Pharmacogenetic activation of midbrain dopaminergic neurons induces hyperactivity

Wang, Shujie; Tan, Yan; Zhang, Ju-en; Luo, Minmin

doi:10.1007/s12264-013-1327-x

Cited by 52 publications

(34 citation statements)

References 19 publications

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“…It is well known that a dopamine agonist or increased dopamine signaling produces hyperactivity, e.g. as measured on an open‐field test (Costall et al ., ; Giros et al ., ; Cagniard et al ., ; Wang et al ., ). As dopamine agonists presumably have a net effect of increasing striatal output, as indicated by measures of immediate early genes (Gross & Marshall, ), these observations suggest that an overall increase in striatal output is also correlated with higher movement velocity.…”

Section: Discussionmentioning

confidence: 97%

Striatal firing rate reflects head movement velocity

Kim

Barter

Sukharnikova

et al. 2014

Eur J of Neuroscience

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Although the basal ganglia have long been implicated in the initiation of actions, their contribution to movement remains a matter of dispute. Using wireless multi-electrode recording and motion tracking, we examined the relationship between single-unit activity in the sensorimotor striatum and movement kinematics. We recorded single-unit activity from medium spiny projection neurons and fast-spiking interneurons while monitoring the movements of mice using motion tracking. In Experiment 1, we trained mice to generate movements reliably by water-depriving them and giving them periodic cued sucrose rewards. We found high correlations between single-unit activity and movement velocity in particular directions. This correlation was found in both putative medium spiny projection neurons and fast-spiking interneurons. In Experiment 2, to rule out the possibility that the observed correlations were due to reward expectancy, we repeated the same procedure but added trials in which sucrose delivery was replaced by an aversive air puff stimulus. The air puff generated avoidance movements that were clearly different from movements on rewarded trials, but the same neurons that showed velocity correlation on reward trials exhibited a similar correlation on air puff trials. These experiments show for the first time that the firing rate of striatal neurons reflects movement velocity for different types of movements, whether to seek rewards or to avoid harm.

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Section: Discussionmentioning

confidence: 97%

Striatal firing rate reflects head movement velocity

Kim

Barter

Sukharnikova

et al. 2014

Eur J of Neuroscience

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“…With respect to the specific findings linking the HR‐SE phenotype to the dHPC, lower levels of DA D 1 and 5‐HT 2A receptor mRNA were detected within this region in samples from HR‐SE rats. DA has been heavily implicated in the locomotor response to a novel environment (Beninger, ; Wang et al ., b). Furthermore, data from both animal and human subjects indicates that hypofunction at 5‐HT 2A receptors increases motor impulsivity (Bjork et al ., ; Higgins et al ., ; Winstanley et al ., ,b; Jakubczyk et al ., ).…”

Section: Discussionmentioning

confidence: 99%

Greater sensitivity to novelty in rats is associated with increased motor impulsivity following repeated exposure to a stimulating environment: implications for the etiology of impulse control deficits

Ferland

Zeeb

et al. 2014

Eur J of Neuroscience

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Heightened motor impulsivity and increased novelty-seeking commonly co-occur in psychiatric disorders, including drug addiction. However, the relationship between these two phenomena remains unclear. One-time tests of novelty sensitivity commonly used in preclinical experiments, such as the open-field or novel-object test, fail to capture the fact that novelty-seekers repeatedly experience novel, stimulating situations. The present study therefore investigated whether repeated exposure to a novel, stimulating environment (SE) altered impulsive action. Male Long-Evans rats were trained to perform the five-choice serial reaction time task (5CSRTT) which measures motor impulsivity in the form of premature responding as well as attention and motivation. Animals were then exposed to a novel SE (1 h/day for 16 days) immediately prior to the 5CSRTT. Significant increases in premature responding were observed in a subgroup of reactive animals termed high responders (HR-SE). These rats were not more impulsive at baseline, and levels of impulsivity normalised once exposure to the SE was discontinued. No other aspect of 5CSRTT performance was affected by the SE challenge. We also determined that HR-SE rats were hyperactive in a novel environment. Biochemical analyses revealed changes in gene and protein expression within the dorsal hippocampus of HR-SE rats, including decreases in mRNA encoding the dopamine D1 receptor and brain-derived neurotrophic factor. These results indicate a novel mechanism by which impulsivity and novelty-reactivity interact that may enhance addiction vulnerability synergistically. Furthermore, studying such context-induced impulsivity may provide insight into the process by which environmental load precipitates psychiatric symptoms in impulse control disorders.

