Role of atypical opiates in OCD. Experimental approach through the study of 5-HT2A/C receptor-mediated behavior

Rojas-Corrales, M.O.; Gibert-Rahola, J.; Micó, Juan Antonio

doi:10.1007/s00213-006-0619-5

Cited by 31 publications

(21 citation statements)

References 69 publications

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“…Each of the targeted neurotransmitter systems associated with the animal models (i.e., 5-HT 2A receptors, dopamine and norepinephrine transporter, and glutamate NMDA receptors, respectively) has been implicated in psychoses and schizophrenia, and drugs within each of these classes can mimic psychosis in humans (Aghajanian and Marek, 2000;Gonzalez-Maeso and Sealfon, 2009;Coyle et al, 2012;Masana et al, 2012), providing the models with some etiological validity. In these animal models, (2)-MBP was compared directly to the prototypical second-generation antipsychotic drug clozapine, which previously had been reported to attenuate the DOI-elicited HTR, and also amphetamineand NMDA antagonist-induced hyperlocomotion (Corbett et al, 1995;Gleason and Shannon, 1997;Rojas-Corrales et al, 2007). (2)-MBP demonstrated similar efficacy as clozapine, although it was less potent.…”

Section: Discussionmentioning

confidence: 99%

A Novel Aminotetralin-Type Serotonin (5-HT)_2CReceptor-Specific Agonist and 5-HT_2ACompetitive Antagonist/5-HT_2BInverse Agonist with Preclinical Efficacy for Psychoses

Canal

Morgan

Felsing

et al. 2014

J Pharmacol Exp Ther

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Development of 5-HT 2C agonists for treatment of neuropsychiatric disorders, including psychoses, substance abuse, and obesity, has been fraught with difficulties, because the vast majority of reported 5-HT 2C selective agonists also activate 5-HT 2A and/or 5-HT 2B receptors, potentially causing hallucinations and/or cardiac valvulopathy. Herein is described a novel, potent, and efficacious human 5-HT 2C receptor agonist, (2) 2)-MBP, however, does not alter locomotion when administered alone, distinguishing it from clozapine, which suppresses locomotion. Finally, consumption of highly palatable food by mice was not increased by (2)-MBP at a dose that produced at least 50% maximal efficacy in the psychoses models. Compared with (2)-MBP, the enantiomer (1)-MBP was much less active across in vitro affinity and functional assays using mouse and human receptors and also translated in vivo with comparably lower potency and efficacy. Results indicate a 5-HT 2C receptor-specific agonist, such as (2)-MBP, may be pharmacotherapeutic for psychoses, without liability for obesity, hallucinations, heart disease, sedation, or motoric disorders.

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Section: Discussionmentioning

confidence: 99%

A Novel Aminotetralin-Type Serotonin (5-HT)_2CReceptor-Specific Agonist and 5-HT_2ACompetitive Antagonist/5-HT_2BInverse Agonist with Preclinical Efficacy for Psychoses

Canal

Morgan

Felsing

et al. 2014

J Pharmacol Exp Ther

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“…The head-twitch test was performed as described by Rojas-Corrales et al 21) with minor modifications. Rats were transferred to the testing room 30 min before testing.…”

Section: Head-twitch Testmentioning

confidence: 99%

Effect of Psilocin on Extracellular Dopamine and Serotonin Levels in the Mesoaccumbens and Mesocortical Pathway in Awake Rats

