Dopamine D4 receptors: significance for molecular psychiatry at the millennium

Abstract

Cloning of dopamine D 4 receptor genesThe human D 4 receptor gene (D4DR) was initially cloned from human neuroblastoma cells using probes complementary to mRNA sequences required to synthesize D 2 receptor proteins, and was found to encode a protein product typically containing 387 amino acids. 3 The D4DR gene was soon localized to region 15.5 of the long (q) arm of human chromosome 11. 4 with an initial external amino terminus and final intracellular segment ending with a carboxy moiety. The third intracellular cytoplasmic loop (IL 3 ) of the receptor peptide chain between the proposed fifth and sixth transmembrane segments (TM V , TM VI ) and the intracytoplasmic carboxyl terminal segment are believed to couple to G-proteins and interact with other molecular elements involved in DA-mediated synaptic neurotransmission. 3 Indeed, the molecular differentiation of the five main members of the DA receptor family is based largely on the length and amino acid sequences of IL 3 and the intracellular carboxy terminal segment. 1 The D 4 receptor protein contains several post-translationally modifiable elements common to D 2 -like DA receptors, including at least one potential site for Nlinked glycosylation in the extracellular amino terminus, several likely phosphorylation sites in IL 3 that may act as targets for protein kinases A and C, a cysteine residue at the end of the carboxyl terminal segment, two serine residues in the third cytoplasmic domain that may provide positive charge involving in 'docking' of the electronegative catechol groups of DA, and two acidic aspartate residues within TM II and TM III that may account for docking of the amino group of DA. 1,3 Additional features include disulfide bridging of TM III and TM IV that may contribute to the stability of a proposed cup-like arrangement of the D 4 receptor protein in the lipid membrane environment. 5 The D 4 receptor peptide sequence also contains several putative domains (the Src homology 3 [SH3] binding regions that strongly interact with small adapter peptides, including Grb2 and Nck, required for full func-

Regulation of Working Memory by Dopamine D4 Receptor in Rats

“…Significant levels of the D 4 receptor in hippocampus (Oaks et al, 2000;Tarazi and Baldessarini, 1999) raise the possibility that behavioral effects of L-745,870 observed in the present study may include actions in the hippocampal complex. Adding one more dimension of complexity, the D 4 receptor has high affinity for both dopamine and norepinephrine (Lanau et al, 1997).…”

“…Dopamine D 4 receptor is expressed preferentially in the limbic system and cortical areas, particularly in PFC (Oaks et al, 2000;Tarazi and Baldessarini, 1999). Several previous studies have examined cognitive effects of D 4 antagonists.…”

“…We propose that PFC is a leading candidate for such actions since PFC is vitally important for working memory (Goldman-Rakic, 2001) and since D 4 receptor mRNA and proteins are highly expressed in PFC (Oaks et al, 2000;Tarazi and Baldessarini, 1999). During working memory tasks, certain groups of pyramidal neurons in PFC increase firing rate after presentation of a spatial cue (for a review, see Goldman-Rakic, 2001).…”

“…D 4 receptor was initially implicated in schizophrenia by the relatively high D 4 receptor affinity for clozapine, an atypical antipsychotic agent (Oaks et al, 2000;Tarazi and Baldessarini, 1999). Subsequent clinical trials with D 4 receptor antagonists have failed to show antipsychotic efficacy of these agents (Corrigan et al, 2004;Kramer et al, 1997).…”

“…Working memory deficits induced by the noncompetitive NMDA antagonist ketamine (Verma and Moghaddam, 1996), the benzodiazepine inverse agonist FG-7142, or physiological stress (Arnsten and Goldman-Rakic, 1998) (Van Tol et al, 1991). In mammalian species, D 4 receptor is detected mainly in the corticolimbic areas, with particularly high levels in PFC (Oaks et al, 2000;Tarazi and Baldessarini, 1999). Because of this unique distribution, we hypothesize that D 4 receptor may play a significant role in working memory.…”