Subcellular and subsynaptic localization of group I metabotropic glutamate receptors in the nucleus accumbens of cocaine-treated rats

Abstract

There is significant pharmacological and behavioral evidence that group I metabotropic glutamate receptors (mGluR1a and mGluR5) in the nucleus accumbens play an important role in the neurochemical and pathophysiological mechanisms that underlie addiction to psychostimulants. To further address this issue, we undertook a detailed ultrastructural analysis to characterize changes in the subcellular and subsynaptic localization of mGluR1a and mGluR5 in the core and shell of nucleus accumbens following acute or chronic cocaine administration in rats. After a single cocaine injection (30mg/kg) and 45 minutes withdrawal, there was a significant decrease in the proportion of plasma membrane-bound mGluR1a in accumbens shell dendrites. Similarly, the proportion of plasma membrane-bound mGluR1a was decreased in large dendrites of accumbens core neurons following chronic cocaine exposure (i.e. 1 week treatment followed by three weeks withdrawal). However, neither acute nor chronic cocaine treatments induced significant change in the localization of mGluR5 in accumbens core and shell, which is in contrast with the significant reduction of plasma membranebound mGluR1a and mGluR5 induced by local intra-accumbens administration of the group I mGluR agonist, DHPG. In conclusion, these findings demonstrate that cocaine-induced glutamate imbalance (Smith et al., 1995;Pierce et al., 1996;Reid et al., 1997) has modest effects on the trafficking of group I mGluRs in the nucleus accumbens. These results provide valuable information on the neuroadaptive mechanisms of accumbens group I mGluRs in response to cocaine administration.

RGS14 is a natural suppressor of both synaptic plasticity in CA2 neurons and hippocampal-based learning and memory

“…Mice were transcardially perfused with Ringer's solution followed by a fixative containing 4% paraformaldehyde and 0.1% glutaraldehyde in phosphate buffer (0.1 M; pH 7.4). Tissue was cut, labeled using preembedding immunoperoxidase staining with RGS14 monoclonal antibody, and prepared for EM as described (45). Sections were examined on the Zeiss EM-10C electron microscope.…”

Cocaine Addiction: Changes in Excitatory and Inhibitory Neurotransmission

“…A single injection of cocaine decreases the proportion of plasma membrane-bound mGluR1a in the NAc shell dendrites 45 minutes after the injection, while chronic cocaine treatment decreased mGluR1a in the NAc core dendrites. This is in contrast to acute and chronic cocaine treatment having no effect on the localization of mGluR5 receptors (Mitrano et al, 2008). Another study found a decrease in mGluR1a in the NAc shell of chronic cocaine treated rats (Ary and Szumlinski., 2007;Uys and LaLumiere., 2008).…”

“…Acute and chronic cocaine treatment alter the normal function, expression or traficking of group I metabotropic receptors in the NAc of rats (Mitrano et al, 2008). A single injection of cocaine decreases the proportion of plasma membrane-bound mGluR1a in the NAc shell dendrites 45 minutes after the injection, while chronic cocaine treatment decreased mGluR1a in the NAc core dendrites.…”

Location-Dependent Signaling of the Group 1 Metabotropic Glutamate Receptor mGlu5

“…The intracellular localization of mGlu5 receptors has been well documented. Electron microscopy studies revealed that the mGlu5 receptor not only localizes on postsynaptic membranes and extrasynaptic regions but that most of this receptor is intracellular (Hubert et al, 2001;López-Bendito et al, 2002;O'Malley et al, 2003;Kuwajima et al, 2004;Mitrano et al, 2008Mitrano et al, , 2010. For example, 50-90% of mGlu5 receptors localize to different intracellular membranes in many different brain regions (Hubert et al, 2001;Paquet and Smith, 2003;Kuwajima et al, 2004).…”

“…Ultrastructure studies also revealed large numbers of mGlu5 receptor gold particles on ER membranes (O'Malley et al, 2003;Mitrano and Smith, 2007;Mitrano et al, 2008Mitrano et al, , 2010. To show functionality of ER-localized mGlu5 receptors, we 1) uncaged 4-methoxy-7-nitroindolinyl-glutamate using laser-induced photolysis onto dendrites in the presence of mGlu5 receptor impermeable antagonists as well as other ionotropic and metabotropic receptor antagonists (Purgert et al, 2014), and 2) we puffed quisqualate onto a dendrite in the presence of the same inhibitors (Y.J.…”