Dopamine D4 Receptor-Knock-Out Mice Exhibit Reduced Exploration of Novel Stimuli

Abstract

The involvement of dopamine neurotransmission in behavioral responses to novelty is suggested by reports that reward is related to increased dopamine activity, that dopamine modulates exploratory behavior in animals, and that Parkinson's disease patients report diminished responses to novelty. Some studies have reported that polymorphisms of the human dopamine D4 receptor (D4R) gene are associated with personality inventory measures of the trait called "novelty-seeking". To explore a potential role for the D4R in behavioral responses to novelty, we evaluated D4R-knock-out (D4RϪ/Ϫ) and wild-type (D4Rϩ/ϩ) mice in three approach-avoidance paradigms: the open field, emergence, and novel object tests. These three paradigms differ in the degree to which they elicit approach, or exploratory behavior, and avoidance, or anxiety-related behavior. Thus, we used these three tests to determine whether the D4R primarily influences the exploratory or the anxious component of responses to approach-avoidance conflicts. D4RϪ/Ϫ mice were significantly less behaviorally responsive to novelty than D4Rϩ/ϩ mice in all three tests. The largest phenotypic differences were observed in the novel object test, which maximizes approach behavior, and the smallest phenotypic differences were found in the open field test, which maximizes avoidance behavior. Hence, D4RϪ/Ϫ mice exhibit reductions in behavioral responses to novelty, reflecting a decrease in novelty-related exploration.

The human dopamine D4 receptor repeat sequences modulate expression

“…6,8,12,13 However, mice deficient in D4 expression display increased anxiety 14 and altered exploratory behavior. 15 Dopamine D4 receptor activation can modulate many intracellular signaling cascades in heterologous expression systems, 1 and has been shown to inhibit adenylyl cyclase, 16,17 inhibit GABAa currents, 18 and stimulate extracellular regulated kinase (ERK) and depress NMDA channel activity via transactivation of the plateletderived growth factor receptor-b in the central nervous system. 19 The biological role of this receptor is less well established, but studies with D4-deficient mice and selective D4 receptor antagonists support a role of this receptor in attention and cognition.…”

“…19 The biological role of this receptor is less well established, but studies with D4-deficient mice and selective D4 receptor antagonists support a role of this receptor in attention and cognition. 14,15,20,21 To date, 36 variants of the polymorphic 48 bp repeat sequence have been identified in humans, and these repeat sequences can be combined into many allelic variants. Up to 11 copies of the repeat, in tandem, have been reported.…”

GABA-A and 5-HT1A Receptor Agonists Block Expression of Fear-Potentiated Startle in Mice

“…Thus, the FPS model may offer enhanced specificity of the interpretation of experimental manipulations without possible motivational (eg Vogel test), approach/avoidance, or locomotor activity confounds (eg elevated plus maze and open field) (Shekhar et al, 2001). This aspect of the FPS model is particularly important when using transgenic mice to describe effects of genes on anxiety-related behaviors, as subtle changes in locomotor activity or approach behavior could confound any putative 'anxiety' phenotype (Dulawa et al, 1999). Second, the model in mice could be used to further characterize the involvement of specific components in the acquisition of fear-related behaviors (eg CREB, Falls et al, 2000) as well as uncover new molecules and mechanisms involved in the expression and extinction of learned fear.…”

Autonomic Changes Associated with Enhanced Anxiety in 5-HT1A Receptor Knockout Mice

“…Therefore, the purpose of the present experiments was to further investigate whether the putative anxious phenotype of 5-HT 1A receptor knockout (KO) mice is also reflected in autonomic nervous system disturbances and paradigms differing from approach-avoidance conflict ones that are easily subject to confounding influences of laboratory environments (Crabbe et al 1999) and largely seem to measure exploration, instead of anxiety-related behavior (Dulawa et al 1999).…”