Serotonin2C receptor stimulation inhibits cocaine-induced Fos expression and DARPP-32 phosphorylation in the rat striatum independently of dopamine outflow

Variants of tryptophan hydroxylase-2 (Tph2), the gene encoding enzyme responsible for the synthesis of brain serotonin (5-HT), have been associated with neuropsychiatric disorders, substance abuse and addiction. This study assessed the effect of Tph2 gene deletion on motor behavior and found that motor activity induced by 2.5 and 5 mg/kg amphetamine was enhanced in Tph2 À/À mice. Using the in vivo microdialysis technique we found that the ability of amphetamine to stimulate noradrenaline (NA) release in the striatum was reduced by about 50% in Tph2 À/À mice while the release of dopamine (DA)was not affected. Tph2 deletion did not affect the release of NA and DA in the prefrontal cortex. The role of endogenous 5-HT in enhancing the effect of amphetamine was confirmed showing that treatment with the 5-HT precursor 5-hydroxytryptophan (10 mg/kg) restored tissue and extracellular levels of brain 5-HT and the effects of amphetamine on striatal NA release and motor activity in Tph2 À/À mice. Treatment with the NA precursor dihydroxyphenylserine (400 mg/kg) was sufficient to restore the effect of amphetamine on striatal NA release and motor activity in Tph2 À/À mice. These findings indicate that amphetamineinduced hyperactivity is attenuated by endogenous 5-HT through the inhibition of striatal NA release. Tph2 À/À mice may be a useful preclinical model to assess the role of 5-HTdependent mechanisms in the action of psychostimulants.

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“…; Devroye et al . ), confirming that serotonergic modulation of psychostimulant‐induced locomotion is largely independent from DA release.…”

Section: Discussionsupporting

confidence: 53%

“…; Devroye et al . ). In addition, recent data show that the ability of 5‐HTP to counteract cognitive deficits in mice expressing a human variant of Tph2 associated with an 80% reduction in 5‐HT synthesis, was mimicked by the pharmacological stimulation of 5‐HT 2C receptors (Del'Guidice et al .…”

Section: Discussionmentioning

confidence: 97%

Tph2 gene deletion enhances amphetamine‐induced hypermotility: effect of 5‐HT restoration and role of striatal noradrenaline release

Carli

Kostoula

Sacchetti

et al. 2015

Journal of Neurochemistry

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“…JJ-3-45 was not as efficacious since activity with 20 mg/kg was still significantly higher than vehicle, whereas 30 mg/kg significantly depressed baseline locomotion. By comparison, lorcaserin had a stimulatory effect on baseline activity at the lowest dose and the reduction in AMPH-induced hyperlocomotion was not dose-dependent-suggesting a complex mechanism of action (see Devroye et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

5-HT2C Agonists Modulate Schizophrenia-Like Behaviors in Mice

Pogorelov

Rodriguiz

Cheng

et al. 2017

Neuropsychopharmacol

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All FDA-approved antipsychotic drugs (APDs) target primarily dopamine D or serotonin (5-HT) receptors, or both; however, these medications are not universally effective, they may produce undesirable side effects, and provide only partial amelioration of negative and cognitive symptoms. The heterogeneity of pharmacological responses in schizophrenic patients suggests that additional drug targets may be effective in improving aspects of this syndrome. Recent evidence suggests that 5-HT receptors may be a promising target for schizophrenia since their activation reduces mesolimbic nigrostriatal dopamine release (which conveys antipsychotic action), they are expressed almost exclusively in CNS, and have weight-loss-promoting capabilities. A difficulty in developing 5-HT agonists is that most ligands also possess 5-HT and/or 5-HT activities. We have developed selective 5-HT ligands and herein describe their preclinical effectiveness for treating schizophrenia-like behaviors. JJ-3-45, JJ-3-42, and JJ-5-34 reduced amphetamine-stimulated hyperlocomotion, restored amphetamine-disrupted prepulse inhibition, improved social behavior, and novel object recognition memory in NMDA receptor hypofunctioning NR1-knockdown mice, and were essentially devoid of catalepsy. However, they decreased motivation in a breakpoint assay and did not promote reversal learning in MK-801-treated mice. Somewhat similar effects were observed with lorcaserin, a 5-HT agonist with potent 5-HT and 5-HT agonist activities, which is approved for treating obesity. Microdialysis studies revealed that both JJ-3-42 and lorcaserin reduced dopamine efflux in the infralimbic cortex, while only JJ-3-42 decreased it in striatum. Collectively, these results provide additional evidence that 5-HT receptors are suitable drug targets with fewer side effects, greater therapeutic selectivity, and enhanced efficacy for treating schizophrenia and related disorders than current APDs.

