Functional study of rat 5‐HT<sub>2A</sub> receptors using antisense oligonucleotides

Oekelen, Dirk Van; Megens, Anton; Meert, Theo; Luyten, Walter; Leysen, Josée E.

doi:10.1046/j.1471-4159.2003.01738.x

Cited by 40 publications

(15 citation statements)

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“…Using factor analysis, the authors found no significant difference between wildtype and 5-HT 2A knockout mice in anxiety-like behavior. Similar findings were reported by Van Oekelen et al [2003] using ASODN to 5-HT 2A -R, leading the authors to hypothesize that downregulation of the functional 5-HT 2A receptors may cause an imbalance in the ratio of the different 5-HT receptor subtypes. Thus, the increased serotonergic transmission due to the surgical implantation of the cannulae may lead to greater activation of receptors other than the 5-HT 2A subtype, resulting in increased locomotor activity.…”

Section: Discussionsupporting

confidence: 79%

Anxiolytic effect and memory improvement in rats by antisense oligodeoxynucleotide to 5-hydroxytryptamine-2A precursor protein

Cohen

2005

Depress. Anxiety

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Serotonergic (5-hydroxytryptamine; 5-HT) mechanisms have been implicated in a number of physiological and pathophysiological processes including mood, anxiety, and cognitive functioning. Among the many 5-HT receptor subtypes, the 5-HT2A receptors (5-HT2A-R) seem to be of particular importance in mediating these effects, and they are prime targets for a variety of psychoactive substances-from hallucinogenic drugs, through atypical antipsychotics, to anxiolytics and antidepressants. Various selective 5-HT2A-R ligands induce different behavioral responses. To determine whether receptor downregulation is an essential part of anxiolytic action, levels of 5-HT2A receptors were manipulated in rats using a nonpharmacological approach-by the administration of an antisense oligodeoxynucleotide (ASODN) to 5-HT2A-R. Each ASODN was injected icv between two and five times at 24-hr intervals. Control rats received injections of either a scrambled oligodeoxynucleotide (ScrODN) or the vehicle only. On Day 6, anxiety-related behavior was assessed in the elevated plus maze paradigm and performance of memory tasks in the Morris water maze. Gene transcripts were measured by quantitative reverse transcription polymerase chain reaction (PCR). The results show that compared to vehicle and ScrODN control animals, icv 5-HT2A-R-ASODN administrations for 4 consecutive days (but not less) significantly decreased anxietylike behavior and improved memory retention performance. The reduction in anxiety-related behavior in 5-HT2A-R-ASODN rats was accompanied by a decrease in 5-HT2A-R-mRNA expression in the frontal cortex and in the hippocampus. Receptor downregulation has been proposed as one of the central mechanisms for anxiolytic drug actions. Antisense-mediated downmanipulation of receptors in this study, especially of 5-HT2A, supports this theory.

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Section: Discussionsupporting

confidence: 79%

Anxiolytic effect and memory improvement in rats by antisense oligodeoxynucleotide to 5-hydroxytryptamine-2A precursor protein

Cohen

2005

Depress. Anxiety

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“…The psychedelic 5-HT 2A/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) has been shown to affect locomotor activity in mice (Gonzalez-Maeso et al, 2007; Halberstadt et al, 2009, 2013) and rats (Krebs-Thomson et al, 1998; Van Oekelen et al, 2003; Marona-Lewicka et al, 2005). Low doses of DOI significantly increase locomotor activity, an effect that is absent in 5-HT 2A knockout mice (Halberstadt et al, 2009).…”

Section: Pharmacological Models Of Psychosis and Antipsychotic Drug Amentioning

confidence: 99%

Preclinical models of antipsychotic drug action

Moreno

González-Maeso

2013

International Journal of Neuropsychopharmacology

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One of the main obstacles faced by translational neuroscience is the development of animal models of psychiatric disorders. Behavioural pharmacology studies indicate that psychedelic drugs, such as lysergic acid diethylamide (LSD) and dissociative drugs, such as phencyclidine (PCP), induce in healthy human volunteers psychotic and cognitive symptoms that resemble some of those observed in schizophrenia patients. Serotonin 5-HT2A and metabotropic glutamate 2 receptors have been involved in the mechanism of action of psychedelic and dissociative drugs. Here we review recent advances using LSD-like and PCP-like drugs in rodent models that implicate these receptors in the neurobiology of schizophrenia and its treatment.

