Advances in Zebrafish as a Comprehensive Model of Mental Disorders

Figure 5

Overview of the mechanisms triggered by psychoactive substances/addictive substances. (a) Based on the effects of ethanol on zebrafish. In zebrafish, it was found that the activity of brain metabolic and glutamatergic neurotransmission was decreased, with the increased of Ca²⁺ permeability and GABA- and glycine-mediated synaptic activity. In addition, ethanol indirectly activated dopaminergic and the activity of serotonergic neuron. Finally, ethanol affects the homeostasis of other pathways, such as cholinergic, noradrenergic, opioid, endocannabinergic, and purinergic systems. The effects of ethanol on zebrafish are complex and interconnected. Ethanol affects metabolizing enzymes such as ADH, ALDH, and CYP2E1; and CREB-related genes, such as NPY, BDNF, ARC, and CRH are modulated by ethanol consumption. (b) Based on the effects of opioids on zebrafish. Opioids positively regulate MOP, KOP, and DOP opioid receptors and activate dopaminergic nervous system, which is also the main cause of addiction. In addition, other pathways such as camp-dependent biochemical pathways, ion conductance, and glutamate pathways are affected. (c) Based on the effects of cannabinoids on zebrafish. Cannabinoids act on CB1 and CB2 receptors to regulate the release of neurotransmitters, including glutamate, GABA, glycine, acetylcholine, NE, DA, 5-HT, and cholecystokinin and then causes the activation of adenylate cyclase, voltage-gated Ca²⁺ channels, and potassium channels, while inhibiting MAP kinase activity and endocannabinoid release. The increase of monoamines promotes addiction. Ayahuasca preparations act on 5-HT1A, 5-HT2A, and 5-HT2C serotonin receptors, and ayahuasca has the property of inhibiting monoamine oxidase, which will lead to an increase in monoamine levels in the brain. (d) Based on the effects of nicotine on zebrafish. Nicotine activates nAChRs (α2-α10, β2-β4) and promotes the release of neurotransmitters, including acetylcholine, dopamine (reward system), serotonin, GABA, glutamate, and NE in the brain, then increases intracellular levels of Ca²⁺, and positively modulates the opioidergic and endocannabinoidergic systems. Finally, nicotine directly affects the levels and adenylyl cyclase activity of nicotine-metabolizing enzymes such as CYP2A, UGT, and FMO, as well as pCREB, CRF, and BDNF. (a–d) These are reproduced with permission from [214]. (e) Based on the effects of cocaine on zebrafish. In the zebrafish larvae experiment, cocaine consumption led to an increase in further cocaine susceptibility and a decrease in isoproterenol susceptibility. Tissue samples reveal telencephalon toxicity, characterized smaller size. In adult zebrafish, cocaine metabolite benzoylecgonine (BE) and EME (ecgonine methyl ester) cause negative change in cell structure, lipid transport, and energy metabolism [215].