Date

August 2009

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Physiology and Pharmacology

Institution

Oregon Health & Science University

Abstract

Alleles of the highly polymorphic human dopamine D4 receptor (D4R) gene (DRD4) containing a 48-base nucleotide sequence tandemly repeated seven times (DRD4.7), within the region coding for the receptor protein’s third intracellular loop, have been widely and reproducibly found in novelty seekers, substance abusers, pathological gamblers, and individuals diagnosed with attention-deficit hyperactivity disorder (ADHD). The in vivo physiological consequences of the DRD4.7 polymorphism, which inserts additional amino acids into the receptor’s G protein- binding third intracellular domain, remain to be established. One hypothesis predicts the resultant protein of the DRD4.7 allele is deficient in G protein-coupled signaling relative to other variants. If attenuated D4R-mediated signaling contributes to the complex behavioral phenotypes associated with the DRD4.7 allele, then wild-type (WT) mice and mice completely lacking D4Rs (D4R KO), congenic on the C57Bl/6J background, might be expected to display significantly different behavioral responses to environmental and chemical stimuli known to affect dopamine signaling, such as novelty (e.g., open field; novel object) and psychostimulant drugs (e.g., methylphenidate, MP). In a battery of behavioral tests to evaluate approach-avoidance components of the behavioral response to novelty, D4R KO mice respond in a manner consistent with previous findings that suggest minimal D4R-mediated effects on novelty-induced exploratory drive, but enhanced anxiety in the absence of D4R signaling. D4R KO mice show a greater locomotor response to high doses of acute MP, and less sensitivity to the stereotypy-inducing effects of high doses of acute MP, but do not differ from WT littermates in the behavioral response to lower doses of MP. D4R KO mice develop significantly greater behavioral sensitization to chronic administration of a moderate dose of MP compared to WT littermates. Affymetrix microarray analysis of prefrontal cortex (PFC) tissue from WT and D4R KO mice sensitized to chronic MP identified several gene transcripts differentially regulated by D4R signaling with potential relevance to the synaptic plasticity associated with behavioral sensitization to MP. A model of D4R activity in PFC neurotransmission is presented to explain the role of D4R signaling in the control of cortical glutamatergic output. Exploring the role of D4R signaling is of clinical relevance to the etiology of ADHD and substance abuse disorders, and may clarify the risks associated with psychostimulant pharmacotherapy of ADHD.

Identifier

doi:10.6083/M4VD6WD4

School

School of Medicine

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