Analysis of Dopamine D4 Receptor Function in Gene Knockout Mice: A Role in Cortical Excitability

Abstract

The prefrontal cortex (PFC) integrates diverse environmental stimuli and contextual cues to appropriately regulate the temporal organization and execution of motor behaviors. Mesocortical dopamine (DA) projections from the ventral tegmental area play a key role in the modulation of these signals to influence complex processes such as arousal, attention, vigilance, novelty-induced stress and learning. Both DA release and turnover rates in the PFC are increased by stress (Roth et al., 1988), while manipulations that attenuate DA transmission in the PFC impair alertness, behavioral reactions to stress and working memory performance. D1-like receptor agonists promote seizure activity in the PFC and conversely, stimulation of D2-like DA receptors is anticonvulsant and diminishes the electrical excitability of pyramidal neurons in the PFC (Starr, 1996). Among the members of the D2-like receptor family, the D4R has been of particular interest because it is densely expressed in the PFC and it has high affinity for various atypical antipsychotics (Van Tol et al., 1991). In addition, the D4R has been implicated in the pathophysiology of psychiatric diseases that involve PFC malfunction such as attention-deficit with hyperactivity disorder and schizophrenia (Seeman et al., 1993). At the molecular-genetic level some alleles of the highly polymorphic human D4R gene (DRD4) have been associated with human diseases, personality traits including attention deficit hyperactivity disorder, opiate and alcohol use, and novelty-seeking behavior.