TY - JOUR

T1 - Taar1-mediated modulation of presynaptic dopaminergic neurotransmission

T2 - Role of D2 dopamine autoreceptors

AU - Leo, D.

AU - Mus, L.

AU - Espinoza, S.

AU - Hoener, M. C.

AU - Sotnikova, T. D.

AU - Gainetdinov, R. R.

N1 - Funding Information: This work was supported in part by research awards to RRG from F. Hoffmann-La Roche Ltd. (Basel, Switzerland) and Fondazione Compagnia di San Paolo (Torino, Italy). We are grateful to Lundbeck A/G and Lundbeck USA for generously providing the TAAR1 knockout mice. We thank Dr. M. Morini, D. Cantatore and F. Piccardi for their excellent technical assistance.

PY - 2014/6

Y1 - 2014/6

N2 - Trace Amine-Associated Receptor 1 (TAAR1) is a G protein-coupled receptor (GPCR) expressed in several mammalian brain areas and activated by "trace amines" (TAs). TAs role is unknown; however, discovery of their receptors provided an opportunity to investigate their functions. In vivo evidence has indicated an inhibitory influence of TAAR1 on dopamine (DA) neurotransmission, presumably via modulation of dopamine transporter (DAT) or interaction with the D2 DA receptor and/or activation of inwardly rectifying K+ channels. To elucidate the mechanisms of TAAR1-dependent modulation, we used TAAR1 knockout mice (TAAR1-KO), a TAAR1 agonist (RO5166017) and a TAAR1 antagonist (EPPTB) in a set of neurochemical experiments. Analysis of the tissue content of TAAR1-KO revealed increased level of the DA metabolite homovanillic acid (HVA), and in vivo microdialysis showed increased extracellular DA in the nucleus accumbens (NAcc) of TAAR1-KO. In fast scan cyclic voltammetry (FSCV) experiments, the evoked DA release was higher in the TAAR1-KO NAcc. Furthermore, the agonist RO5166017 induced a decrease in the DA release in wild-type that could be prevented by the application of the TAAR1 antagonist EPPTB. No alterations in DA clearance, which are mediated by the DAT, were observed. To evaluate the interaction between TAAR1 and D2 autoreceptors, we tested the autoreceptor-mediated dynamics. Only in wild type mice, the TAAR1 agonist was able to potentiate quinpirole-induced inhibitory effect on DA release. Furthermore, the short-term plasticity of DA release following paired pulses was decreased in TAAR1-KO, indicating less autoinhibition of D2 autoreceptors. These observations suggest a close interaction between TAAR1 and the D2 autoreceptor regulation.

AB - Trace Amine-Associated Receptor 1 (TAAR1) is a G protein-coupled receptor (GPCR) expressed in several mammalian brain areas and activated by "trace amines" (TAs). TAs role is unknown; however, discovery of their receptors provided an opportunity to investigate their functions. In vivo evidence has indicated an inhibitory influence of TAAR1 on dopamine (DA) neurotransmission, presumably via modulation of dopamine transporter (DAT) or interaction with the D2 DA receptor and/or activation of inwardly rectifying K+ channels. To elucidate the mechanisms of TAAR1-dependent modulation, we used TAAR1 knockout mice (TAAR1-KO), a TAAR1 agonist (RO5166017) and a TAAR1 antagonist (EPPTB) in a set of neurochemical experiments. Analysis of the tissue content of TAAR1-KO revealed increased level of the DA metabolite homovanillic acid (HVA), and in vivo microdialysis showed increased extracellular DA in the nucleus accumbens (NAcc) of TAAR1-KO. In fast scan cyclic voltammetry (FSCV) experiments, the evoked DA release was higher in the TAAR1-KO NAcc. Furthermore, the agonist RO5166017 induced a decrease in the DA release in wild-type that could be prevented by the application of the TAAR1 antagonist EPPTB. No alterations in DA clearance, which are mediated by the DAT, were observed. To evaluate the interaction between TAAR1 and D2 autoreceptors, we tested the autoreceptor-mediated dynamics. Only in wild type mice, the TAAR1 agonist was able to potentiate quinpirole-induced inhibitory effect on DA release. Furthermore, the short-term plasticity of DA release following paired pulses was decreased in TAAR1-KO, indicating less autoinhibition of D2 autoreceptors. These observations suggest a close interaction between TAAR1 and the D2 autoreceptor regulation.

KW - Dopamine (DA)

KW - Dopamine receptor 2 (D2R)

KW - Fast scan cyclic voltammetry (FSCV)

KW - Neuropsychiatric disorders

KW - Schizophrenia

KW - Trace amine-associate receptor 1 (TAAR1)

UR - http://www.scopus.com/inward/record.url?scp=84896134874&partnerID=8YFLogxK

U2 - 10.1016/j.neuropharm.2014.02.007

DO - 10.1016/j.neuropharm.2014.02.007

M3 - Article

C2 - 24565640

AN - SCOPUS:84896134874

VL - 81

SP - 283

EP - 291

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

ER -