The Abuse Potential of Novel Synthetic Phencyclidine Derivative 1-(1-(4-Fluorophenyl)Cyclohexyl)Piperidine (4'-F-PCP) in Rodents.

The dissociative anesthetic phencyclidine (PCP) and PCP derivatives, including 4'-F-PCP, are illegally sold and abused worldwide for recreational and non-medical uses. The psychopharmacological properties and abuse potential of 4'-F-PCP have not been fully characterized. In this study, we evaluated the psychomotor, rewarding, and reinforcing properties of 4'-F-PCP using the open-field test, conditioned place preference (CPP), and self-administration paradigms in rodents. Using Western immunoblotting, we also investigated the expression of dopamine (DA)-related proteins and DA-receptor-mediated downstream signaling cascades in the nucleus accumbens (NAc) of 4'-F-PCP-self-administering rats. Intraperitoneal administration of 10 mg/kg 4'-F-PCP significantly increased locomotor and rearing activities and increased CPP in mice. Intravenous administration of 1.0 mg/kg/infusion of 4'-F-PCP significantly enhanced self-administration during a 2 h session under fixed ratio schedules, showed a higher breakpoint during a 6 h session under progressive ratio schedules of reinforcement, and significantly altered the expression of DA transporter and DA D1 receptor in the NAc of rats self-administering 1.0 mg/kg 4'-F-PCP. Additionally, the expression of phosphorylated (p) ERK, pCREB, c-Fos, and FosB/ΔFosB in the NAc was significantly enhanced by 1.0 mg/kg 4'-F-PCP self-administration. Taken together, these findings suggest that 4'-F-PCP has a high potential for abuse, given its robust psychomotor, rewarding, and reinforcing properties via activation of DAergic neurotransmission and the downstream signaling pathways in the NAc.

Preferentially Disrupted Core Hubs Within the Default-Mode Network in Patients With End-Stage Renal Disease: A Resting-State Functional Magnetic Resonance Imaging Study.

Neuroimaging evidence implies that cognitive impairment in patients with end-stage renal disease (ESRD) is related to the disruption of the default-mode network (DMN). The DMN can be divided into three functionally independent subsystems, which include the cortical hub subsystem [consisting of the posterior cingulate cortex (PCC) and the anterior medial prefrontal cortex (aMPFC)], the dorsal medial prefrontal cortex (dMPFC) subsystem, and the medial temporal lobe (MTL) subsystem. However, it is unknown how the functional connectivity (FC) in DMN subsystems is differentially impaired in ESRD. This prospective study was carried out at the Affiliated Hospital of Qingdao University, China, between August 2018 and July 2020. Thirty-two ESRD patients and forty-five healthy controls (HCs) were recruited for this study and received resting-state functional magnetic resonance imaging (rs-fMRI) scanning, and FCs on predefined regions of interest (ROIs) were individually calculated in three DMN subsystems using both ROI- and seed-based FC analyses to examine FC alterations within and between DMN subsystems. The two-sample t-test was used for the comparisons between groups. We also tested the associations between FC changes and clinical information using Pearson's correlation analysis. The results demonstrated that ESRD patients, compared with HCs, exhibit reduced FC specifically within the cortical hubs and between the DMN hubs and two subsystems (the dMPFC and MTL subsystems). Moreover, the FC values between the aMPFC and PCC were positively correlated with creatinine and urea levels in the ESRD patients. Our results suggest that the cortical hubs (PCC and aMPFC) are preferentially disrupted and that other subsystems may be progressively damaged to a certain degree as the disease develops.