Increased vulnerability to cocaine in mice lacking dopamine D3 receptors.
Neuroimaging studies using positron emission tomography suggest that reduced dopamine D(2) receptor availability in the neostriatum is associated with increased vulnerability to drug addiction in humans and experimental animals. The role of D(3) receptors (D3Rs) in the neurobiology of addiction remains unclear, however. Here we report that D(3)R KO (D(3)(-/-)) mice display enhanced cocaine self-administration and enhanced motivation for cocaine-taking and cocaine-seeking behavior. This increased vulnerability to cocaine is accompanied by decreased dopamine response to cocaine secondary to increased basal levels of extracellular dopamine in the nucleus accumbens, suggesting a compensatory response to decreased cocaine reward in D(3)(-/-) mice. In addition, D(3)(-/-) mice also display up-regulation of dopamine transporters in the striatum, suggesting a neuroadaptative attempt to normalize elevated basal extracellular dopamine. These findings suggest that D(3)R deletion increases vulnerability to cocaine, and that reduced D(3)R availability in the brain may constitute a risk factor for the development of cocaine addiction.
One of the most challenging issues in drug abuse research is understanding the etiology of addiction. Identification of neurobiological factors conferring vulnerability to drug use and abuse may provide important therapeutic targets for the development of medications to treat addiction. Cumulative evidence suggests that certain vulnerability traits, such as high impulsivity, stress reactivity, novelty-seeking, negative emotionality, and abnormal structure of the frontostriatal brain system, may predispose humans to drug abuse and addiction. However, the neurobiological mechanisms by which such traits affect drug-taking and drug-seeking behavior are poorly understood. PET studies suggest that reduced dopamine (DA) D2 receptor (D2R) availability in the neostriatum is associated with reduced orbitofrontal cortex functional activity, which is linked to risk for impulsivity and compulsive cocaine administration in both humans and nonhuman primates (2, 13). Whether reducedD2R availability is a determinant or consequence of cocaine abuse remains unclear, however. It should be noted that the reduced D2R availability observed in PET or micro-PET studies is based on the use of D2R-preferring ligands, such as [11C] raclopride (10- to 20-fold selectivity for D2 overD3). This raises the question of whether striatal D3Rs are also involved in increased susceptibility to drug-taking behavior. Compared with D2Rs, which are expressed uniformly throughout the striatum, D3Rs are expressed preferentially in the nucleus accumbens (NAc) shell, islands of Calleja, and olfactory tubercle. A recent neuroimaging study with the D3R-preferring ligand [11C]-PHNO (with 10-fold selectivity for D3 over D2) revealed significant reduction in D3R binding in the dorsal striatum of heavy methamphetamine polydrug users. In rodents, a significant reduction in D2R/D3R binding, as assessed using [11C] raclopride or [18F] fallypride, was found in the NAc but not in the dorsal striatum and was associated with increased cocaine intake in highly impulsive rats and enhanced cocaine-conditioned preference in rats (20). These findings implicate D3Rs in vulnerability to enhanced cocaine-taking or cocaine-seeking behavior in rats.However, the use of low-selective D2/D3- preferring receptor ligands in the foregoing studies makes it impossible to dissociate the roles of D2Rs and D3Rs in vulnerability to drug use and abuse. Therefore, in the present study, we used D3R gene-deleted (D3−/−) mice to study whether D3R deletion alters cocaine-taking and cocaine-seeking behavior during acquisition and maintenance of cocaine self-administration, extinction, and reinstatement of drug-seeking behavior. The purpose of this study was to determine whether D3R loss is a risk factor for cocaine use and abuse. In addition, we also investigated neuroadapative responses in the mesolimbic DA system in D3/− mice to determine whether an increase or a decrease in mesolimbic DA response to cocaine underlies changes in cocaine-taking and cocaine-seeking after D3R deletion.