Lack of inhibitory control over apparently voluntary motor acts is a behavioral symptom found in attention deficit hyperactivity disorder, drug addiction, Tourette's Syndrome, and obsessive-compulsive disorder. It is highly debated whether impaired inhibitory control is due to hyper- or hypo-dopaminergic activity. To investigate its neurobiological basis, we have generated """"""""hyperdopaminergic"""""""" transgenic mice by reducing the dopamine transporter expression (DAT knockdown). Our preliminary studies suggest that DAT knockdown mice model aspects of impaired inhibitory control and that impaired postsynaptic dopamine D2 receptor function may underlie such behavioral deficits.
Aim 1 of the proposed studies is to determine the specific biochemical changes underlying impaired inhibitory control in DAT knockdown mice. We will first identify the behavioral mechanisms underlying impaired inhibitory control in DAT knockdown mice: whether it's delay aversion or response inhibition, two processes implicated as core behavioral deficits in impaired inhibitory control. We will then investigate what signaling molecule is responsible for the impaired postsynaptic D2 receptor function in DAT knockdown mice: receptor, G protein, receptor-G protein coupling or adenytyl cyclase activity. We will take both behavioral measures and biochemical measures from each animal and examine the degree of association between them.
Aim 2 is to test the hypothesis that impaired postsynaptic D2 receptor function underlies impaired inhibitory control using a pharmacological rescue approach. Our preliminary studies suggest that chronic D2 antagonist treatment is able to reverse behavioral deficits in DAT knockdown mice. We will analyze D2 signaling and behavioral changes in DAT knockdown mice after chronic treatment with D2 antagonists. We will test the hypothesis that such treatment will reverse D2 signaling and behavioral deficits in DAT knockdown mice.
Aim 3 is to test directly the hypothesis that impaired D2 receptor function underlies impaired inhibitory control using mice that lack or have reduced postsynaptic D2 receptors.
| Cagniard, Barbara; Sotnikova, Tatyana D; Gainetdinov, Raul R et al. (2014) The dopamine transporter expression level differentially affects responses to cocaine and amphetamine. J Neurogenet 28:112-21 |
| Kheirbek, Mazen A; Beeler, Jeff A; Chi, Wanhao et al. (2010) A molecular dissociation between cued and contextual appetitive learning. Learn Mem 17:148-54 |
| Kheirbek, Mazen A; Britt, Jon P; Beeler, Jeff A et al. (2009) Adenylyl cyclase type 5 contributes to corticostriatal plasticity and striatum-dependent learning. J Neurosci 29:12115-24 |
| Beeler, Jeff A; Cao, Zhen Fang Huang; Kheirbek, Mazen A et al. (2009) Loss of cocaine locomotor response in Pitx3-deficient mice lacking a nigrostriatal pathway. Neuropsychopharmacology 34:1149-61 |
| Frazier, Cristianne R M; Mason, Peggy; Zhuang, Xiaoxi et al. (2008) Sucrose exposure in early life alters adult motivation and weight gain. PLoS One 3:e3221 |
| Kheirbek, Mazen A; Beeler, Jeff A; Ishikawa, Yoshihiro et al. (2008) A cAMP pathway underlying reward prediction in associative learning. J Neurosci 28:11401-8 |
| Sanders, Amy Cecilia; Hussain, Ali J; Hen, Rene et al. (2007) Chronic blockade or constitutive deletion of the serotonin transporter reduces operant responding for food reward. Neuropsychopharmacology 32:2321-9 |
| Tilley, Michael R; Cagniard, Barbara; Zhuang, Xiaoxi et al. (2007) Cocaine reward and locomotion stimulation in mice with reduced dopamine transporter expression. BMC Neurosci 8:42 |
| Yin, Henry H; Zhuang, Xiaoxi; Balleine, Bernard W (2006) Instrumental learning in hyperdopaminergic mice. Neurobiol Learn Mem 85:283-8 |
| Cagniard, Barbara; Beeler, Jeff A; Britt, Jonathan P et al. (2006) Dopamine scales performance in the absence of new learning. Neuron 51:541-7 |
