The identification and quantification of mitochondrial effects of novel antipsychotics (brexpiprazole, cariprazine, loxapine, and lurasidone) were studied in vitro in pig brain mitochondria. Selected parameters of mitochondrial metabolism, electron transport chain (ETC) complexes, citrate synthase (CS), malate dehydrogenase (MDH), monoamine oxidase (MAO), mitochondrial respiration, and total ATP and reactive oxygen species (ROS) production were evaluated and associated with possible adverse effects of drugs. All tested antipsychotics decreased the ETC activities (except for complex IV, which increased in activity after brexpiprazole and loxapine addition). Both complex I- and complex II-linked respiration were dose-dependently inhibited, and significant correlations were found between complex I-linked respiration and both complex I activity (positive correlation) and complex IV activity (negative correlation). All drugs significantly decreased mitochondrial ATP production at higher concentrations. Hydrogen peroxide production was significantly increased at 10 µM brexpiprazole and lurasidone and at 100 µM cariprazine and loxapine. All antipsychotics acted as partial inhibitors of MAO-A, brexpiprazole and loxapine partially inhibited MAO-B. Based on our results, novel antipsychotics probably lacked oxygen uncoupling properties. The mitochondrial effects of novel antipsychotics might contribute on their adverse effects, which are mostly related to decreased ATP production and increased ROS production, while MAO-A inhibition might contribute to their antidepressant effect, and brexpiprazole- and loxapine-induced MAO-B inhibition might likely promote neuroplasticity and neuroprotection. The assessment of drug-induced mitochondrial dysfunctions is important in development of new drugs as well as in the understanding of molecular mechanism of adverse or side drug effects.

• Keywords
• ATP, Dopamine system stabilizers, Mitochondrial respiration, Monoamine oxidase, Oxidative phosphorylation, Reactive oxygen species,
• MeSH
• Adenosine Triphosphate biosynthesis   MeSH
• Antipsychotic Agents classification   pharmacology   MeSH
• Quinolones pharmacology   MeSH
• Electron Transport Chain Complex Proteins drug effects   MeSH
• Energy Metabolism drug effects   MeSH
• Monoamine Oxidase Inhibitors pharmacology   MeSH
• Loxapine pharmacology   MeSH
• Lurasidone Hydrochloride pharmacology   MeSH
• Mitochondria drug effects   metabolism   MeSH
• Hydrogen Peroxide metabolism   MeSH
• Piperazines pharmacology   MeSH
• Swine MeSH
• Reactive Oxygen Species metabolism   MeSH
• Receptors, Neurotransmitter drug effects   MeSH
• Oxygen Consumption drug effects   MeSH
• Thiophenes pharmacology   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Adenosine Triphosphate MeSH
• Antipsychotic Agents MeSH
• brexpiprazole MeSH Browser
• cariprazine MeSH Browser
• Quinolones MeSH
• Electron Transport Chain Complex Proteins MeSH
• Monoamine Oxidase Inhibitors MeSH
• Loxapine MeSH
• Lurasidone Hydrochloride MeSH
• Hydrogen Peroxide MeSH
• Piperazines MeSH
• Reactive Oxygen Species MeSH
• Receptors, Neurotransmitter MeSH
• Thiophenes MeSH

Brain monoamines are involved in many of the same processes affected by neuropsychiatric disorders and psychotropic drugs, including cannabinoids. This study investigated in vitro effects of cannabinoids on the activity of monoamine oxidase (MAO), the enzyme responsible for metabolism of monoamine neurotransmitters and affecting brain development and function. The effects of the phytocannabinoid Delta(9)-tetrahydrocannabinol (THC), the endocannabinoid anandamide (N-arachidonoylethanolamide [AEA]), and the synthetic cannabinoid receptor agonist WIN 55,212-2 (WIN) on the activity of MAO were measured in a crude mitochondrial fraction isolated from pig brain cortex. Monoamine oxidase activity was inhibited by the cannabinoids; however, higher half maximal inhibitory concentrations (IC(50)) of cannabinoids were required compared to the known MAO inhibitor iproniazid. The IC(50) was 24.7 micromol/l for THC, 751 micromol/l for AEA, and 17.9 micromol/l for WIN when serotonin was used as substrate (MAO-A), and 22.6 micromol/l for THC, 1,668 micromol/l for AEA, and 21.2 micromol/l for WIN when phenylethylamine was used as substrate (MAO-B). The inhibition of MAOs by THC was noncompetitive. N-Arachidonoylethanolamide was a competitive inhibitor of MAO-A and a noncompetitive inhibitor of MAO-B. WIN was a noncompetitive inhibitor of MAO-A and an uncompetitive inhibitor of MAO-B. Monoamine oxidase activity is affected by cannabinoids at relatively high drug concentrations, and this effect is inhibitory. Decrease of MAO activity may play a role in some effects of cannabinoids on serotonergic, noradrenergic, and dopaminergic neurotransmission.

• MeSH
• Benzoxazines administration & dosage   pharmacology   MeSH
• Endocannabinoids MeSH
• Inhibitory Concentration 50 MeSH
• Monoamine Oxidase Inhibitors administration & dosage   pharmacology   MeSH
• Iproniazid administration & dosage   pharmacology   MeSH
• Arachidonic Acids administration & dosage   pharmacology   MeSH
• Monoamine Oxidase drug effects   metabolism   MeSH
• Morpholines administration & dosage   pharmacology   MeSH
• Brain drug effects   enzymology   MeSH
• Naphthalenes administration & dosage   pharmacology   MeSH
• Polyunsaturated Alkamides administration & dosage   pharmacology   MeSH
• Swine MeSH
• Dronabinol administration & dosage   pharmacology   MeSH
• Dose-Response Relationship, Drug MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Names of Substances
• (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone MeSH Browser
• anandamide MeSH Browser
• Benzoxazines MeSH
• Endocannabinoids MeSH
• Monoamine Oxidase Inhibitors MeSH
• Iproniazid MeSH
• Arachidonic Acids MeSH
• Monoamine Oxidase MeSH
• Morpholines MeSH
• Naphthalenes MeSH
• Polyunsaturated Alkamides MeSH
• Dronabinol MeSH