Cocaine shifts dopamine D2 receptor sensitivity to gate conditioned behaviors

Divergent properties and independent regulation of striatal dopamine and GABA co-transmission

“…In the presence of antagonists to block NMDA, AMPA, GABA B , muscarinic, nicotinic, and D1 receptors, optogenetic stimulation of ChR2-expressing DA axons (1 ms) evoked GABA A - and D2- inhibitory postsynaptic currents (IPSCs) in dorsal striatal D2-MSNs ( Figure 1B ). As D2-IPSCs can be evoked in D2-MSNs but not in D1-MSNs ( Gong et al, 2021 ; Marcott et al, 2018 ), D2-MSNs were identified by the presence of D2-IPSCs. GABA A -IPSCs were present in 97.4% of MSNs (371 out of 381 cells).…”

“…In this case, when ChR2 was expressed more uniformly, we again found a lack of correlation between D2 and GABA A amplitudes ( Figure 1H ). We centered recordings in regions of the dorsal striatum with the highest levels of tdTomato expression, which we have previously found limits the variability in GIRK2 expression across cells such that dopamine evokes consistent D2 receptor-mediated GIRK2 currents ( Gong et al, 2021 ). As such the distribution of D2-IPSCs is unlikely to be due to cellular variability in the expression of GIRK2.…”

“…Although the time course of DA that underlies the activation of D2 receptors in the striatum has yet to be defined, it has been estimated that at SNc somatodendritic sites a high concentration of dopamine (30–100 μM) binds to D2 receptors near the site of release, activating the GIRK conductance within ~50 ms ( Beckstead et al, 2004 ; Condon et al, 2021 ; Courtney and Ford, 2014 ; Ford et al, 2009 ). As D2 receptor G βγ -mediated signaling in D2-MSNs has relatively low sensitivity for DA ( Gong et al, 2021 ; Marcott et al, 2014 , 2018 ), the activation of D2 receptors that underlies the D2-IPSC in D2-MSNs may similarly result from a local high concentration of DA. While the activation of GIRK channels by G i/o -coupled GPCRs, such as D2 receptors, has been proposed to involve either a local rearrangement of preformed macromolecular complex of GPCR/G-proteins/GIRK channels ( Riven et al, 2006 ) or a high concentration of locally generated G βγ subunits that activate nearby GIRK channels ( Sungkaworn et al, 2017 ; Touhara and MacKinnon, 2018 ), our measurements of D2 receptor activation via GIRK channels still rely on a cascade involving G-protein activation of potassium channels which differs from the more direct intramolecular changes that underlie the activation of the GABA A conductance.…”

“…To activate ChR-expressing dopamine axons, 470 nm blue light (1 ms duration) was used to produce wide-field illumination. All recordings from GIRK2 + MSNs were centered in DStr regions showing robust tdTomato reporter fluorescence, which limits the variability of D2-receptor mediated GIRK outward currents between cells and among animals ( Gong et al, 2021 ). Where indicated, electrical stimulation was used to dopamine or GABA release using a monopolar glass stimulating electrode filled with aCSF positioned ~200 μm away from the recorded cell (0.7 ms, 20–40 μA).…”

BXD Recombinant Inbred Mice as a Model to Study Neurotoxicity

“…Cocaine interacts with the dopamine transporter (DAT), blocking dopamine uptake and increasing its synaptic availability. Increased DAT expression has been reported in regions of the human brain of cocaine-abusing individuals [ 52 , 53 ]. Using BXD RI strains and progenitors, genes on proximal chromosome 19, which influence DAT expression, were mapped and correlated with DAT expression levels in 20 BXD RI strains in terms of behavior (locomotor response) and thermic responses (hypo- or hyperthermia).…”