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“…In this design, it is impossible to separate out the effects of activation of the DREADD from any unexpected effects of CNO, which could be the enhancement or blockade of the expected result of DREADD activation. In terms of dosing, a wide range of doses (0.2–10 mg/kg) is regularly used in DREADD experiments (Alexander et al, 2009; Ferguson et al, 2011, 2013; Ray et al, 2011; Agulhon et al, 2013; Anderson et al, 2013; Farrell et al, 2013; Michaelides et al, 2013; Wang et al, 2013; Boender et al, 2014; Bull et al, 2014; Dell’Anno et al, 2014; Kätzel et al, 2014; Robinson et al, 2014; Zhu et al, 2014; Chang et al, 2015; Gompf et al, 2015; Mizoguchi et al, 2015; Pienaar et al, 2015; Scofield et al, 2015; Yau and McNally, 2015; Grace et al, 2016; Ma et al, 2016; Marchant et al, 2016; Qiu et al, 2016; Sengupta et al, 2016; Wicker and Forcelli, 2016), and there is seldom any explanation given as to how the dose that was used was decided upon. Using the lowest effectual dose in the assay to be performed, that which in the non-DREADD-expressing animals is experimentally silent, would seem the most straightforward way to minimize any off-target effects of CNO.…”

Section: Relevance To the Dreadd System: Is Cno An Inert Ligand?mentioning

confidence: 99%

Clozapine N-Oxide Administration Produces Behavioral Effects in Long–Evans Rats: Implications for Designing DREADD Experiments

MacLaren

Browne

Shaw

et al. 2016

eNeuro

312

247

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Clozapine N-oxide (CNO) is a ligand for a powerful chemogenetic system that can selectively inhibit or activate neurons; the so-called Designer Receptors Exclusively Activated by Designer Drugs (DREADD) system. This system consists of synthetic G-protein-coupled receptors, which are not believed to be activated by any endogenous ligand, but are activated by the otherwise inert CNO. However, it has previously been shown that the administration of CNO in humans and rats leads to detectable levels of the bioactive compounds clozapine and N-desmethylclozapine (N-Des). As a follow-up, experiments were conducted to investigate the effects of CNO in male Long–Evans rats. It was found that 1 mg/kg CNO reduced the acoustic startle reflex but had no effect on prepulse inhibition (PPI; a measure of sensorimotor gating). CNO (2 and 5 mg/kg) had no effect on the disruption to PPI induced by the NMDA antagonist phencyclidine or the muscarinic antagonist scopolamine. In locomotor studies, CNO alone (at 1, 2, and 5 mg/kg) had no effect on spontaneous locomotion, but 5 mg/kg CNO pretreatment significantly attenuated d-amphetamine-induced hyperlocomotion. In line with the behavioral results, fast-scan cyclic voltammetry found that 5 mg/kg CNO significantly attenuated the d-amphetamine-induced increase in evoked dopamine. However, the effects seen after CNO administration cannot be definitively ascribed to CNO because biologically relevant levels of clozapine and N-Des were found in plasma after CNO injection. Our results show that CNO has multiple dose-dependent effects in vivo and is converted to clozapine and N-Des emphasizing the need for a CNO-only DREADD-free control group when designing DREADD-based experiments.

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Pharmacogenetic activation of midbrain dopaminergic neurons induces hyperactivity

Cited by 52 publications

References 19 publications

Striatal firing rate reflects head movement velocity

Striatal firing rate reflects head movement velocity

Greater sensitivity to novelty in rats is associated with increased motor impulsivity following repeated exposure to a stimulating environment: implications for the etiology of impulse control deficits

Clozapine N-Oxide Administration Produces Behavioral Effects in Long–Evans Rats: Implications for Designing DREADD Experiments

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