Biochemical and Functional Characterization of the Trace Amine-Associated Receptor 1 (TAAR1) Agonist RO5263397.

peer reviewe

Altered Sexual Behavior in Dopamine Transporter (DAT) Knockout Male Rats: A Behavioral, Neurochemical and Intracerebral Microdialysis Study

peer reviewe

Novelty-related behavior of young and adult dopamine transporter knockout rats: Implication for cognitive and emotional phenotypic patterns.

peer reviewe

Novelty-related behavior of young and adult dopamine transporter knockout rats: Implication for cognitive and emotional phenotypic patterns.

peer reviewe

Biochemical and Functional Characterization of the Trace Amine-Associated Receptor 1 (TAAR1) Agonist RO5263397.

peer reviewe

Trace Amine-Associated Receptor 5 Provides Olfactory Input Into Limbic Brain Areas and Modulates Emotional Behaviors and Serotonin Transmission

peer reviewe

Dopamine transporter knockout rats as the new preclinical model of hyper- and hypo-dopaminergic disorders.

peer reviewe

Presynaptic action of neurotensin on dopamine release through inhibition of D2 receptor function

<p>Abstract</p> <p>Background</p> <p>Neurotensin (NT) is known to act on dopamine (DA) neurons at the somatodendritic level to regulate cell firing and secondarily enhance DA release. In addition, anatomical and indirect physiological data suggest the presence of NT receptors at the terminal level. However, a clear demonstration of the mechanism of action of NT on dopaminergic axon terminals is lacking. We hypothesize that NT acts to increase DA release by inhibiting the function of terminal D2 autoreceptors. To test this hypothesis, we used fast-scan cyclic voltammetry (FCV) to monitor in real time the axonal release of DA in the nucleus accumbens (NAcc).</p> <p>Results</p> <p>DA release was evoked by single electrical pulses and pulse trains (10 Hz, 30 pulses). Under these two stimulation conditions, we evaluated the characteristics of DA D₂autoreceptors and the presynaptic action of NT in the NAcc shell and shell/core border region. The selective agonist of D₂autoreceptors, quinpirole (1 μM), inhibited DA overflow evoked by both single and train pulses. In sharp contrast, the selective D₂receptor antagonist, sulpiride (5 μM), strongly enhanced DA release triggered by pulse trains, without any effect on DA release elicited by single pulses, thus confirming previous observations. We then determined the effect of NT (8–13) (100 nM) and found that although it failed to increase DA release evoked by single pulses, it strongly enhanced DA release evoked by pulse trains that lead to prolonged DA release and engage D₂autoreceptors. In addition, initial blockade of D₂autoreceptors by sulpiride considerably inhibited further facilitation of DA release generated by NT (8–13).</p> <p>Conclusion</p> <p>Taken together, these data suggest that NT enhances DA release principally by inhibiting the function of terminal D₂autoreceptors and not by more direct mechanisms such as facilitation of terminal calcium influx.</p

Behavioral Phenotyping of Dopamine Transporter Knockout Rats: Compulsive Traits, Motor Stereotypies, and Anhedonia

Alterations in dopamine neurotransmission are generally associated with diseases such as attention-deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). Such diseases typically feature poor decision making and lack of control on executive functions and have been studied through the years using many animal models. Dopamine transporter (DAT) knockout (KO) and heterozygous (HET) mice, in particular, have been widely used to study ADHD. Recently, a strain of DAT KO rats has been developed (1). Here, we provide a phenotypic characterization of reward sensitivity and compulsive choice by adult rats born from DAT-HET dams bred with DAT-HET males, in order to further validate DAT KO rats as an animal model for preclinical research. We first tested DAT KO rats' sensitivity to rewarding stimuli, provided by highly appetitive food or sweet water; then, we tested their choice behavior with an Intolerance-to-Delay Task (IDT). During these tests, DAT KO rats appeared less sensitive to rewarding stimuli than wild-type (WT) and HET rats: they also showed a prominent hyperactive behavior with a rigid choice pattern and a wide number of compulsive stereotypies. Moreover, during the IDT, we tested the effects of amphetamine (AMPH) and RO-5203648, a trace amine-associated receptor 1 (TAAR1) partial agonist. AMPH accentuated impulsive behaviors in WT and HET rats, while it had no effect in DAT KO rats. Finally, we measured the levels of tyrosine hydroxylase, dopamine receptor 2 (D2), serotonin transporter, and TAAR1 mRNA transcripts in samples of ventral striatum, finding no significant differences between WT and KO genotypes. Throughout this study, DAT KO rats showed alterations in decision-making processes and in motivational states, as well as prominent motor and oral stereotypies: more studies are warranted to fully characterize and efficiently use them in preclinical research

