Cell . . . Addiction treatment drugs with few side effects.

At present, drug addiction has become a global public health problem, and there is no effective response.addiction is a chronic recurrent disease, which is characterized by the disorder of dopamine system in the midbrain border of the brain.previous studies have shown that targeting the neuropeptide neurotensin (NTS) and its receptor ntsr1 can restore steady-state dopamine signal transduction [1].as a widely expressed neuropeptide in the central and peripheral nervous system, NTS activates G protein through neurotensin receptor 1 (ntsr1), which is a G protein coupled receptor (GPCR), and mediates downstream signaling pathways by binding with β - arrestin protein.and neurotensin receptor 1 (ntsr1) agonists are more effective in the treatment of drug addiction.on January 9, 2018, Malan research team of the Institute of brain science, Fudan University published an article in the Journal of Science Signaling: β - arrestin – biased β - adrenergic signaling promoters extension learning of cocaine award Memory revealed that the β - adrenergic receptor / β - arrestin signaling pathway in subcortical prefrontal cortex can regulate the regression learning ability of cocaine addicted mice and promote the regression of addiction.on May 28, 2020, the research team of Marc g. Caron of Duke University published a paper on the cell: β - arrestin biased allosteric modulator of ntsr1 selectively attenuates additive behaviors. Through drug screening experiments for ntsr1 of β - arrestin2, a series of allosteric modulators of ntsr1 were identified, including sbi-553, which had little side effects.in vitro binding experiments showed that sbi-553 could bind to the allosteric site of ntsr1, and showed the characteristics of positive allosteric modulator (PAM).molecular experiments further confirmed that sbi-553 phosphorylated ntsr1 and recruited β - arrestin2 protein onto ntsr1 membrane.sbi-553 antagonized NTS induced Gq protein mediated ERK phosphorylation, but promoted NTS induced β - arrestin2 protein mediated ERK phosphorylation.these results indicate that sbi-553 is a β - arrestin2 protein biased ntsr1 ligand.the researchers conducted a series of behavioral experiments to evaluate the role of sbi-553 in addiction.intraperitoneal injection of sbi-553 significantly reduced the excitatory movement induced by cocaine and methamphetamine.after the training of cocaine administration, the number of times of pressing on the side lever of cocaine increased, and the reward effect was formed. However, intraperitoneal injection of sbi-553 also significantly reduced the side lever of pressing cocaine and inhibited the addiction behavior of cocaine.at the same time, the onset time of lever reaction was prolonged.more interestingly, when the concentration of cocaine is low (0.1-0.3mg / kg), sbi-553 has stronger inhibitory effect, but when the concentration of cocaine is high (1mg / kg), sbi-553 can not inhibit addiction behavior.previous studies have shown that ntr1 agonist pd149163 has side effects such as hypotension, hypothermia and impaired exercise ability in the treatment of central nervous system diseases. however, the researchers found that after intraperitoneal injection of sbi-553, the physiological status of mice such as core temperature, exercise coordination and blood pressure were normal, and there were no side effects similar to those of pd149163. these studies indicate that sbi-553 is a ntsr1 ligand biased by β - arrestin protein, so β - arrestin2 may be involved in the addiction behavior regulated by sbi-553. even after intraperitoneal injection of sbi-553, the excitatory movement induced by cocaine and methamphetamine in β - arrestin2 knockout mice did not decrease. further, the β - arrestin2 of dopamine type 1 receptor neurons, dopamine type 2 receptor neurons, midbrain dopamine type 2 receptor neurons and striatum dopamine type 2 receptor neurons were specifically knocked out in a variety of tool mice. It was found that intraperitoneal injection of sbi-553 could reduce the methamphetamine induced excitatory movement of dopamine type 1 receptor neurons in β - arrestin2 knockout mice, But it had no effect on β - arrestin2 knockout mice. that is to say, the addiction behavior regulated by sbi-553 requires β - arrestin2 on dopamine type 2 receptor neurons, especially dopamine type 2 receptor neurons in striatum. in general, it has been found that although non biased ntsr1 agonists have the potential to treat addictive behaviors, they have serious side effects. In this paper, we found that the β - arrestin2 biased ntsr1 ligand sbi-553 can also play a role in the treatment of addictive behavior, but there is no very small side effect. original link: plate maker: old wings References: 1. Ferraro, L., tiozzo fasiolo, L., beggiato, S., Borelli, A.C., pomierny chamiolo, L., frankowska, M., Antonelli, T., tomasini, M.C., fuzzy, K., and Filip, M. (2016)