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“…DRD1 is a subfamily of dopamine receptors and one of multiple types of GPCRs expressed in MSPNs, including serotonin (5-HT 2 C receptor [108]), noradrenaline ( α 2 -adrenoceptor, β 1 -adrenoceptor [109], acetylcholine (muscarinic M4 receptor; M4R), adenosine (A2a receptors; A2aR) and dopamine receptors of D 2 -like family. The last three, alongside DRD1, were modelled by Nair et al [17], who simulated the reward prediction error (defined as the difference between the received and expected reward).…”

Section: Biophysical Models Of Synaptic Plasticitymentioning

confidence: 99%

Analysis of proteins in computational models of synaptic plasticity

Heil

Wysocka

Sorokina

et al. 2018

Preprint

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The desire to explain how synaptic plasticity arises from interactions between ions, proteins and other signalling molecules has propelled the development of biophysical models of molecular pathways in hippocampal, striatal and cerebellar synapses. The experimental data underpinning such models is typically obtained from low-throughput, hypothesis-driven experiments. We used high-throughput proteomic data and bioinformatics datasets to assess the coverage of biophysical models.To determine which molecules have been modelled, we surveyed biophysical models of synaptic plasticity, identifying which proteins are involved in each model. We were able to map 4.2% of previously reported synaptic proteins to entities in biophysical models. Linking the modelled protein list to Gene Ontology terms shows that modelled proteins are focused on functions such as calmodulin binding, cellular responses to glucagon stimulus, G-alpha signalling and DARPP-32 events.We cross-linked the set of modelled proteins with sets of genes associated with common neurological diseases. We find some examples of disease-associated molecules that are well represented in models, such as voltage-dependent calcium channel family (CACNA1C ), dopamine D1 receptor, and glutamate ionotropic NMDA type 2A and 2B receptors. Many other disease-associated genes have not been included in models of synaptic plasticity, for example catechol-O-methyltransferase (COMT ) and MAOA. By incorporating pathway enrichment results, we identify LAMTOR, a gene uniquely associated with Schizophrenia, which is closely linked to the MAPK pathway found in some models.Our analysis provides a map of how molecular pathways underpinning neurological diseases relate to synaptic biophysical models that can in turn be used to explore how these molecular events might bridge scales into cellular processes and beyond. The map illustrates disease areas where biophysical models have good coverage as well as domain gaps that require significant further research. Author summaryThe 100 billion neurons in the human brain are connected by a billion trillion structures called synapses. Each synapse contains hundreds of different proteins. Some proteins sense the activity of the neurons connecting the synapse. Depending on what they sense, . 28, 2018; the proteins in the synapse are rearranged and new proteins are synthesised. This changes how strongly the synapse influences its target neuron, and underlies learning and memory. Scientists build computational models to reason about the complex interactions between proteins. Here we list the proteins that have been included in computational models to date. For good reasons, models do not always specify proteins precisely, so to make the list we had to translate the names used for proteins in models to gene names, which are used to identify proteins. Our translation could be used to label computational models in the future. We found that the list of modelled proteins contains only 4.2% of proteins associated with synapses, suggesting mor...

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Serotonin2C receptor stimulation inhibits cocaine-induced Fos expression and DARPP-32 phosphorylation in the rat striatum independently of dopamine outflow

Cited by 14 publications

References 58 publications

Tph2 gene deletion enhances amphetamine‐induced hypermotility: effect of 5‐HT restoration and role of striatal noradrenaline release

Tph2 gene deletion enhances amphetamine‐induced hypermotility: effect of 5‐HT restoration and role of striatal noradrenaline release

5-HT2C Agonists Modulate Schizophrenia-Like Behaviors in Mice

Analysis of proteins in computational models of synaptic plasticity

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