Enhanced Expression of Dopamine D 1 and Glutamate NMDA Receptors in Dopamine D 4 Receptor Knockout Mice Lu Gan, 1 Tomas L. Falzone, 2 Kehong Zhang, 1 Marcelo Rubinstein, 2 Ross J. Baldessarini, 1 and Frank I. Tarazi* ,1 1 Mailman Research Center, McLean Division of Massachusetts General Hospital, Belmont, MA 02478; Department of Psychiatry and Neuroscience Program, Harvard Medical School; Boston, MA 02115; and 2 Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina Received July 29, 2003; Accepted August 24, 2003 Abstract Expression of dopamine ([DA] D 1 and D 2 ) and glutamate ([Glu], (N-methyl-D-aspartic acid [NMDA], α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA], and kanaic acid [KA]) receptor types were analyzed autoradiographically in forebrain regions of D 4 receptor knockout mice and their wild-type controls. Selective radioligand binding to D 4 receptors was virtually absent in D 4 receptor knockout mouse brain in con- trast to significant specific D 4 binding in forebrain tissue of wild-type controls. Labeling of D 1 receptors was significantly increased in nucleus accumbens (NAc; 39%) and caudate putamen (CPu; 42%) of D 4 -knockout mice vs wild-type controls. In addition, NMDA receptor labeling was significantly increased in NAc (31%), CPu (40%), and hippocampal CA 1 (21%) and CA 3 (25%) regions of D 4 knockouts vs wild-type controls. No changes in D 2 , AMPA or KA receptors were found. The findings suggest that D 1 , D 4 , and NMDA receptors might inter- act functionally and that developmental absence of D 4 receptors might trigger compensatory mechanisms that enhance expression of D 1 receptors in NAc and CPu, and NMDA receptors in NAc, CPu, and hippocampus. The findings also encourage cautious interpretation of results in knockout mice with targeted absence of spe- cific genes, as complex adaptive changes not directly related to the missing gene might contribute to physio- logical and behavioral responses. Index Entries: Autoradiography; caudate putamen; dopamine receptors; D 4 -receptor; genetic knockout; glutamate receptors; mutant mice. Journal of Molecular Neuroscience Copyright © 2004 Humana Press Inc. All rights of any nature whatsoever reserved. ISSN0895-8696/04/22:167–177/$25.00 Journal of Molecular Neuroscience 167 Volume 22, 2004 Introduction Dopamine (DA) D 4 receptors are members of the D 2 -like receptor family, which also includes D 2 and D 3 receptors. Other well-characterized DA receptors (D 1 , D 5 ) constitute the D 1 -like family. Members of each family share similar molecular structures and pharmacological profiles but differ greatly in rela- tive abundance and neuroanatomical distribution (Baldessarini and Tarazi, 1996; Neve and Neve, 1997). Several functional activities have been ascribed to D 4 receptor stimulation, including inhibition of adenylyl cyclase activity, activation of arachidonic acid release, blockade of L-type calcium currents, ORIGINAL ARTICLE *Author to whom all correspondence and reprint requests should be addressed. E-mail: ftarazi@hms.harvard.edu