Sakashita

Abe

Katagiri

et al. 2015

Biological ^|^ Pharmaceutical Bulletin

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Psilocin (3-[2-(dimethylamino)ethyl]-1H-indol-4-ol) is a hallucinogenic component of the Mexican mushroom Psilocybe mexicana and a skeletal serotonin (5-HT) analogue. Psilocin is the active metabolite of psilocybin (3-[2-(dimethylamino)ethyl]-1H-indol-4-yl dihydrogen phosphate).In the present study, we examined the effects of systemically administered psilocin on extracellular dopamine and 5-HT concentrations in the ventral tegmental area (VTA), nucleus accumbens, and medial prefrontal cortex of the dopaminergic pathway in awake rats using in vivo microdialysis. Intraperitoneal administration of psilocin (5, 10 mg/kg) significantly increased extracellular dopamine levels in the nucleus accumbens. Psilocin did not affect the extracellular 5-HT level in the nucleus accumbens. Conversely, systemic administration of psilocin (10 mg/kg) significantly increased extracellular 5-HT levels in the medial prefrontal cortex of rats, but dopamine was decreased in this region. However, neither extracellular dopamine nor 5-HT levels in the VTA were altered by administration of psilocin. Behaviorally, psilocin significantly increased the number of head twitches. Thus, psilocin affects the dopaminergic system in the nucleus accumbens. In the serotonergic system, psilocin contribute to a crucial effect in the medial prefrontal cortex. The present data suggest that psilocin increased both the extracellular dopamine and 5-HT concentrations in the mesoaccumbens and/or mesocortical pathway.Key words psilocin; dopamine; serotonin; nucleus accumbens; ventral tegmental area; medial prefrontal cortex Native peoples in Mexico have used Psilocybe mushrooms throughout history in religious ceremonies and for healing. Naturally occurring hallucinogenic substances such as psilocybin and mescaline have been recognized for their ability to alter perception, cognition, and emotion.1,2) Both psilocin and psilocybin are hallucinogenic components of the Mexican mushroom Psilocybe mexicana and are serotonin (5-HT) analogues. Psilocin is the active metabolite of psilocybin and is considered a pharmacologically active species.3,4) A number of previous studies have examined the hallucinogenic effects of psilocybin in human volunteers. [5][6][7][8] Psilocybin produces changes in mood, disturbances in thinking, illusions, and complex visual hallucinations in healthy human volunteers. 9)Moreover, preliminary clinical trials have determined that psilocybin is effective at reducing the symptoms of obsessivecompulsive disorder 10) and is an effective anxiolytic agent in terminal cancer patients with anxiety. 11)Recent pharmacological studies suggest that the hallucinogenic effects of psilocin and psilocybin are produced mainly because these compounds act as 5-HT receptor agonists that bind 5-HT 1A , 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors with moderate to high affinity.12,13) The effects of psilocybin are blocked by pretreatment with the 5-HT 2A antagonist ketanserin, indicating that the hallucinogenic effects of psilocybin are mediated primarily by 5-HT 2A...

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“…Persistence (T maze) SSRI [58] Singular behavior DOI 5-HT 2A/2C agonist Head twitch SSRI [99] Singular behavior mCPP (5-HT 1A/1B/2C agonist)…”

