Dopamine D2 receptor desensitization by dopamine or corticotropin releasing factor in ventral tegmental area neurons is associated with increased glutamate release

Abstract

Neurons of the ventral tegmental area (VTA) are the source of dopaminergic (DAergic) input to important brain regions related to addiction. Prolonged exposure of these VTA neurons to moderate concentrations of dopamine (DA) causes a time-dependent decrease in DA-induced inhibition, a complex desensitization called DA inhibition reversal (DIR). DIR is mediated by conventional protein kinase C (cPKC) through concurrent stimulation of D2 and D1-like DA receptors, or by D2 stimulation concurrent with activation of some Gq-linked receptors. Corticotropin releasing factor (CRF) acts via Gq, and can modulate glutamatergic neurotransmission in the VTA. In the present study, we used brain slice electrophysiology to characterize the interaction of DA, glutamate antagonists, and CRF agonists in the induction and maintenance of DIR in the VTA. Glutamate receptor antagonists blocked induction but not maintenance of DIR. Putative blockers of neurotransmitter release and store-operated calcium channels blocked and reversed DIR. CRF and the CRF agonist urocortin reversed inhibition produced by the D2 agonist quinpirole, consistent with our earlier work indicating that Gq activation reverses quinpirole-mediated inhibition. In whole cell recordings, the combination of urocortin and quinpirole, but not either agent alone, increased spontaneous excitatory postsynaptic currents (sEPSCs) in VTA neurons. Likewise, the combination of a D1-like receptor agonist and quinpirole, but not either agent alone, increased sEPSCs in VTA neurons. In summary, desensitization of D2 receptors induced by dopamine or CRF on DAergic VTA neurons is associated with increased glutamatergic signaling in the VTA.

A role for corticotropin-releasing factor signaling in the lateral habenula and its modulation by early-life stress

“…In fact, in addition to an increase in the amplitude of fAHP, CRF significantly lowered AP threshold suggesting that a hyperpolarized inter-spike membrane potential during high AP firing rates might be maintained by fAHPs to prevent voltage-gated Na + channel inactivation and promote suppression of SK channel function by CRF. Activated CRFR1 primarily signals by Gs protein coupling, resulting in the induction of PKA activity and increase in hippocampal neuronal excitability (50) although CRFR1 can also affect protein kinase C (PKC) activity through Gq-coupling (51). We found that postsynaptic inhibition of PKA in LHb neurons significantly blocked CRF’s action on LHb intrinsic excitability and AHPs suggesting that PKA-dependent modulation of AHPs through opposing actions on BK and SK channel activity underlie CRF’s excitatory effects.…”

Corticotropin-Releasing Factor (CRF) and Addictive Behaviors

“…In addition, PKC enhanced the I(h) current and increased the firing rate in VTA dopamine neurons (Wanat et al, 2008). Interestingly, the Brodie lab has reported that CRF and the CRF receptor agonist urocortin reversed inhibition produced by the D2 agonist quinpirole via increased glutamatergic signaling in the VTA (Nimitvilai et al, 2014). …”

Diacylglycerol lipase disinhibits VTA dopamine neurons during chronic nicotine exposure

“…Electrophysiology procedures were as recently reported (44,45) and are described briefly. Coronal sections (300 μm) through the midbrain were cut on a Leica VT1000S (Leica Microsystems) and placed in oxygenated (95% O 2 /5% CO 2 ) artificial cerebrospinal fluid (aCSF) solution composed of 130 mM NaCl, 3.5 mM KCl, 2 mM CaCl 2 , 1.5 mM MgClSO 4 , 1.25 mM NaH 2 PO 4 , 24 mM NaHCO 3 , 10 mM glucose.…”