Emergence of Endocytosis-Dependent mGlu1 LTD at Nucleus Accumbens Synapses After Withdrawal From Cocaine Self-Administration.

Andrew F Scheyer,Daniel T Christian,Marina E Wolf,Kuei Y Tseng

doi:10.3389/fnsyn.2018.00036

Abstract

Extended-access cocaine self-administration induces a progressive intensification of cue-induced drug craving during withdrawal termed “incubation of cocaine craving”. Rats evaluated after >1 month of withdrawal (when incubation of craving is robust) display alterations in excitatory synapses onto medium spiny neurons (MSNs) of the nucleus accumbens (NAc), including elevated levels of Ca2+-permeable AMPA receptors (CP-AMPAR) and a transition from group I metabotropic glutamate receptor (mGluR) mGlu5- to mGlu1-mediated synaptic depression. It is important to further characterize the emergent form of mGlu1-mediated synaptic depression because it has been demonstrated that mGlu1 stimulation, by normalizing CP-AMPAR transmission, reduces cue-induced cocaine craving. In the present study, we conducted whole-cell patch-clamp recordings in NAc core MSNs, comparing rats that underwent >35 days of withdrawal from cocaine self-administration to control rats that had self-administered saline. Bath application of the nonselective group I mGluR agonist dihydroxyphenylglycine (DHPG) produced a transient mGlu5-mediated synaptic depression in saline controls, whereas a persistent mGlu1-mediated synaptic depression emerged in cocaine rats. This form of long-term depression (LTD) was abolished by the inclusion of dynamin inhibitory peptide (DIP) in the recording electrode, indicating that it is mediated by removal of CP-AMPARs through a dynamin-dependent endocytosis mechanism. We further showed that CP-AMPAR endocytosis is normally coupled to the PICK1-mediated insertion of Ca2+-impermeable AMPARs (CI-AMPAR). Interestingly, this coupling is not obligatory because disruption of PICK1-mediated CI-AMPAR insertion with pep2-EVKI spared mGlu1-mediated CP-AMPAR endocytosis. Collectively, these results reveal similarities but also differences from mGlu1-LTD observed in other brain regions, and further our understanding of a form of plasticity that may be targeted to reduce cue-induced craving for cocaine and methamphetamine.

Highlights

Ca2+-permeable AMPARs (CP-AMPARs) participate in a number of forms of synaptic plasticity (Isaac et al, 2007; Lee, 2012; Hanley, 2014), including cocaine-induced plasticity in brain regions associated with reward, motivation and addiction such as the ventral tegmental area (VTA) and the nucleus accumbens (NAc; Wolf and Tseng, 2012)
In several cell types in which CP-AMPARs contribute significantly to synaptic transmission, metabotropic glutamate receptor 1 stimulation elicits a form of long-term depression (LTD) in which CP-AMPARs are removed from synapses and lower conductance Ca2+-impermeable AMPARs (CI-AMPARs) are inserted in their place (Loweth et al, 2013)
We have previously shown that bath application of DHPG (50 μM) produced a form of synaptic depression in NAc medium spiny neurons (MSNs) that is mGlu5-dependent in rats that had self-administered saline and metabotropic glutamate receptor 1 (mGlu1)-mediated in rats that had undergone incubation of cocaine craving (McCutcheon et al, 2011a)

Summary

Introduction

Ca2+-permeable AMPARs (CP-AMPARs) participate in a number of forms of synaptic plasticity (Isaac et al, 2007; Lee, 2012; Hanley, 2014), including cocaine-induced plasticity in brain regions associated with reward, motivation and addiction such as the ventral tegmental area (VTA) and the nucleus accumbens (NAc; Wolf and Tseng, 2012). In several cell types in which CP-AMPARs contribute significantly to synaptic transmission, metabotropic glutamate receptor 1 (mGlu1) stimulation elicits a form of long-term depression (LTD) in which CP-AMPARs are removed from synapses and lower conductance Ca2+-impermeable AMPARs (CI-AMPARs) are inserted in their place (Loweth et al, 2013) This mGlu1-LTD has been described in VTA dopamine neurons of cocaine-exposed rats (Bellone and Lüscher, 2005, 2006; Mameli et al, 2007, 2009; Bellone et al, 2011), in cerebellar stellate cells (Kelly et al, 2009; see Liu and Cull-Candy, 2000, 2005) and in the lateral amygdala (Clem and Huganir, 2010). MGlu is a promising target for reducing the risk of cue-induced relapse in recovering cocaine and methamphetamine addicts (Loweth et al, 2013)

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