Cocaine Decreases Metabotropic Glutamate Receptor mGluR1 Currents in Dopamine Neurons by Activating mGluR5

Abstract

Midbrain dopamine neurons are important mediators of reward and movement and are sensitive to cocaine-induced plasticity. After even a single injection of cocaine, there is an increase in AMPA-dependent synaptic transmission. The present study examines cocaine-induced plasticity of mGluR-dependent currents in dopamine neurons in the substantia nigra. Activation of mGluR1 and mGluR5 resulted in a mixture of inward and outward currents mediated by a nonselective cation conductance and a calcium-activated potassium conductance (SK), respectively. A single injection of cocaine decreased the current activated by mGluR1 in dopamine neurons, and it had no effect on the size of the mGluR5-mediated current. When the injection of cocaine was preceded by treatment of the animals with a blocker of mGluR5 receptors (MPEP), cocaine no longer decreased the mGluR1 current. Thus, the activation of mGluR5 was required for the cocaine-mediated suppression of mGluR1-mediated currents in dopamine neurons. The results support the hypothesis that mGluR5 coordinates a reduction in mGluR1 functional activity after cocaine treatment.

Calcium Release from Stores Inhibits GIRK

“…Iontophoretic application of aspartate at 45s intervals activated an SK current mediated by mGlu receptors (mGluR1 and mGluR5 (Kramer and Williams, 2015)). All experiments were carried out in the presence of ionotropic glutamate antagonists (see methods).…”

“…For example, G i/o GABA B receptors (GABA B R) and dopamine D2 receptors (D2R) increase a G protein-gated inwardly rectifying potassium (GIRK) conductance (Beckstead et al, 2004; Arora et al, 2010). By contrast, G q group I metabotropic glutamate receptors (mGluR1 and mGluR5) activate the small conductance calcium gated potassium channel SK (Fiorillo and Williams, 1998; Kramer and Williams, 2015). Thus, two signaling pathways activate distinct potassium conductances that hyperpolarize and pause action potential generation in dopamine neurons.…”

“…It is known, however, that group I mGluRs signal differently depending on the method of activation. Steady state application of a selective agonist (DHPG) produced a tonic inward current, whereas transient activation via iontophoresis of aspartate or synaptic release of glutamate produced an outward current (Morikawa et al, 2003; Kramer and Williams, 2015). Thus distinct intracellular signaling pathways underlie the two methods of activation, and the question of how physiologically relevant receptor activation of group I mGluRs affects GIRK currents remains unexplored.…”

Ventral tegmental area subcircuits process rewarding and aversive experiences

“…; Brown et al . ) from the laterally located substantia nigra neurons (SN; Kramer and Williams ). While the VTA TH + neurons show a homogenous pattern of organization, glutamatergic neurons (vGluT2 + and vGluT2 + ‐TH + ) tend to densely distribute in the dorsomedial region of the VTA (Morales and Root ).…”

“…Anatomically, the medial terminal nucleus of the accessory optic tract (MT) is used as reference point to distinguish the medially located VTA neurons (Margolis et al 2006;Brown et al 2010) from the laterally located substantia nigra neurons (SN; Kramer and Williams 2015). While the VTA TH + neurons show a homogenous pattern of organization, glutamatergic neurons (vGluT2 + and vGluT2 + -TH + ) tend to densely distribute in the dorsomedial region of the VTA (Morales and Root 2014).…”