Archives of Medical Research 32 (2001) 35–38
0188-4409/01 $–see front matter. Copyright © 2001 IMSS. Published by Elsevier Science Inc.
PII S0188-4409(00)00257-5
ORIGINAL ARTICLE
Dopamine D4 Receptor (DRD4) Gene Polymorphism in the
First Psychotic Episode
Gina Rinetti,* Beatriz Camarena,* Carlos Cruz,* Rogelio Apiquián,* Ana Fresán,* Francisco Páez**
and Humberto Nicolini*
*Unidad de Genética Molecular Psiquiátrica, Programación Universitaria de Investigación en Salud (PUIS-IMP),
División de Investigaciones Clínicas, Instituto Mexicano de Psiquiatría (IMP), Mexico City, Mexico
**Servicio de Investigación, Hospital Fray Bernardino Alvarez, Secretaría de Salud (SSa), Mexico City, Mexico
Received for publication October 19, 1999; accepted August 23, 2000 (99/193).
Background. Dopamine D4 receptor (DRD4) has shown some interesting properties at
genetic and possibly functional levels. It has been suggested that some molecular variants
of the DRD4 gene (e.g., four and seven alleles) could be implicated in the pathogenesis of
psychotic disorders. Additionally, the VNTR polymorphism could be implicated in part of
the response to treatment with neuroleptics. This study tested the possible association be-
tween the 48-bp tandem repeats in exon 3 of the DRD4 gene and patients experiencing
their first psychotic episode.
Methods. Patients with a first psychotic episode (FPE, n = 37) were diagnosed and com-
pared with a matched control group ( n = 37). The FPE group was subdivided into two cate-
gories: those with nonaffective and those with affective psychoses. The variable number of
tandem repeats (VNTR) region of the DRD4 gene was amplified by PCR procedures. Chi-
square statistics and appropriate corrections and adjustments were used for data analysis.
Results. A significantly lower frequency of the four repeat (4-R) carriers in the FPE group
was observed. This association was sustained mainly by the affective psychotic group (
2
=
9.99 df = 2, p = 0.0073).
Conclusions. Although these results require testing with stringent methods, it is suggested
that the DRD4-4R allele may confer some protection against psychosis, mainly of the af-
fective subtype. © 2001 IMSS. Published by Elsevier Science Inc.
Key Words: DRD4 receptor, Gene, First psychotic episode.
Introduction
One of the most important physiopathologic explanations
for psychotic syndromes has been the dopamine hypothesis
(1). This hypothesis proposes that the dopaminergic system
is overactive (2). The majority of this evidence relies upon
the proven elevation in the number of dopamine D4 recep-
tors (DRD4) in the striatum and nucleus accumbens of post-
mortem schizophrenic brains (3–6). In addition, it relies on
the fact that antipsychotics block dopamine receptors (2).
This pharmacologic approach is supported by the mecha-
nism of action of the atypical antipsychotic clozapine,
which blocks the serotonin-5HT2a and dopamine D4 recep-
tors. The effect on the latter is due mainly to the fact that
clozapine displays a 10-fold higher affinity for DRD4 com-
pared to D2 or D3 receptors (2).
In addition, the dopamine D4 receptor possesses some
interesting properties at the genetic level. A polymorphism
in the third exon of the DRD4 gene (chromosome 11p15.5),
consisting of a 2–10 imperfect repetition of a 48-bp se-
quence (2R, 3R, 4R, 5R, 6R, 7R, 8R, 9R, and 10R) has been
described. This variable number of tandem repeats (VNTR)
polymorphism codifies for the third cytoplasmic loop of the
dopamine D4 protein receptor (7). Interestingly, it has been
demonstrated in vitro that variants with a greater number of
repeats (e.g., 7R) have a higher affinity (one order of magni-
Address reprint requests to: Humberto Nicolini, Subdirección de
Investigación Clínica, Instituto Mexicano de Psiquiatría (IMP), Calzada
México-Xochimilco 101, Col. San Lorenzo Huipulco, 14080 México, D.F.,
México. Tel.: (+525) 573-2437; FAX: (+525) 513-3722; E-mail:
nicolini_humberto@yahoo.com