Development of hyperactivity and anxiety responses in dopamine transporter-deficient mice

Abstract

Dopamine (DA) is a catecholamine neurotransmitter that regulates many aspects of motivated behavior in animals. Extracellular DA is highly regulated by the presynaptic high-affinity dopamine transporter (DAT), and drug- or genetically induced deficiencies in DAT function result in loss of DA reuptake. Mice in which DAT expression has been ablated have been previously proposed to be a relevant model of attention deficit hyperactivity disorder and have led to mechanistic insights regarding psychostimulant drug actions. However, very little previous work has emphasized the biobehavioral development of DAT-deficient mice. We therefore examined motoric, emotional and cognitive phenotypes in preadolescent (P22-26) DAT mutant mice. Consistent with previous reports in adult DAT(-/-) mice, we observed a hyperlocomotive phenotype in preadolescent mice across multiple assays. Somewhat surprisingly, spatial working memory in a Y-maze appeared intact, suggesting that cognitive phenotypes may emerge relatively late in development following hyperdopaminergia. Anxiety levels appeared to be reduced in DAT(-/-) mice, as defined by elevated plus maze and light-dark preference assays. No significant differences were observed between wild-type and heterozygous mice, suggesting a minimal impact of DAT haploinsufficiency on neurobehavioral status. Taken together, these data for the first time establish behavioral phenotypes of DAT mutant mice during development and suggest complex developmental stage-dependent effects of DA signaling on cognitive and emotional behaviors.