The Psychoactive Designer Drug and Bath Salt Constituent MDPV Causes Widespread Disruption of Brain Functional Connectivity

Abstract

The abuse of 'bath salts' has raised concerns because of their adverse effects, which include delirium, violent behavior, and suicide ideation in severe cases. The bath salt constituent 3,4-methylenedioxypyrovalerone (MDPV) has been closely linked to these and other adverse effects. The abnormal behavioral pattern produced by acute high-dose MDPV intake suggests possible disruptions of neural communication between brain regions. Therefore, we determined if MDPV exerts disruptive effects on brain functional connectivity, particularly in areas of the prefrontal cortex. Male rats were imaged following administration of a single dose of MDPV (0.3, 1.0, or 3.0 mg/kg) or saline. Resting state brain blood oxygenation level-dependent (BOLD) images were acquired at 4.7 T. To determine the role of dopamine transmission in MDPV-induced changes in functional connectivity, a group of rats received the dopamine D 1 /D 2 receptor antagonist cis-flupenthixol (0.5 mg/kg) 30 min before MDPV. MDPV dose-dependently reduced functional connectivity. Detailed analysis of its effects revealed that connectivity between frontal cortical and striatal areas was reduced. This included connectivity between the prelimbic prefrontal cortex and other areas of the frontal cortex and the insular cortex with hypothalamic, ventral, and dorsal striatal areas. Although the reduced connectivity appeared widespread, connectivity between these regions and somatosensory cortex was not as severely affected. Dopamine receptor blockade did not prevent the MDPV-induced decrease in functional connectivity. The results provide a novel signature of MDPV's in vivo mechanism of action. Reduced brain functional connectivity has been reported in patients suffering from psychosis and has been linked to cognitive dysfunction, audiovisual hallucinations, and negative affective states akin to those reported for MDPV-induced intoxication. The present results suggest that disruption of functional connectivity networks involving frontal cortical and striatal regions could contribute to the adverse effects of MDPV.

The Cathinones MDPV and α-PVP Elicit Different Behavioral and Molecular Effects Following Acute Exposure

“…Since dopamine-induced activation of cortical regions drive and sustain nervousness, irritability, aggressiveness and paranoia that approximate schizophrenia (Morton 1999;Seo et al 2008), it is reasonable to speculate that the increased neuronal activity in the frontal lobe may sustain some of the aggressive and bizarre behaviors herein observed. Of note, MDPV has been recently shown to alter functional connectivity between cortical and subcortical regions (Colon-Perez et al 2016), further corroborating a drug-induced loss of control over the "top-down" neuronal connection, which is essential for the control of impulsive behaviors (Dalley et al 2011) and may contribute to explain the high addictive properties of these drugs. Although the different pharmacokinetic profile does not result in different reinforcing properties of the drugs (Aarde et al 2013;Watterson and Olive 2014), we cannot rule out the possibility that the more persistent activation of neuronal activity promoted by MDPV may initiate and sustain neuroadaptive changes caused by repeated exposure to the drug: this possibility will be investigated in the future by employing chronic treatment regimens with these two cathinones.…”

Multi-scale Imaging Reveals Aberrant Connectome Organization and Elevated Dorsal Striatal Arc Expression in Advanced Age

“…The masks were used to crop images and remove non-brain voxels. The cropped brain images were aligned with a rat brain template using the FMRIB Software Library linear registration program flirt (Jenkinson et al, 2002), using previously published parameters (Colon-Perez et al, 2016). Registration matrices were saved and used to subsequently transform functional datasets into atlas space for preprocessing and analysis.…”

Longitudinal Characterization and Biomarkers of Age and Sex Differences in the Decline of Spatial Memory

“…The first nine images in each functional time series were not used to avoid unstable fMRI signal intensity variations that are typically found in the initial images. Voxelwise cross-correlations were conducted to create correlation coefficient (Pearson r) maps (Colon-Perez et al, 2016) and the Pearson r coefficients were then subjected to a voxelwise z-transformation. Pearson r coefficients were exported for seed-based functional connectivity and network analyses in MATLAB (MathWorks).…”