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Abstract
Knockout (KO) mice that lack the dopamine transporter (SL6A3; DAT) display increased locomotion that can be attenuated, under some circumstances, by administration of drugs that normally produce psychostimulant-like effects, such as amphetamine and methylphenidate. These results have led to suggestions that DAT KO mice may model features of attention deficit hyperactivity disorder (ADHD) and that these drugs may act upon serotonin (5-HT) systems to produce these unusual locomotor decreasing effects. Evidence from patterns of brain expression and initial pharmacologic studies led us to use genetic and pharmacologic approaches to examine the influence of altered 5-HT1B receptor activity on hyperactivity in DAT KO mice. Heterozygous 5-HT1B KO and pharmacologic 5-HT1B antagonism both attenuated locomotor hyperactivity in DAT KO mice. Furthermore, DAT KO mice with reduced, but not eliminated, 5-HT1B receptor expression regained cocaine-stimulated locomotion, which was absent in DAT KO mice with normal levels of 5-HT1B receptor expression. Further experiments demonstrated that the degree of habituation to the testing apparatus determined whether cocaine had no effect on locomotion in DAT KO or reduced locomotion, helping to resolve differences among prior reports. These findings of complementation of the locomotor effects of DAT KO by reducing 5-HT1B receptor activity underscore roles for interactions between specific 5-HT receptors and dopamine (DA) systems in basal and cocaine-stimulated locomotion and support evaluation of 5-HT1B antagonists as potential, non-stimulant ADHD therapeutics.
Highlights
Dopamine (DA) systems have long been implicated in the control of basal [1, 2] and stimulant-induced locomotion [3,4,5]
Under some conditions, decreased locomotion is observed in DAT KO mice after administration of cocaine or other psychostimulant drugs [13], mimicking the therapeutic effects that stimulants provide for many individuals with attention deficit hyperactivity disorder (ADHD) [14, 15]
This genetic complementation supports at least some 5-HT1B-dependence of the development or expression of some of the adaptive processes found in DAT KO mice, including those that contribute to basal hyperactivity and to elimination of cocaine-stimulated locomotion [10,11,12]
Summary
Dopamine (DA) systems have long been implicated in the control of basal [1, 2] and stimulant-induced locomotion [3,4,5]. The elimination of DAT expression in DAT KO mice leads to profound changes in DA release dynamics [8], elevated basal levels of extracellular DA [8, 9] and profound locomotor hyperactivity [10, 11]. Cocaine-induced locomotion is eliminated in DAT KO mice [10, 12]. Under some conditions, decreased locomotion is observed in DAT KO mice after administration of cocaine or other psychostimulant drugs [13], mimicking the therapeutic effects that stimulants provide for many individuals with attention deficit hyperactivity disorder (ADHD) [14, 15]. Similar to the effects of these drugs on locomotion, they improve PPI in DAT KO mice, they produce impairments in wildtype (WT) mice
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