Preclinical molecular imaging of glutamatergic and dopaminergic neuroreceptor kinetics in obsessive compulsive disorder

Servaes, Stijn; Glorie, Dorien; Verhaeghe, Jeroen; Stroobants, Sigrid; Staelens, Steven

doi:10.1016/j.pnpbp.2017.02.027

Cited by 16 publications

(17 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The sustained activation of D 2 receptors by a selective agonist activates ERK signaling in iMSNs, possibly through D 2 receptor internalization (Brami-Cherrier et al, 2002; Shioda et al, 2017), resulting in the activation of rather than the inhibition of iMSNs. Supporting this idea, both in OCD patients and in QNP-sensitized rats after challenge with QNP, D 2 receptor occupancy was decreased (Denys et al, 2013; Servaes et al, 2017), suggesting increased the D 2 receptor signaling (e.g., increased baseline dopamine release) and/or facilitation of D 2 receptor internalization. Accordingly, repeated QNP injection might mimic the abnormal D 2 receptor signaling, resulting in activation of iMSNs.…”

Section: Discussionmentioning

confidence: 86%

See 1 more Smart Citation

An Adenosine A_2AReceptor Antagonist Improves Multiple Symptoms of Repeated Quinpirole-Induced Psychosis

Asaoka

Nishitani

Kinoshita

et al. 2019

eNeuro

View full text Add to dashboard Cite

Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder characterized by the repeated rise of concerns (obsessions) and repetitive unwanted behavior (compulsions). Although selective serotonin reuptake inhibitors (SSRIs) is the first-choice drug, response rates to SSRI treatment vary between symptom dimensions. In this study, to find a therapeutic target for SSRI-resilient OCD symptoms, we evaluated treatment responses of quinpirole (QNP) sensitization-induced OCD-related behaviors in mice. SSRI administration rescued the cognitive inflexibility, as well as hyperactivity in the lateral orbitofrontal cortex (lOFC), while no improvement was observed for the repetitive behavior. D 2 receptor signaling in the central striatum (CS) was involved in SSRI-resistant repetitive behavior. An adenosine A 2A antagonist, istradefylline, which rescued abnormal excitatory synaptic function in the CS indirect pathway medium spiny neurons (MSNs) of sensitized mice, alleviated both of the QNP-induced abnormal behaviors with only short-term administration. These results provide a new insight into therapeutic strategies for SSRI-resistant OCD symptoms and indicate the potential of A 2A antagonists as a rapid-acting anti-OCD drug.

show abstract

Section: Discussionmentioning

confidence: 86%

“…For QNP sensitization, mice were intraperitoneally injected with QNP (1 mg/kg) every weekday. For rat, a dose of 0.5 mg/kg was usually used (Szechtman et al, 1998; Servaes et al, 2017). We calculated a dose for mice based on the body surface area (Nair and Jacob, 2016).…”

Section: Methodsmentioning

confidence: 99%

An Adenosine A_2AReceptor Antagonist Improves Multiple Symptoms of Repeated Quinpirole-Induced Psychosis

Asaoka

Nishitani

Kinoshita

et al. 2019

eNeuro

View full text Add to dashboard Cite

show abstract

“…Antagonism of the D2 receptor with eticlopride was shown to increase the abundance of synaptic mGluR5 and tyrosine phosphorylation of mGluR5 in cultured striatal neurons (Mao and Wang, 2016). Furthermore, recent evidence demonstrated chronic, but not acute, treatment with the D2 receptor agonist, quinpirole, increased in vivo mGluR5 binding in the rat NAc, indicating time-dependent effects of D2 receptor activity on Group 1 mGluRs (Servaes et al, 2017).…”

Section: Introductionmentioning

confidence: 95%

Effects of short- and long-term aripiprazole treatment on Group I mGluRs in the nucleus accumbens: Comparison with haloperidol