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“…More recently, increased threshold to kainic acid-induced seizures was observed in mice with genetically increased 5-HT levels ( Tripathi et al, 2008 ). These findings are corroborated by data showing that mice lacking the 5-HT 1A - ( Sarnyai et al, 2000 ; Parsons et al, 2001 ), 5-HT 2C - ( Applegate and Tecott, 1998 ), 5-HT 4 - ( Compan et al, 2004 ) and, 5-HT 7 -Rs ( Witkin et al, 2007 ), but also rats knocked-down for the 5-HT 2A -Rs by antisense oligonucleotide treatment ( Van Oekelen et al, 2003 ) are extremely susceptible to chemical and electrical-induced seizures. Nevertheless, since only 5-HT 2C -R KO mice are prone to spontaneous death from seizures ( Tecott et al, 1995 ), and seizures have not been reported with pharmacological blockade of different 5-HT-Rs, adaptive changes involving different mechanisms may play a role in the low seizure thresholds observed in 5-HT-R KO mice.…”

Section: The 5-ht 2a -Rs In the Regulation Of Epilmentioning

confidence: 54%

Central serotonin-2A (5-HT2A) receptor dysfunction in depression and epilepsy: the missing link?

2015

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5-Hydroxytryptamine 2A receptors (5-HT2A-Rs) are G-protein coupled receptors. In agreement with their location in the brain, they have been implicated not only in various central physiological functions including memory, sleep, nociception, eating and reward behaviors, but also in many neuropsychiatric disorders. Interestingly, a bidirectional link between depression and epilepsy is suspected since patients with depression and especially suicide attempters have an increased seizure risk, while a significant percentage of epileptic patients suffer from depression. Such epidemiological data led us to hypothesize that both pathologies may share common anatomical and neurobiological alteration of the 5-HT2A signaling. After a brief presentation of the pharmacological properties of the 5-HT2A-Rs, this review illustrates how these receptors may directly or indirectly control neuronal excitability in most networks involved in depression and epilepsy through interactions with the monoaminergic, GABAergic and glutamatergic neurotransmissions. It also synthetizes the preclinical and clinical evidence demonstrating the role of these receptors in antidepressant and antiepileptic responses.

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Functional study of rat 5‐HT_2A receptors using antisense oligonucleotides

Abstract: We studied the effects in rats of a 6-day intracerebroventricular (i.

Cited by 40 publications

References 28 publications

Anxiolytic effect and memory improvement in rats by antisense oligodeoxynucleotide to 5-hydroxytryptamine-2A precursor protein

Anxiolytic effect and memory improvement in rats by antisense oligodeoxynucleotide to 5-hydroxytryptamine-2A precursor protein

Preclinical models of antipsychotic drug action

Central serotonin-2A (5-HT2A) receptor dysfunction in depression and epilepsy: the missing link?

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Functional study of rat 5‐HT2A receptors using antisense oligonucleotides

Abstract: We studied the effects in rats of a 6-day intracerebroventricular (i.

Cited by 40 publications

References 28 publications

Anxiolytic effect and memory improvement in rats by antisense oligodeoxynucleotide to 5-hydroxytryptamine-2A precursor protein

Anxiolytic effect and memory improvement in rats by antisense oligodeoxynucleotide to 5-hydroxytryptamine-2A precursor protein

Preclinical models of antipsychotic drug action

Central serotonin-2A (5-HT2A) receptor dysfunction in depression and epilepsy: the missing link?

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Functional study of rat 5‐HT_2A receptors using antisense oligonucleotides