Effort-based decision-making is particularly relevant to psychiatric conditions where motivation deficits are prominent features. Despite its clinical significance, the neurochemical mechanisms of this cognitive process remain unclarified. This study explores the impact of serotonin synthesis inhibition (PCPA) and modulation of serotonin release and 5-HT1A receptor agonism (8-OH-DPAT) on effort-based decision-making in rats. Adult male rats were trained in a modified T-maze task where they could obtain a high reward for climbing a mesh barrier or a low reward for no extra effort. Following training, rats received either acute 8-OH-DPAT treatment or subchronic PCPA treatment and were tested on their choices between high- and low-effort arms. The goal-arm choices and goal-arm entrance latencies were recorded. Next, homovanillic acid and 5-hydroxyindoleacetic acid, metabolites of dopamine and serotonin, respectively, were quantified in the rats' prefrontal cortex, striatum, and hippocampus. 8-OH-DPAT significantly increased low-effort, low-reward choices and increased goal-arm latency. In contrast, PCPA treatment did not affect these measures. Both PCPA and 8-OH-DPAT significantly decreased 5-hydroxyindoleacetic acid levels in the prefrontal cortex and the hippocampus. 8-OH-DPAT treatment was also associated with decreased homovanillic acid levels in the hippocampus. Our findings suggest that the overall reduction of serotonin levels alone does not affect effort-based decision-making and highlights the possible role of the hippocampus and the 5-HT1A receptor in this cognitive process.
- MeSH
- 8-hydroxy-2-(di-N-propylamino)tetralin * farmakologie MeSH
- agonisté serotoninového receptoru 5-HT1 farmakologie MeSH
- bludiště - učení účinky léků fyziologie MeSH
- chování zvířat účinky léků MeSH
- krysa rodu Rattus MeSH
- odměna MeSH
- potkani Sprague-Dawley MeSH
- rozhodování * fyziologie účinky léků MeSH
- serotonin * metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- 8-hydroxy-2-(di-N-propylamino)tetralin * MeSH
- agonisté serotoninového receptoru 5-HT1 MeSH
- serotonin * MeSH
Chronic sensitization to serotonin 1A and 7 receptors agonist 8-OH-DPAT induces compulsive checking and perseverative behavior. As such, it has been used to model obsessive-compulsive disorder (OCD)-like behavior in mice and rats. In this study, we tested spatial learning in the 8-OH-DPAT model of OCD and the effect of co-administration of memantine and riluzole-glutamate-modulating agents that have been shown to be effective in several clinical trials. Rats were tested in the active place avoidance task in the Carousel maze, where they learned to avoid the visually imperceptible shock sector. All rats were subcutaneously injected with 8-OH-DPAT (0.25 mg/kg) or saline (control group) during habituation. During acquisition, they were pretreated with riluzole (1 mg/kg), memantine (1 mg/kg), or saline solution 30 min before each session and injected with 8-OH-DPAT ("OH" groups) or saline ("saline" groups) right before the experiment. We found that repeated application of 8-OH-DPAT during both habituation and acquisition significantly increased locomotion, but it impaired the ability to avoid the shock sector. However, the application of 8-OH-DPAT in habituation had no impact on the learning process if discontinued in acquisition. Similarly, memantine and riluzole did not affect the measured parameters in the "saline" groups, but in the "OH" groups, they significantly increased locomotion. In addition, riluzole increased the number of entrances and decreased the maximum time avoided of the shock sector. We conclude that monotherapy with glutamate-modulating agents does not reduce but exacerbates cognitive symptoms in the animal model of OCD.
- Klíčová slova
- 8-OH-DPAT, memantine, memory, obsessive-compulsive disorder, riluzole, spatial learning,
- MeSH
- 8-hydroxy-2-(di-N-propylamino)tetralin škodlivé účinky farmakologie MeSH
- chování zvířat účinky léků MeSH
- krysa rodu Rattus MeSH
- memantin farmakologie MeSH
- modely nemocí na zvířatech MeSH
- obsedantně kompulzivní porucha * chemicky indukované farmakoterapie patofyziologie MeSH
- paměť účinky léků MeSH
- potkani Long-Evans MeSH
- prostorové učení účinky léků MeSH
- riluzol farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 8-hydroxy-2-(di-N-propylamino)tetralin MeSH
- memantin MeSH
- riluzol MeSH
The purpose of the present study was to investigate the opposite effect of the pre- and postsynaptic serotonin-1A (5-HT(1A)) receptors on the psychotic-like behavior induced by a non-competitive antagonist of the NMDA receptor, dizocilpine (MK-801). Male Wistar rats received two doses (0.025mg/kg and 1mg/kg) of 5-HT(1A) receptor agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino) tetralin) and/or MK-801 in two different doses, 0.1mg/kg or 0.3mg/kg. We measured sensorimotor gating by testing prepulse inhibition of acoustic startle response (PPI) and locomotor activity of rats. We found an opposite effect of the low and high 5-HT(1A) receptor agonist doses on MK-801 induced deficit in PPI and hyperlocomotion in habituated rats. The low dose of 8-OH-DPAT, which preferentially acts on presynaptic 5-HT(1A) receptors, restored the deficit in PPI and hyperlocomotion in MK-801 (0.1mg/kg)-treated habituated rats. However, the high dose of 8-OH-DPAT, which activates both pre- and postsynaptic 5-HT(1A) receptors, decreased PPI and increased locomotor activity after administration of the low dose of MK-801. Administration of 8-OH-DPAT itself dose-dependently decreased PPI. However, only the high dose of 8-OH-DPAT increased spontaneous locomotor activity of rats. Our results indicate that there is an interaction between the NMDA and 5-HT(1A) receptors. In addition, these findings could indicate that activation of the 5-HT(1A) autoreceptor could be effective as a treatment in schizophrenia, but full potent agonism of the receptor could worsen the psychotic symptoms.
- MeSH
- 8-hydroxy-2-(di-N-propylamino)tetralin farmakologie MeSH
- agonisté serotoninových receptorů farmakologie MeSH
- akustická stimulace metody MeSH
- analýza rozptylu MeSH
- antagonisté excitačních aminokyselin farmakologie MeSH
- chování zvířat účinky léků MeSH
- dizocilpinmaleát farmakologie MeSH
- krysa rodu Rattus MeSH
- nervový útlum účinky léků MeSH
- pohybová aktivita účinky léků MeSH
- potkani Wistar MeSH
- úleková reakce účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 8-hydroxy-2-(di-N-propylamino)tetralin MeSH
- agonisté serotoninových receptorů MeSH
- antagonisté excitačních aminokyselin MeSH
- dizocilpinmaleát MeSH
