Acute serotonin 2A receptor activation impairs behavioral flexibility in mice.
Dionisio A Amodeo, Omron Hassan, Landon M. Klein, Adam L. Halberstadt, Susan B Powell
Behavioural Brain Research October 1, 2020 DOI: 10.1016/j.bbr.2020.112861 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Male C57BL/6J mice |
| Interventions | DOI 25CN-NBOH SER-082 |
| Dose | 2.5 mg/kg DOI, 1.0 mg/kg 25CN-NBOH, 1.0 mg/kg SER-082 |
| Topics | Serotonin |
| Keywords | 5-ht2a Behavioral flexibility Probabilistic reversal learning |
| Citations | 25 |
| Key findings | Activation of 5-HT2A receptors impairs probabilistic reversal learning in male mice, and 5-HT2A and 5-HT2C receptors exert opposing effects on behavioral flexibility. |
Abstract
Serotonin 2A (5-HT2A) receptors are the primary site of action of hallucinogenic drugs and the target of atypical antipsychotics. 5-HT2A receptors are also implicated in executive function, including behavioral flexibility. Previous studies showed that 5-HT2A receptor blockade improved behavioral flexibility in rodent models related to autism spectrum disorder and schizophrenia. The current study instead was conducted to examine the impact of acute 5-HT2A receptor activation on behavior flexibility in the control C57BL/6 J strain. Because of the therapeutic potential of serotonergic hallucinogens and the unknown impact of many of these compounds on cognition, the present study examined how the 5-HT2A/2C agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the more selective 5-HT2A agonist 25CN-NBOH impacted behavioral flexibility in C57BL/6 J mice. Male mice were tested on a probabilistic spatial discrimination and reversal learning task after an intraperitoneal injection of vehicle, 2.5 mg/kg DOI, 1.0 mg/kg 25CN-NBOH, 1.0 mg/kg of the 5-HT2C receptor antagonist SER-082 or combined treatment with SER-082 (1.0 mg/kg) and 2.5 mg/kg DOI before testing of probabilistic reversal learning. All groups demonstrated comparable performance on the initial spatial discrimination, i.e. similar trials to criterion. DOI alone did not impair reversal learning, whereas 25CN-NBOH increased the number of trials to criterion during reversal learning. Because 5-HT2A and 5-HT2C receptors have been shown to functionally antagonize each other in several behavioral paradigms, we also tested whether blockade of 5-HT2C receptors would unmask 5-HT2A receptor activation by DOI and impair reversal learning. Mice treated with SER-082 in combination with DOI required significantly more trials to reach criterion. In an additional experiment, a dose response experiment with 25CN-NBOH revealed that the 1.0 mg/kg dose tested in reversal learning did not affect locomotor activity. Together, these findings indicate that activation of 5-HT2A receptors impairs probabilistic reversal learning and that 5-HT2A and 5-HT2C receptors exert opposing effects on behavioral flexibility in male mice.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 18
- Psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder. Translational Psychiatry November 8, 2021
- Models of psychedelic drug action: modulation of cortical-subcortical circuits Brain October 22, 2021
- Acute psilocybin enhances cognitive flexibility in rats Neuropsychopharmacology February 20, 2023
- Psilocybin restrains activity-based anorexia in female rats by enhancing cognitive flexibility: contributions from 5-HT1A and 5-HT2A receptor mechanisms Molecular Psychiatry April 27, 2024
- Effect of lysergic acid diethylamide (LSD) on reinforcement learning in humans. Psychological Medicine October 1, 2023
and 13 more in the library
Cites 10
- Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. Neuropharmacology May 1, 2020
- LSD Acutely Impairs Fear Recognition and Enhances Emotional Empathy and Sociality Neuropsychopharmacology June 1, 2016
- Therapeutic Use of LSD in Psychiatry: A Systematic Review of Randomized-Controlled Clinical Trials Frontiers in Psychiatry January 21, 2020
- LSD acutely impairs working memory, executive functions, and cognitive flexibility, but not risk-based decision-making Psychological Medicine September 10, 2019
- The selective 5-HT2A receptor agonist 25CN-NBOH: structure-activity relationship, in vivo pharmacology, and in vitro and ex vivo binding characteristics of [3H]25CN-NBOH. Biochemical Pharmacology April 13, 2020
and 5 more in the library