Zebrafish (Danio rerio) are ideal model organisms for investigating nervous system function, both in health and disease. Nevertheless, functional characteristics of dopamine (DA) release and uptake regulation are still not well-understood in zebrafish. In this study, we assessed D3 autoreceptor function in the telencephalon of whole zebrafish brains ex vivo by measuring the electrically stimulated DA release ([DA]_max) and uptake at carbon fiber microelectrodes with fast-scan cyclic voltammetry. Treatment with pramipexole and 7-OH-DPAT, selective D3 autoreceptor agonists, sharply decreased [DA]_max. Conversely, SB277011A, a selective D3 antagonist, nearly doubled [DA]_max and decreased k, the first-order rate constant for the DA uptake, to about 20% of its original value. Treatment with desipramine, a selective norepinephrine transporter blocker, failed to increase current, suggesting that our electrochemical signal arises solely from the release of DA. Furthermore, blockage of DA uptake with nomifensine-reversed 7-OH-DPAT induced decreases in [DA]_max. Collectively, our data show that, as in mammals, D3 autoreceptors regulate DA release, likely by inhibiting uptake. The results of this study are useful in the further development of zebrafish as a model organism for DA-related neurological disorders such as Parkinson's disease, schizophrenia, and drug addiction.

2022-06-01·Journal of physiology and pharmacology : an official journal of the Polish Physiological Society

Effect of selective dopamine D₃ and D₄ receptor agonists on trunk pulmonary artery vascular reactivity from control and monocrotaline-treated rats.

Article

作者: de Jesus, L ; de J Gomez Villalobos, Ma ; Perez-Lopez, R ; Flores, G

Dopamine D1-like and D2-like receptors are expressed in the pulmonary arteries, however there is a little information about their effect on vascular tone in pulmonary circulation, even the vascular effect of activation of the dopamine D₃ and D₄ subtypes in physiological and pathological conditions such as pulmonary hypertension is unknown. The objective of this study was to evaluate the vascular response of trunk pulmonary artery rings from saline and monocrotaline-treated rats in the presence of selective dopamine receptor agonists. In trunk pulmonary artery rings with intact and denuded endothelium, cumulative concentration-response curves were performed for phenylephrine, acetylcholine, and dopamine receptor agonists (apomorphine-D2-like, SKF38393-D₁, quinpirole-D₂/D₃, 7-OH-DPATD₃, and PD168077-D₄) alone and in the presence of corresponding selective dopamine receptor antagonists (SCH23390-D₁, raclopride-D₂/D₃, U99194 maleate-D₃, and L-745,870-D₄). Contractile and relaxant effects generated during the activation with phenylephrine and acetylcholine, respectively, were significantly reduced in intact and denuded endothelium trunk pulmonary artery rings from monocrotaline rats in comparison with control rats. All dopamine receptor agonists, except the 7-OH-DPAT, produced significant vascular relaxation in intact trunk pulmonary artery rings precontracted with phenylephrine in both experimental groups. Also, the vascular relaxation of SKF38393, and particularly apomorphine and PD168077 was significant in denuded endothelium trunk pulmonary artery rings from control and monocrotaline groups. Furthermore, the vasorelaxation induced by these dopamine agonists was significantly reduced in pulmonary preparations from monocrotaline-treated rats in comparison to that recorded in preparations from control rats. The effect of dopamine receptor agonists decreased significantly in the presence of the corresponding antagonist in both experimental groups. The results support that dopamine D₄ receptor agonist induces significant vascular relaxation, whereas dopamine D₃ receptor agonist induces vasoconstriction in intact and denuded endothelium trunk pulmonary artery rings in control and monocrotaline-induced pulmonary arterial hypertension rats.

2019-09-01·Neurochemistry International3区 · 医学

Blonanserin ameliorates social deficit through dopamine-D3 receptor antagonism in mice administered phencyclidine as an animal model of schizophrenia

3区 · 医学

Article

作者: Kitagaki, Shinji ; Uchida, Mizuki ; Ozaki, Norio ; Yoshimi, Akira ; Noda, Yukihiro ; Hida, Hirotake ; Takeuchi, Saori ; Naruse, Ryo

Blonanserin differs from other antipsychotic drugs, such as risperidone and olanzapine, and exhibits a higher affinity for dopamine-D_2/3 receptors than for serotonin 5-HT_2A receptors. We investigated the involvement of dopamine-D₃ receptors in the effect of blonanserin on the social deficit observed in an animal model of schizophrenia and sought to elucidate the molecular mechanism underlying its action. Mice received phencyclidine (PCP: 10 mg/kg/day, s.c.), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, once a day for 14 consecutive days. We then evaluated the sociability, using a social interaction test, and the expression of GluN1 subunit, an essential subunit of the NMDA receptors, in these mice. Blonanserin significantly ameliorated the PCP-induced social deficit, whereas olanzapine and haloperidol did not. This effect of blonanserin was antagonized by 7-OH-DPAT, a dopamine-D₃ receptor agonist, and SCH23390, a dopamine-D₁ receptor antagonist. However, the ameliorating effect of blonanserin was not inhibited by DOI, a serotonin 5-HT_2A receptor agonist. The PCP-induced social deficit was also ameliorated by U99194, a dopamine-D₃ receptor antagonist and SKF38393, a dopamine-D₁ receptor agonist, being effects antagonized by 7-OH-DPAT or SCH23390. Blonanserin significantly inhibited the decrease in the phosphorylation levels of GluN1 at Ser⁸⁹⁷ by protein kinase A (PKA) in the prefrontal cortex (PFC) in PCPadministered mice. These results suggest that activation of NMDA receptors due to Ser⁸⁹⁷-phosphorylation of GluN1 subunit, which is a step linked to dopamine-D₁ receptor-PKA signaling through dopamine-D₃ receptor antagonism in the PFC, is required for the ameliorating effect of blonanserin on the PCP-induced social deficit. These findings also provide in vivo evidence that blonanserin antagonism of the dopamine-D₃ receptors may be useful as a novel treatment strategy and that the dopamine-D₃ receptors can be a novel therapeutic target molecule for the social deficit observed in schizophrenia.

100 项与 7-OH-DPAT 相关的药物交易

登录后查看更多信息