Integrative Roles of Dopamine Pathway and Calcium Channels Reveal a Link between Schizophrenia and Opioid Use Disorder.

Several theories have been proposed to explain the mechanisms of substance use in schizophrenia. Brain neurons pose a potential to provide novel insights into the association between opioid addiction, withdrawal, and schizophrenia. Thus, we exposed zebrafish larvae at 2 days post-fertilization (dpf) to domperidone (DPM) and morphine, followed by morphine withdrawal. Drug-induced locomotion and social preference were assessed, while the level of dopamine and the number of dopaminergic neurons were quantified. In the brain tissue, the expression levels of genes associated with schizophrenia were measured. The effects of DMP and morphine were compared to vehicle control and MK-801, a positive control to mimic schizophrenia. Gene expression analysis revealed that α1C, α1Sa, α1Aa, drd2a, and th1 were up-regulated after 10 days of exposure to DMP and morphine, while th2 was down-regulated. These two drugs also increased the number of positive dopaminergic neurons and the total dopamine level but reduced the locomotion and social preference. The termination of morphine exposure led to the up-regulation of th2, drd2a, and c-fos during the withdrawal phase. Our integrated data implicate that the dopamine system plays a key role in the deficits in social behavior and locomotion that are common in the schizophrenia-like symptoms and opioid dependence.

Receptor-Mediated AKT/PI3K Signalling and Behavioural Alterations in Zebrafish Larvae Reveal Association between Schizophrenia and Opioid Use Disorder.

The link between substance abuse and the development of schizophrenia remains elusive. In this study, we assessed the molecular and behavioural alterations associated with schizophrenia, opioid addiction, and opioid withdrawal using zebrafish as a biological model. Larvae of 2 days post fertilization (dpf) were exposed to domperidone (DMP), a dopamine-D2 dopamine D2 receptor antagonist, and morphine for 3 days and 10 days, respectively. MK801, an N-methyl-D-aspartate (NMDA) receptor antagonist, served as a positive control to mimic schizophrenia-like behaviour. The withdrawal syndrome was assessed 5 days after the termination of morphine treatment. The expressions of schizophrenia susceptibility genes, i.e., pi3k, akt1, slc6a4, creb1 and adamts2, in brains were quantified, and the levels of whole-body cyclic adenosine monophosphate (cAMP), serotonin and cortisol were measured. The aggressiveness of larvae was observed using the mirror biting test. After the short-term treatment with DMP and morphine, all studied genes were not differentially expressed. As for the long-term exposure, akt1 was downregulated by DMP and morphine. Downregulation of pi3k and slc6a4 was observed in the morphine-treated larvae, whereas creb1 and adamts2 were upregulated by DMP. The levels of cAMP and cortisol were elevated after 3 days, whereas significant increases were observed in all of the biochemical tests after 10 days. Compared to controls, increased aggression was observed in the DMP-, but not morphine-, treated group. These two groups showed reduction in aggressiveness when drug exposure was prolonged. Both the short- and long-term morphine withdrawal groups showed downregulation in all genes examined except creb1, suggesting dysregulated reward circuitry function. These results suggest that biochemical and behavioural alterations in schizophrenia-like symptoms and opioid dependence could be controlled by common mechanisms.

Evaluation of the Effect of Aqueous Momordica charantia Linn. Extract on Zebrafish Embryo Model through Acute Toxicity Assay Assessment.

Momordica charantia Linn., commonly known as bitter gourd, has many protective roles due to its medicinal value as it contains bioactive components. However, this extract showed possible toxicity effect on zebrafish embryo. Thus this study was designed to differentiate the toxicity activities in two types of M. charantia sample which are Indian and Chinese M. charantia, as well as to compare between two different aqueous extraction methods, hot and cold aqueous method, using zebrafish embryo assay assessment. It was observed that the survival rate of zebrafish embryo decreased as the concentration of test extract increased for all samples of M. charantia. The LC50 values of hot aqueous Chinese M. charantia, hot aqueous Indian M. charantia, and cold aqueous Chinese M. charantia were 144.54 µg/ml, 199.53 µg/ml, and 251.19 µg/ml, respectively. However, cold aqueous Indian M. charantia has a higher LC50 which was not in the range of the tested concentration. Hatchability of Danio rerio embryo reduced as the concentration of M. charantia extract increased while no hatching was observed in the highest concentration (1000 µg/ml). Scoliosis of zebrafish larvae was only seen in higher concentrations (125-1000 µg/ml) of extract. The heartbeat of zebrafish larvae treated with M. charantia extract was within the normal range, 120-180 bpm, but at higher concentrations (125-1000 µg/ml) the heartbeat differed for all samples of test extract. Hence, although this plant extract was safe to be consumed due to its pharmaceutical effect, it still exhibited mild toxicity effect at higher concentration when it was evaluated on zebrafish embryo.