Lum

Pan

Deng

et al. 2018

Psychiatry Research

View full text Add to dashboard Cite

The D2 receptor partial agonist, aripiprazole, has shown increased therapeutic efficacy for schizophrenia, autism and Tourette's syndrome compared to traditional antipsychotics such as the D2 receptor antagonist, haloperidol. Recent evidence suggests this superior profile may be associated with downstream effects on glutamatergic synapses. Group 1 metabotropic glutamate receptors (mGluRs) and their endogenous modulators, Norbin and Homer1, are regulated by D2 receptor activity, particularly within the nucleus accumbens (NAc), a target region of aripiprazole and haloperidol. This study sought to evaluate the effects of aripiprazole on Group 1 mGluRs, Norbin and Homer1 in the NAc, in comparison to haloperidol. Sprague-Dawley rats were orally administered daily doses of aripiprazole (2.25mg/kg), haloperidol (0.3mg/kg) or vehicle for 1 or 10-weeks. Immunoblot analyses revealed Group 1 mGluR protein levels were not altered following 1-week and 10-week aripiprazole or haloperidol treatment, compared to vehicle treated rodents. However, 1-week aripiprazole and haloperidol treatment significantly elevated Homer1a and Norbin protein expression, respectively. After 10 weeks of treatment, aripiprazole, but not haloperidol, significantly increased Norbin expression. These findings indicate the antipsychotics, aripiprazole and haloperidol, exert differential temporal effects on Norbin and Homer1 expression that may have consequences on synaptic glutamatergic transmission underlying their therapeutic profile.

show abstract

“…Evidence for this came from the modulation of the N-methyl-D-aspartate receptors (NMDAR), as it significantly reduced the compulsive behaviour, both in animal models [15] and in humans [16]. Furthermore, our own group has previously highlighted a glutamatergic dysfunction in a preclinical model for OCD [17]. Another PET study in humans found a significant positive correlation between the occupancy of the metabotropic glutamate-5-receptor (mGluR5) and the actual presence of obsessions [18].…”

Section: Introductionmentioning

confidence: 99%

Neuroreceptor kinetics in rats repeatedly exposed to quinpirole as a model for OCD

et al. 2019

View full text Add to dashboard Cite

Background Obsessive-compulsive disorder (OCD) is a chronic, incapacitating, early onset psychiatric disorder that is characterized by obsessions and compulsions originating from a disturbance in the cortico-striato-thalamico-cortical circuit. We implemented the preclinical quinpirole (QP) rat model for compulsive checking in OCD to analyse the behaviour and visualize the D2R, mGluR5 and GLT1 density in order to contribute to the understanding of the neuroreceptor kinetics. Methods Animals (n = 14) were exposed to either saline (1 mL/kg) or QP (dopamine D2-agonist, 0.5 mg/kg) twice-weekly during 7 weeks. After each injection animals were placed on an open field test. After model setup, animals were placed in a behavioural cage equipped with tracking software and hardware in order to analyse the behaviour. Subsequently, sagittal slides were made of the CP in the right hemisphere and a staining was done with the D2R, mGluR5 and GLT-1 antibody to visualize the corresponding receptor. Results The QP animals displayed a strong increase in travelled distance (+596.70%) and in the number of homebase visits (+1222.90%) compared to the control animals. After chronic exposure to QP, animals had a significantly (p < 0.05) higher percentage of D2R density in the CP (7.92% ± 0.48%) versus 6.66% ± 0.28% in animals treated with saline. There were no differences for mGluR5 and GLT1 receptor density. Conclusions Chronic exposure to QP leads to hyperlocomotion and an increase in D2R density. Furthermore, as mGluR5 and GLT1 density did not seem to be directly affected, decreased levels of glutamate might have influenced the binding potential in earlier reports.

show abstract

Preclinical molecular imaging of glutamatergic and dopaminergic neuroreceptor kinetics in obsessive compulsive disorder

Cited by 16 publications

References 51 publications

An Adenosine A_2AReceptor Antagonist Improves Multiple Symptoms of Repeated Quinpirole-Induced Psychosis

An Adenosine A_2AReceptor Antagonist Improves Multiple Symptoms of Repeated Quinpirole-Induced Psychosis

Effects of short- and long-term aripiprazole treatment on Group I mGluRs in the nucleus accumbens: Comparison with haloperidol

Neuroreceptor kinetics in rats repeatedly exposed to quinpirole as a model for OCD

Contact Info

Product

Resources

About

Preclinical molecular imaging of glutamatergic and dopaminergic neuroreceptor kinetics in obsessive compulsive disorder

Cited by 16 publications

References 51 publications

An Adenosine A2AReceptor Antagonist Improves Multiple Symptoms of Repeated Quinpirole-Induced Psychosis

An Adenosine A2AReceptor Antagonist Improves Multiple Symptoms of Repeated Quinpirole-Induced Psychosis

Effects of short- and long-term aripiprazole treatment on Group I mGluRs in the nucleus accumbens: Comparison with haloperidol

Neuroreceptor kinetics in rats repeatedly exposed to quinpirole as a model for OCD

Contact Info

Product

Resources

About

An Adenosine A_2AReceptor Antagonist Improves Multiple Symptoms of Repeated Quinpirole-Induced Psychosis

An Adenosine A_2AReceptor Antagonist Improves Multiple Symptoms of Repeated Quinpirole-Induced Psychosis