Trace amine associate receptor 1 (TAAR1) as a new target for the treatment of cognitive dysfunction in Alzheimer disease

editorial reviewedAlzheimer disease (AD) is the main cause of dementia with approximately 27 million people affected worldwide. Beta-Amyloid peptide (Ab) is elevated in the brains of patients with AD and is believed to be causative in the disease process. Ab can reduce long-term potentiation (LTP), a form of synaptic plasticity that is closely associated with learning and memory [1]. LTP involves postsynaptic phosphorylation and glutamate receptor trafficking, particularly; it has been shown that amyloid can cause reduction of glutamatergic transmission and inhibition of synaptic plasticity via increased endocytosis of NMDA receptors. Trace Amines (TAs) are a family of endogenous compounds with strong structural similarity to the classical monoamine neurotransmitters. The molecular mechanism of the TAs involves binding to a novel G protein-coupled receptor, called TAAR (trace amine-associated receptor). TAAR1 is distributed in the CNS. Recently, it has been shown that selective activation of TAAR1 are able to reverse glutamatergic hypofunction induced by selective NMDA receptor antagonists suggesting that TAAR1 activation may enhance also glutamatergic function. There are several lines of evidence suggesting pro-cognitive action of TAAR1 agonists in various behavioral experimental protocols and there is evidence indicating that TAAR1 can modulate frontal cortex glutamate NMDA receptor- related functions. [2-5]. Objectives: 1. To study in vitro the role of TAAR1 agonists on basal cortical glutamatergic transmission and their beneficial effect on Ab-induced dysfunction. 2. To study, in vivo, the role of TAAR1 in cognitive dysfunction induced by Ab and the beneficial role of TAAR1 agonists on cognition in Alzheimer's mouse models. Methods: In vitro experiments were conducted on primary cortical cultures. Cortices of E17 embryo from TAAR1 and control mice were isolated and incubated for 14 days at 37 °C and 5% CO2. Cells were then stimulated with Ab 1-42 (1 µM, AnaSpec, USA), TAAR1 agonist (RO5256390, Sigma Aldrich, Belgium, 1 µM) or both 1hr at 37°C and NMDA surface expression was assessed using biotinylation assay and Western blots. In vivo studies were performed using 10-weeks mice ICV injected with: Ab 1-42 (3 µl), TAAR1 agonist (3µl) or both and vehicle treated controls. 7 days later, a series of behavioral tests were performed to evaluate the effects of Ab 1-42 and TAAR1 agonist, including Morris Water Maze (MWM), novel object recognition (NOR) and open field. Results: In vitro data showed that, as expected in WT mice, Ab 1-42 significantly decreased NMDA surface (NR1: -35± 2.6%; NR2A: -38± 1.8%; NR2B: -47± 4.2% ) expression while TAAR1 agonist promotes their membrane localization (NR1: +48±4.8%; NR2A: +67±3.5%; NR2B: +52±3.8% p<0.05, Student t test) on cortical cells. Conclusion: Altogether, our results showed that in vitro, TAAR1 agonist displayed the ability of increasing NMDA receptors surface expression, suggesting the possibility of displaying therapeutic effect on cognitive Ab induced impairments. Whether these effects are reproducible in vivo, are currently addressed. References [1] Selkoe DJ. Alzheimer's disease is a synaptic failure. Science 2002; 298(5594):789-91. [2] Guise KG, Shapiro ML. Medial Prefrontal Cortex Reduces Memory Interference by Modifying Hippocampal Encoding. Neuron. 2017 ; 5;94(1):183-192.e8. [3] Flores-Martínez E, Peña-Ortega F. Amyloid b Peptide-Induced Changes in Prefrontal Cortex Activity and Its Response to Hippocampal Input. Int J Pept. 2017; 7386809. [4] Banks PJ, Burroughs AC, Barker GR, Brown JT, Warburton EC, Bashir ZI. Disruption of hippocampal-prefrontal cortex activity by dopamine D2R-dependent LTD of NMDAR transmission. Proc Natl Acad Sci U S A. 2015; 1;112(35):11096-101. [5] Feld M, Krawczyk MC, Sol Fustiñana M, Blake MG, Baratti CM, Romano A, Boccia MM. Decrease of ERK/MAPK overactivation in prefrontal cortex reverses early memory deficit in a mouse model of Alzheimer's disease. J Alzheimers Dis. 2014;40(1):69-82