Section: -Ht 1b/1d Receptormentioning

confidence: 99%

Role of Serotonin in Obsessive–Compulsive Disorder

2008

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Obsessive-compulsive disorder (OCD) is a psychiatric disorder consisting of obsessions and compulsions. Over the past two decades, it has been suggested that OCD might be related to the functioning of brain serotonin systems, mainly because of the antiobsessional efficacy of selective serotonin-reuptake inhibitors (SSRIs). Although the efficacy of SSRIs suggests a role of the serotonergic system in OCD, the exact function of serotonin is still unclear. Is the serotonergic system implicated in the pathophysiology of OCD, or is it implicated in the treatment effect in OCD? Do SSRIs compensate for a fundamental abnormality of the serotonergic system, or do SSRIs modulate an intact serotonergic system to compensate for another neurotransmitter mechanism? This review summarizes evidence supporting a role for the serotonin transporter and serotonin receptor subtypes in the pathophysiology and treatment of OCD.Obsessive-compulsive disorder (OCD) is a psychiatric disorder that consists of obsessions and compulsions. Obsessions are unwanted ideas or impulses that repeatedly well up in the mind, such as persistent fears to harm a loved one, an unreasonable concern with becoming contaminated or an excessive need to do things correctly or perfectly. Compulsions are repetitive behaviors or rituals, such as washing and checking, counting, mentally repeating phrases, list making or endlessly rearranging objects.Over the past two decades, it has been suggested that OCD might be related to the functioning of brain serotonin (5-HT) systems, mainly because of the antiobsessional efficacy of selective serotonin-reuptake inhibitors (SSRIs). The 5-HT hypothesis originated from the observed efficacy of SSRIs in OCD compared with the inefficacy of selective noradrenergic and dopaminergic reuptake inhibitors, suggesting a specific abnormality of the serotonergic system in OCD [1]. However, the exact function of 5-HT in OCD is still unclear:• Is the serotonergic system implicated in the pathophysiology of OCD, or is it implicated in the treatment effect in OCD?• Is the serotonergic system primary in the treatment effect of OCD and does it compensate for a fundamental abnormality of the serotonergic system?• Is the serotonergic system secondary and do SSRIs modulate an intact serotonergic system to compensate for another neurotransmitter mechanism involved in OCD?This review provides a brief overview of the evidence supporting a role for the 5-HT transporter (5-HTT) and each 5-HT receptor subtype in OCD. This article reviews five lines of evidence that have been cited in support of the 5-HT hypothesis: • Pharmacotherapeutic studies • Pharmacochallenge studies • Receptor-binding studies • Genetic association studies • Animal models 5-HT transporterThe 5-HTT is an integral membrane protein that transports the neurotransmitter 5-HT from synaptic spaces into presynaptic neurons. This transport of 5-HT by the 5-HTT protein terminates the action of 5-HT and recycles it. In the absence of the 5-HTT, the 5-HT levels in the synaptic cleft are eleva...

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Role of atypical opiates in OCD. Experimental approach through the study of 5-HT2A/C receptor-mediated behavior

Cited by 31 publications

References 69 publications

A Novel Aminotetralin-Type Serotonin (5-HT)_2CReceptor-Specific Agonist and 5-HT_2ACompetitive Antagonist/5-HT_2BInverse Agonist with Preclinical Efficacy for Psychoses

A Novel Aminotetralin-Type Serotonin (5-HT)_2CReceptor-Specific Agonist and 5-HT_2ACompetitive Antagonist/5-HT_2BInverse Agonist with Preclinical Efficacy for Psychoses

Effect of Psilocin on Extracellular Dopamine and Serotonin Levels in the Mesoaccumbens and Mesocortical Pathway in Awake Rats

Role of Serotonin in Obsessive–Compulsive Disorder

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Role of atypical opiates in OCD. Experimental approach through the study of 5-HT2A/C receptor-mediated behavior

Cited by 31 publications

References 69 publications

A Novel Aminotetralin-Type Serotonin (5-HT)2CReceptor-Specific Agonist and 5-HT2ACompetitive Antagonist/5-HT2BInverse Agonist with Preclinical Efficacy for Psychoses

A Novel Aminotetralin-Type Serotonin (5-HT)2CReceptor-Specific Agonist and 5-HT2ACompetitive Antagonist/5-HT2BInverse Agonist with Preclinical Efficacy for Psychoses

Effect of Psilocin on Extracellular Dopamine and Serotonin Levels in the Mesoaccumbens and Mesocortical Pathway in Awake Rats

Role of Serotonin in Obsessive–Compulsive Disorder

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A Novel Aminotetralin-Type Serotonin (5-HT)_2CReceptor-Specific Agonist and 5-HT_2ACompetitive Antagonist/5-HT_2BInverse Agonist with Preclinical Efficacy for Psychoses

A Novel Aminotetralin-Type Serotonin (5-HT)_2CReceptor-Specific Agonist and 5-HT_2ACompetitive Antagonist/5-HT_2BInverse Agonist with Preclinical Efficacy for Psychoses