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Hyperactivity and impaired response habituation in hyperdopaminergic mice.

ABSTRACT: Abnormal dopaminergic transmission is implicated in schizophrenia, attention deficit hyperactivity disorder, and drug addiction. In an attempt to model aspects of these disorders, we have generated hyperdopaminergic mutant mice by reducing expression of the dopamine transporter (DAT) to 10% of wild-type levels (DAT knockdown). Fast-scan cyclic voltammetry and in vivo microdialysis revealed that released dopamine was cleared at a slow rate in knockdown mice, which resulted in a higher extracellular dopamine concentration. Unlike the DAT knockout mice, the DAT knockdown mice do not display a growth retardation phenotype. They have normal home cage activity but display hyperactivity and impaired response habituation in novel environments. In addition, we show that both the indirect dopamine receptor agonist amphetamine and the direct agonists apomorphine and quinpirole inhibit locomotor activity in the DAT knockdown mice, leading to the hypothesis that a shift in the balance between dopamine auto and heteroreceptor function may contribute to the therapeutic effect of psychostimulants in attention deficit hyperactivity disorder.

SUBMITTER: Zhuang X

PROVIDER: S-EPMC29368 | biostudies-literature | 2001 Feb

REPOSITORIES: biostudies-literature

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Hyperactivity and impaired response habituation in hyperdopaminergic mice.

Zhuang X X Oosting R S RS Jones S R SR Gainetdinov R R RR Miller G W GW Caron M G MG Hen R R

Proceedings of the National Academy of Sciences of the United States of America 20010201 4

Abnormal dopaminergic transmission is implicated in schizophrenia, attention deficit hyperactivity disorder, and drug addiction. In an attempt to model aspects of these disorders, we have generated hyperdopaminergic mutant mice by reducing expression of the dopamine transporter (DAT) to 10% of wild-type levels (DAT knockdown). Fast-scan cyclic voltammetry and in vivo microdialysis revealed that released dopamine was cleared at a slow rate in knockdown mice, which resulted in a higher extracellul ...[more]

PMID: 11172062

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Project description:Current approaches to quantifying resilience make extensive use of self-reported data. Problematically, this type of scales is plagued by response distortions-both deliberate and unintentional, particularly in occupational populations. The aim of the current study was to develop an objective index of resilience. The study was conducted in 30 young healthy adults. Following completion of the Connor-Davidson Resilience Scale (CD-RISC) and Depression/Anxiety/Stress Scale (DASS), they were subjected to a series of 15 acoustic startle stimuli (95 dB, 50 ms) presented at random intervals, with respiration, skin conductance and ECG recorded. As expected, resilience (CD-RISC) significantly and negatively correlated with all three DASS subscales-Depression (r = -0.66, p<0.0001), Anxiety (r = -0.50, p<0.005) and Stress (r = -0.48, p<0.005). Acoustic stimuli consistently provoked transient skin conductance (SC) responses, with SC slopes indexing response habituation. This slope significantly and positively correlated with DASS-Depression (r = 0.59, p<0.005), DASS-Anxiety (r = 0.35, p<0.05) and DASS-Total (r = 0.50, p<0.005) scores, and negatively with resilience score (r = -0.47; p = 0.006), indicating that high-resilience individuals are characterized by steeper habituation slopes compared to low-resilience individuals. Our key finding of the connection between habituation of the skin conductance responses to repeated acoustic startle stimulus and resilience-related psychometric constructs suggests that response habituation paradigm has the potential to characterize important attributes of cognitive fitness and well-being-such as depression, anxiety and resilience. With steep negative slopes reflecting faster habituation, lower depression/anxiety and higher resilience, and slower or no habituation characterizing less resilient individuals, this protocol may offer a distortion-free method for objective assessment and monitoring of psychological resilience.

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Hyperactivity and impaired response habituation in hyperdopaminergic mice.

Publications

Hyperactivity and impaired response habituation in hyperdopaminergic mice.

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