OBJECTIVE: Monoamine oxidase (MAO), the enzyme responsible for metabolism of monoamine neurotransmitters, has an important role in the brain development and function, and MAO inhibitors have a range of potential therapeutic uses. We investigated systematically in vitro effects of pharmacologically different antidepressants and mood stabilizers on MAO activity. Methods: Effects of drugs on the activity of MAO were measured in crude mitochondrial fraction isolated from cortex of pig brain, when radiolabeled serotonin (for MAO-A) or phenylethylamine (for MAO-B) was used as substrate. The several antidepressants and mood stabilizers were compared with effects of well known MAO inhibitors such as moclobemide, iproniazid, pargyline, and clorgyline. Results: In general, the effect of tested drugs was found to be inhibitory. The half maximal inhibitory concentration, parameters of enzyme kinetic, and mechanism of inhibition were determined. MAO-A was inhibited by the following drugs: pargyline > clorgyline > iproniazid > fluoxetine > desipramine > amitriptyline > imipramine > citalopram > venlafaxine > reboxetine > olanzapine > mirtazapine > tianeptine > moclobemide, cocaine > lithium, valproate. MAO-B was inhibited by the following drugs: pargyline > clorgyline > iproniazid > fluoxetine > venlafaxine > amitriptyline > olanzapine > citalopram > desipramine > reboxetine > imipramine > tianeptine > mirtazapine, cocaine > moclobemide, lithium, valproate. The mechanism of inhibition of MAOs by several antidepressants was found various. Conclusions: It was concluded that MAO activity is acutely affected by pharmacologically different antidepressants at relatively high drug concentrations; this effect is inhibitory. There are differences both in inhibitory potency and in mechanism of inhibition between both several drugs and the two MAO isoforms. While MAO inhibition is not primary biochemical effect related to their therapeutic action, it can be supposed that decrease of MAO activity may be concerned in some effects of these drugs on serotonergic, noradrenergic, and dopaminergic neurotransmission.
- MeSH
- afekt účinky léků MeSH
- amitriptylin farmakologie MeSH
- antidepresiva farmakologie MeSH
- antimanika farmakologie MeSH
- benzodiazepiny farmakologie MeSH
- citalopram farmakologie MeSH
- cyklohexanoly farmakologie MeSH
- desipramin farmakologie MeSH
- fluoxetin farmakologie MeSH
- imipramin farmakologie MeSH
- inhibitory MAO farmakologie MeSH
- iproniazid farmakologie MeSH
- klorgylin farmakologie MeSH
- kokain farmakologie MeSH
- kyselina valproová farmakologie MeSH
- lithium farmakologie MeSH
- mianserin analogy a deriváty farmakologie MeSH
- mitochondrie účinky léků enzymologie MeSH
- moklobemid farmakologie MeSH
- monoaminoxidasa účinky léků metabolismus MeSH
- morfoliny farmakologie MeSH
- mozková kůra cytologie MeSH
- pargylin farmakologie MeSH
- prasata MeSH
- thiazepiny farmakologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- techniky in vitro 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
- benzoxaziny aplikace a dávkování farmakologie MeSH
- inhibiční koncentrace 50 MeSH
- inhibitory MAO aplikace a dávkování farmakologie MeSH
- iproniazid aplikace a dávkování farmakologie MeSH
- kyseliny arachidonové aplikace a dávkování farmakologie MeSH
- monoaminoxidasa účinky léků metabolismus MeSH
- morfoliny aplikace a dávkování farmakologie MeSH
- mozek účinky léků enzymologie MeSH
- naftaleny aplikace a dávkování farmakologie MeSH
- polynenasycené alkamidy aplikace a dávkování farmakologie MeSH
- prasata MeSH
- tetrahydrokanabinol aplikace a dávkování farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
