AIMS: Haloperidol is an antipsychotic agent and acts as dopamine D2 receptor (D2R) antagonist, as a prototypical ligand of sigma1 receptors (Sig1R) and it increases expression of type 1 IP3 receptors (IP3R1). However, precise mechanism of haloperidol action on cardiomyocytes through dopaminergic signaling was not described yet. This study investigated a role of dopamine receptors in haloperidol-induced increase in IP3R1 and Sig1R, and compared physiological effect of melperone and haloperidol on basic heart parameters in rats. MATERIALS AND METHODS: We used differentiated NG-108 cells and H9c2 cells. Gene expression, Western blot and immunofluorescence were used to evaluate haloperidol-induced differences; proximity ligation assay (PLA) and immunoprecipitation to determine interactions of D1/D2 receptors. To evaluate cardiac parameters, Wistar albino male rats were used. KEY FINDINGS: We have shown that antagonism of D2R with either haloperidol or melperone results in upregulation of both, IP3R1 and Sig1R, which is associated with increased D2R, but reduced D1R expression. Immunofluorescence, immunoprecipitation and PLA support formation of heteromeric D1/D2 complexes in H9c2 cells. Treatment with haloperidol (but not melperone) caused decrease in systolic and diastolic blood pressure and significant increase in heart rate. SIGNIFICANCE: Because D1R/D2R complexes can engage Gq-like signaling in other experimental systems, these results are consistent with the possibility that disruption of D1R/D2R complex in H9c2 cells might cause a decrease in IP3R1 activity, which in turn may account for the increase expression of IP3R and Sig1R. D2R is probably not responsible for changes in cardiac parameters, since melperone did not have any effect.
- MeSH
- antagonisté dopaminu D2 farmakologie MeSH
- antagonisté dopaminu farmakologie MeSH
- buněčné linie MeSH
- haloperidol farmakologie MeSH
- potkani Wistar MeSH
- receptory dopaminu D1 genetika metabolismus MeSH
- receptory dopaminu D2 genetika metabolismus MeSH
- regulace genové exprese účinky léků MeSH
- signální transdukce účinky léků MeSH
- srdce účinky léků MeSH
- srdeční frekvence účinky léků MeSH
- vazba proteinů účinky léků MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Porucha pozornosti s hyperaktivitou – ADHD (Attention Deficit Hyperactivity Disorder) představuje široce rozšířenou neurobiologickou poruchu v dětském věku s poměrně vysokou mírou genetické podmíněnosti. Heritabilita symptomů ADHD je uváděna až na úrovni 75 %. Mechanizmus genetického přenosu však stále není zcela objasněn. Největší pozornost je v současné době zaměřena na geny dopaminergního a serotoninergního systému, ale i řadu genů dalších. Článek přináší souhrnné informace o nejvýznamnějších genetických asociacích u ADHD.
Attention deficit hyperactivity disorder (ADHD) is a common, probably highly genetically conditioned, neurobiological disorder. Heritability of ADHD symptoms is up to about 75%. However, the mechanism is still not fully understood. Attention is focused mainly on genes of the dopaminergic and serotonergic system as well as many other genes. The paper presents a summary of the most significant genetic associations with ADHD.
- MeSH
- dopamin-beta-hydroxylasa genetika MeSH
- dopamin genetika MeSH
- genetická predispozice k nemoci MeSH
- genetické asociační studie * MeSH
- hyperkinetická porucha * genetika MeSH
- lékařská genetika * MeSH
- lidé MeSH
- monoaminoxidasa MeSH
- proteiny přenášející dopamin přes plazmatickou membránu genetika MeSH
- receptory dopaminu D1 genetika MeSH
- receptory dopaminu D2 genetika MeSH
- receptory dopaminu D3 genetika MeSH
- selektivní inhibitory zpětného vychytávání serotoninu MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
OBJECTIVES: In our previous studies we found that both acute administration of CB1 receptor agonist methanandamide and repeated methanandamide pre-treatment prior to methamphetamine challenge dose elicited increase in the CB1 receptor mRNA expression in the mouse mesencephalon. As a reciprocal cross-talk is reported between the cannabinoid CB1 and dopamine receptors, that are highly co-localized on brain neurones, we targeted possible changes in relative expression of dopamine D1 and D2 receptor mRNA in mesencephalon in mice sensitized by repeated treatments to methamphetamine stimulatory effects and cross-sensitized to methamphetamine by cannabinoid CB1 receptor agonist methanandamide pre-treatment. METHODS: To confirm development of behavioural sensitization or cross-sensitization, respectively, we observed changes in locomotion using the open field test. Mice were treated repeatedly with either methamphetamine or methamphetamine after repeated pre-treatment with methanandamide. After each measurement of locomotion one third of animals were sacrificed and the brain was stored. RNA was isolated from the midbrain and used for reverse transcription and subsequent real-time PCR. RESULTS AND CONCLUSION: As in many of our earlier studies with the same dosage regimen we found in the behavioural part both development of sensitization to methamphetamine stimulatory effects after repeated treatment and cross-sensitization to them by pre-treatment with cannabinoid receptor CB1 agonist methanandamide. Real-time PCR analyses showed an increase in D1 receptor mRNA expression after the first dose of methamphetamine (that persisted also after the last dose of methamphetamine) and after the first dose of methanandamide (which also persisted after the methamphetamine challenge dose). In opposite a significant decrease in D2 receptor mRNA expression both after the first dose of methamphetamine and methanandamide (that persisted also after the methamphetamine challenge doses) was registered. Thus, our results suggest that both methamphetmine and methanandamide treatment can provoke changes in dopamine receptor density in mouse mesenpcephalon, the increase in D1 and decrease in D2 receptor subtypes.
- MeSH
- chování zvířat účinky léků MeSH
- dopaminové látky farmakologie MeSH
- interakce mezi receptory a ligandy účinky léků MeSH
- kyseliny arachidonové farmakologie MeSH
- lékové interakce MeSH
- messenger RNA analýza MeSH
- methamfetamin farmakologie MeSH
- mezencefalon účinky léků metabolismus MeSH
- myši inbrední ICR MeSH
- myši MeSH
- náhodné rozdělení MeSH
- pohybová aktivita účinky léků MeSH
- receptor kanabinoidní CB1 agonisté MeSH
- receptory dopaminu D1 účinky léků genetika metabolismus MeSH
- receptory dopaminu D2 účinky léků genetika metabolismus MeSH
- rozvrh dávkování léků MeSH
- senzibilizace centrálního nervového systému účinky léků MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- etika farmaceutická MeSH
- genetické nemoci vrozené MeSH
- kanabinoidy škodlivé účinky MeSH
- komunitní psychiatrie trendy MeSH
- lékařská etika MeSH
- lidé MeSH
- magnetická rezonanční tomografie metody MeSH
- mozek MeSH
- poruchy spojené s užíváním psychoaktivních látek komplikace MeSH
- psychoterapie etika trendy výchova MeSH
- receptory dopaminu D1 genetika MeSH
- receptory dopaminu D2 genetika MeSH
- schizofrenie MeSH
- věznice MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- kongresy MeSH
