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

Prog Neuropsychopharmacol Biol Psychiatry. 2017 Jul 3:77:90-98. doi: 10.1016/j.pnpbp.2017.02.027. Epub 2017 Mar 30.

Abstract

Background: Molecular neuroimaging was applied in the quinpirole rat model for compulsive checking in OCD to visualize the D2- and mGluR5-receptor occupancy with Raclopride and ABP-688 microPET/CT.

Methods: Animals (n=48) were exposed to either saline (CTRL; 1mL/kg) or quinpirole (QP; dopamine D2-agonist, 0.5mg/kg) in a single injection (RAC and ABP acute groups) or twice-weekly during 7weeks (chronic group). Animals underwent PET/CT after the 1st injection (acute) or before initial exposure and following the 10th injection in week 5 (chronic). For the latter, each injection was paired with an open field test and video tracking.

Results: The QP animals displayed a strong increase in visiting frequency (checking) in the chronic group (+699.29%) compared to the control animals. Acute administration of the drug caused significant (p<0.01) decreases in D2R occupancy in the CP (-42.03%±4.01%). Chronical exposure resulted in significantly stronger decreases in the CP (-52.29%±3.79%). Furthermore significant increases in mGluR5 occupancy were found in the CP (10.36%±4.09%), anterior cingulate cortex (13.26%±4.01%), amygdala (24.36%±6.86%), entorhinal cortex (18.49%±5.14%) and nucleus accumbens (13.8%±4.87%) of the chronic group, not present after acute exposure.

Conclusions: Compared to acute exposure, sensitisation to QP as a model for OCD differs both on a dopaminergic and glutamateric level, indicating involvement of processes such as receptor internalization and changes in extracellular availability of both neurotransmitters.

Keywords: Dopamine; Glutamate; MicroPET; OCD; Preclinical.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism
  • Carbon Radioisotopes / metabolism
  • Central Nervous System Sensitization / drug effects
  • Functional Neuroimaging
  • Kinetics
  • Male
  • Molecular Imaging*
  • Motor Activity / drug effects
  • Obsessive-Compulsive Disorder / metabolism*
  • Oximes / pharmacology
  • Positron-Emission Tomography
  • Pyridines / pharmacology
  • Quinpirole / pharmacology
  • Radioligand Assay
  • Rats
  • Receptor, Metabotropic Glutamate 5 / antagonists & inhibitors
  • Receptor, Metabotropic Glutamate 5 / metabolism*
  • Receptors, Dopamine D2 / agonists
  • Receptors, Dopamine D2 / metabolism*
  • Time Factors

Substances

  • 3-(6-methylpyridin-2-ylethynyl)cyclohex-2-enone-O-methyloxime
  • Carbon Radioisotopes
  • Grm5 protein, rat
  • Oximes
  • Pyridines
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Dopamine D2
  • Quinpirole