14 Aza-nakayama, Noyori-cho, Toyohashi, Aichi, 441-8124, Japan Abstract ÐIn the current study we focus on the involvement of dopamine D 2 receptors in the ventral hippocampus in memory performance and acetylcholine release. Using the aversively motivated 14-unit T-maze (Stone maze) the injection of raclopride, a D 2 receptor antagonist, into the ventral hippocampus (8 mg/kg) was found to impair memory performance. Co-injection of quinpirole, a D 2 receptor agonist (8 mg/kg), overcame the impairment in performance. Microdialysis study revealed that quinpirole infusion (10±500 mM) into the ventral hippocampus stimulated acetylcholine release in a dose- dependent manner, and systemic injection of quinpirole (0.5 mg/kg, i.p.) also stimulated acetylcholine release in the ventral hippocampus. Infusion of eticlopride, another D 2 receptor antagonist, into the ventral hippocampus suppressed acetylcholine release in the hippocampus induced by systemic injection of quinpirole. Taken together, we suggest that D 2 receptors in the ventral hippocampus are involved in memory performance, possibly through the regulation of acetylcholine. q 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved. Key words: memory, quinpirole, raclopride, eticlopride, microdialysis. Many past studies have focused on the interaction of cholinergic and dopaminergic systems in learning and memory. 20,21 The putative loci for this interaction include the septum, nucleus accumbens, basal ganglia, ventral tegmental area and hippocampus. 20 In the current study, we focus on acetylcholine (ACh)±dopamine (DA) interactions in the hippocampus. Hippocampal ACh innervation originates from the medial septal nucleus, 2,24 whereas DA innervation pro- jects from the ventral tegmental area with some DA ®bers in the posterior hippocampus from the substantia nigra. 30 ACh receptors include both muscarinic and nico- tinic subtypes 8 and both D 1 and D 2 subtypes of the DA receptor (D 1 R and D 2 R, respectively) are found in hippocampus. 3,4 Increases in hippocampal levels of both DA and ACh are associated with learning processes. For example, using a hippocampal microdialysis probe, Yamamuro et al. 35 recorded increased levels of DA and ACh in rats hippocampi during learning in an operant task. 35 Molinengo and Ghi 25 reported increased levels of hippo- campal ACh concomitant to improved performance of rats in a maze task when treated with the monoamine oxidase inhibitor l-deprenyl. Performance of rats in a passive avoidance task was improved by treatment with GBR 12783, a DA uptake inhibitor, and this effect was blocked by the muscarinic antagonist scopolamine. 27 McGurk et al. 22 demonstrated that systemic injections of both the nicotinic antagonist mecamylamine and the D 2 R antagonist raclopride in rats caused an additive impairment in radial arm maze performance compared with low-dose treatments of either antagonist alone. Treatment with a speci®c D 2 R agonist, quinpirole, was observed to attenuate the impairment in radial arm performance of rats induced by systemic mecamylamine treatment. 19 However, this result contrasts with an earlier report that systemic treatment with quinpirole impaired performance of rats in the radial arm maze. 18 Studies using hippocampal injections of drugs acting on ACh or DA receptors can provide more direct infor- mation on the interaction of these two systems as well as to identify the receptor speci®city. To this end, Wilkerson and Levin 34 injected either the D 1 R agonist dihydrexidine or the D 2 R agonist quinpirole into the ventral hippocampus of rats and noted improved perform- ance in a radial arm maze only in the quinpirole-treated animals. Similarly, while the D 1 R antagonist SCH 23390 D 2 R in complex maze learning and ACh release 27 27 Neuroscience Vol. 103, No. 1, pp. 27±33, 2001 q 2001 IBRO. Published by Elsevier Science Ltd Printed in Great Britain. All rights reserved 0306-4522/01 $20.00+0.00 PII: S0306-4522(00)00542-X Pergamon www.elsevier.com/locate/neuroscience *Corresponding author. Tel.: 181-52-744-2364; fax: 181-52-744- 2371. E-mail address: umegaki@tsuru.med.nagoya-u.ac.jp (H. Umegaki). Abbreviations: ACh, acetylcholine; ANOVA, analysis of variance; DA, dopamine; D 1 R, dopamine D 1 receptor; D 2 R, dopamine D 2 receptor; ECD, electrochemical detection; EDTA, ethylenediamine- tetra-acetate; HPLC, high-performance liquid chromatography.