Several studies report the presence of bile acids (BAs) in the brain. Recently, it has been discovered in mice that bile diversion surgery increases circulating BAs, affects dopamine dynamics in the nucleus accumbens and reduces reward-related behavior induced by cocaine. Feeding obeticholic acid (OCA), an FDA-approved semi-synthetic bile acid, to mice induced the same effects in the absence of surgery. These modifications in vivo were dependent on the presence of the plasma membrane Takeda G protein-coupled receptor 5 (TGR5). TGR5 is expressed in the intestine, as well as in astrocytes and neurons. Dopamine is a neurotransmitter involved in different physiological functions including reward. The dopamine re-uptake is mediated by the dopamine transporter (DAT). This work investigates the interaction between OCA and mDAT heterologously expressed in Xenopus laevis oocytes. The dopamine transport behavior was studied by two electrodes voltage clamp. The data show that the OCA acts directly on mDAT, independently from the expression of TGR5. The binding of OCA with mDAT induces a small fast-inward current in sodium buffer and blocks the lithium leak current. Dose-response experiments in the presence of OCA resulted in unaltered Imax and K0.5. Perfusing a different bile acid, lithocholic acid (LCA), induces similar behavior of the transporter. These preliminary results indicate a novel and undocumented interaction between DAT (and potentially other NTTs) and BAs.

The interaction of bile acids with dopamine transporter heterologously expressed in Xenopus laevis oocytes

Tiziana Romanazzi;Angela Di Iacovo;Manan Bhatt;Cristina Roseti;Raffaella Cinquetti;Elena Bossi;
2021-01-01

Abstract

Several studies report the presence of bile acids (BAs) in the brain. Recently, it has been discovered in mice that bile diversion surgery increases circulating BAs, affects dopamine dynamics in the nucleus accumbens and reduces reward-related behavior induced by cocaine. Feeding obeticholic acid (OCA), an FDA-approved semi-synthetic bile acid, to mice induced the same effects in the absence of surgery. These modifications in vivo were dependent on the presence of the plasma membrane Takeda G protein-coupled receptor 5 (TGR5). TGR5 is expressed in the intestine, as well as in astrocytes and neurons. Dopamine is a neurotransmitter involved in different physiological functions including reward. The dopamine re-uptake is mediated by the dopamine transporter (DAT). This work investigates the interaction between OCA and mDAT heterologously expressed in Xenopus laevis oocytes. The dopamine transport behavior was studied by two electrodes voltage clamp. The data show that the OCA acts directly on mDAT, independently from the expression of TGR5. The binding of OCA with mDAT induces a small fast-inward current in sodium buffer and blocks the lithium leak current. Dose-response experiments in the presence of OCA resulted in unaltered Imax and K0.5. Perfusing a different bile acid, lithocholic acid (LCA), induces similar behavior of the transporter. These preliminary results indicate a novel and undocumented interaction between DAT (and potentially other NTTs) and BAs.
2021
Romanazzi, Tiziana; DI IACOVO, Angela; Bhatt, MANAN JUGGNU; Roseti, Cristina; Cinquetti, Raffaella; Zanella, Daniele; Bossi, Elena; Galli, Aurelio
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11383/2146211
 Attenzione

L'Ateneo sottopone a validazione solo i file PDF allegati

Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact