A selective serotonin reuptake inhibitor ameliorates obsessive–compulsive disorder-like perseverative behavior by attenuating 5-HT2C receptor signaling in the orbitofrontal cortex

Hatakama, Hikari; Asaoka, Nozomi; Nagayasu, Kazuki; Shirakawa, Hisashi; Kaneko, Shuji

doi:10.1016/j.neuropharm.2021.108926

Cited by 4 publications

(10 citation statements)

References 48 publications

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“…Deficits in reversal learning have been reported for SAPAP-3 knockout mice (van den Boom et al, 2019 ) and OFC-lesioned monkeys (Dias et al, 1996 ), rats (Boulougouris et al, 2007 ), and monkeys with selective 5-HT depletion in the OFC (Clarke et al, 2004 , 2008 ). Recently, Hatakama et al ( 2022 ) have demonstrated that SSRI administration augmented behavioural rigidity during reversal learning in mice, by down-regulating 5-HT 2C receptor signalling in the OFC. Conversely, measuring neurochemical signalling in the marmoset caudate nucleus has shown reversal learning to be modulated by dopaminergic activity (Clarke et al, 2011 ).…”

Section: Neurobehavioural Models Of Ocdmentioning

confidence: 99%

Opening new vistas on obsessive-compulsive disorder with the observing response task

Pickenhan,

Milton

2024

Cogn Affect Behav Neurosci

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Obsessive-compulsive disorder (OCD), a highly prevalent and debilitating disorder, is incompletely understood in terms of underpinning behavioural, psychological, and neural mechanisms. This is attributable to high symptomatic heterogeneity; cardinal features comprise obsessions and compulsions, including clinical subcategories. While obsessive and intrusive thoughts are arguably unique to humans, dysfunctional behaviours analogous to those seen in clinical OCD have been examined in nonhuman animals. Genetic, ethological, pharmacological, and neurobehavioural approaches all contribute to understanding the emergence and persistence of compulsive behaviour. One behaviour of particular interest is maladaptive checking, whereby human patients excessively perform checking rituals despite these serving no purpose. Dysfunctional and excessive checking is the most common symptom associated with OCD and can be readily operationalised in rodents. This review considers animal models of OCD, the neural circuitries associated with impairments in habit-based and goal-directed behaviour, and how these may link to the compulsions observed in OCD. We further review the Observing Response Task (ORT), an appetitive instrumental learning procedure that distinguishes between functional and dysfunctional checking, with translational application in humans and rodents. By shedding light on the psychological and neural bases of compulsive-like checking, the ORT has potential to offer translational insights into the underlying mechanisms of OCD, in addition to being a platform for testing psychological and neurochemical treatment approaches.

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Section: Neurobehavioural Models Of Ocdmentioning

confidence: 99%

Opening new vistas on obsessive-compulsive disorder with the observing response task

Pickenhan,

Milton

2024

Cogn Affect Behav Neurosci

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“…Repeated injections of a D 2 R agonist (QNP) elicit OCD-like behavioural and neurological abnormalities in mice [ 12 , 13 , 17 ]. We assessed the effects of PPIs on QNP-induced OCD-like behaviours to obtain preclinical proof-of-concept.…”

Section: Resultsmentioning

confidence: 99%

“…Mice (6–15 weeks old) were housed at a constant ambient temperature of 24 ± 1 °C on a 12 h light–dark cycle with ad libitum access to food and water. As previously reported [ 12 , 17 ], the mice were intraperitoneally injected with QNP (1 mg/kg) weekday; citalopram hydrobromide was dissolved in drinking water (0.2 mg/mL) and administered for 4 weeks.…”

Section: Methodsmentioning

confidence: 99%

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Amelioration of obsessive-compulsive disorder by intracellular acidification of cortical neurons with a proton pump inhibitor

Hatakama,

Asaoka,

Nagayasu

et al. 2024

Transl Psychiatry

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Obsessive-compulsive disorder (OCD) is a highly prevalent neuropsychiatric disorder poorly controlled with pharmacological treatment because of the wide variation in symptom patterns. We analysed real-world data on adverse self-reports and insurance claims to identify a novel therapeutic target for OCD. We found that dopamine D2 receptor (D2R) agonists increased the incidence of OCD-like symptoms, which were suppressed by the concomitant use of proton pump inhibitors (PPIs). Further, OCD-like repetitive and habitual behaviours were observed in mice repeatedly injected with a D2R agonist, quinpirole. However, these abnormalities were suppressed by short-term PPI treatment. In quinpirole-treated mice, PPI inhibited pyramidal neuron hyperactivity in the lateral orbitofrontal cortex, a region where the P-type proton pump gene Atp4a is abundantly expressed. In primary cultured cortical neurons, short-term PPI treatment lowered intracellular pH and decreased firing activity, which was mimicked by Atp4a knockdown. Our findings show that inhibition of P-type proton pumps may be a novel therapeutic strategy for OCD.

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“…Dysregulation of the serotonin system is thought to be important in the pathology of psychiatric disorders such as major depressive disorder (MDD) [3] , [4] , [5] , [6] . Selective serotonin reuptake inhibitors (SSRIs) block serotonin reuptake, ostensibly increasing the extracellular levels of serotonin within the CNS and are used extensively clinically for MDD, obsessive–compulsive disorder (OCD) [7] , [8] , anxiety disorders [9] , post-traumatic stress disorder (PTSD) [10] , and borderline personality disorder (BPD) [11] . Furthermore, SSRIs have been used to treat alcohol use disorder (AUD) [12] , nicotine and other substance use disorders [9] , [13] .…”

Section: Introductionmentioning

confidence: 99%

SmartFSCV: An Artificial Intelligence Enabled Miniaturised FSCV Device Targeting Serotonin

Corva,

Doeven,

Parke

et al. 2024

IEEE Open J. Eng. Med. Biol.

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Goal: Dynamically monitoring serotonin in real-time within target brain regions would significantly improve the diagnostic and therapeutic approaches to a variety of neurological and psychiatric disorders. Current systems for measuring serotonin lack immediacy and portability and are bulky and expensive. Methods: We present a new miniaturised device, named SmartFSCV, designed to monitor dynamic changes of serotonin using fast-scan cyclic voltammetry (FSCV). This device outputs a precision voltage potential between −3 to +3 V, and measures current between −1.5 to +1.5 μA with nano-ampere accuracy. The device can output modifiable arbitrary waveforms for various measurements and uses an N-shaped waveform at a scan-rate of 1000 V/s for sensing serotonin. Results: Four experiments were conducted to validate SmartFSCV: static bench test, dynamic serotonin test and two artificial intelligence (AI) algorithm tests. Conclusions: These tests confirmed the ability of SmartFSCV to accurately sense and make informed decisions about the presence of serotonin using AI.

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A selective serotonin reuptake inhibitor ameliorates obsessive–compulsive disorder-like perseverative behavior by attenuating 5-HT2C receptor signaling in the orbitofrontal cortex

Cited by 4 publications

References 48 publications

Opening new vistas on obsessive-compulsive disorder with the observing response task

Opening new vistas on obsessive-compulsive disorder with the observing response task

Amelioration of obsessive-compulsive disorder by intracellular acidification of cortical neurons with a proton pump inhibitor

SmartFSCV: An Artificial Intelligence Enabled Miniaturised FSCV Device Targeting Serotonin

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