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

Abstract

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.

Plasticity-Related Activity in the Hippocampus, Anterior Cingulate, Orbitofrontal, and Prefrontal Cortex Following a Repeated Treatment with D2/D3 Agonist Quinpirole

“…We found that the expression of Homer1a and Arc in OFC, ACC, and mPFC remained comparable in QNP treated and control rats. Similarly, to our results, studies using MicroPET/CT and local cerebral glucose utilization using the [14C]2-deoxyglucose (2-DG) did not detect statistically significant changes in OFC, ACC or mPFC following QNP treatment [ 40 , 41 ]. In contrast, Asaoka et al reported that OFC was hyperactive in QNP treated rats using electrophysiological recordings [ 41 ].…”

“…Similarly, to our results, studies using Mi-croPET/CT and local cerebral glucose utilization using the [14C]2-deoxyglucose (2-DG) did not detect statistically significant changes in OFC, ACC or mPFC following QNP treatment [40,41]. In contrast, Asaoka et al reported that OFC was hyperactive in QNP treated rats using electrophysiological recordings [41]. However, plasticity-related IEG expression may not directly correspond to changes in electrophysiological hyperactivity.…”

Striatal TRPV1 activation by acetaminophen ameliorates dopamine D2 receptor antagonist–induced orofacial dyskinesia

“…Recording neural activity. Electrophysiological recordings were performed as previously described (42). Briefly, 4 weeks after AAV injection into Adora2A-Cre mice, coronal brain slices (200-μm thick) containing the striatum were prepared and allowed to recover in oxygenated ACSF (composition in mM: 124 NaCl, 3 KCl, 26 NaHCO3, 1 NaH2PO4, 2.4 mM CaCl2, 1.2 mM MgCl2, and 10 D-glucose, pH 7.3) at 32 °C for at least 1 h before recording.…”

Crosstalk Between Kappa Opioid and Dopamine Systems in Compulsive Behaviors

“…Today, quinpirole repeated administration is a validated model for OCD (Szechtman et al, 1999;Szechtman et al, 2001;Eilam and Szechtman, 2005;Stuchlik et al, 2016;Szechtman et al, 2017), based on the observation that the behavior of rats becomes increasingly structured and inflexible, reminiscent of the ritual behavior characteristic of compulsive checking behavior (Szechtman et al, 1998;Szechtman et al, 2017). Recent studies show that repeated quinpirole also induces compulsive behaviors in mice, such as compulsive checking (Sun et al, 2019), behavioral inflexibility and compulsive chewing (Asaoka et al, 2019), the latter reverted by D2Rs blockade in the striatum, further supporting that repeated D2Rs activation is needed to induce compulsive behaviors. Together the data points to a crucial role of D2Rs within the midbrain dopamine pathways to induce locomotor sensitization and compulsivity.…”