GPR88 in D1R-Type and D2R-Type Medium Spiny Neurons Differentially Regulates Affective and Motor Behavior

Abstract

Visual Abstract

Dopaminergic dysfunction in the 3xTg-AD mice model of Alzheimer’s disease

“…Finally, medium-spiny neurons of the striatum are also involved in the regulation of anxiety 58 . In the literature, 3xTg-AD females do not appear to show changes in anxiety at the light/dark and elevated plus maze tests 59 , 60 .…”

Orphan G Protein Coupled Receptors in Affective Disorders

“…Altogether, these findings suggest that GPR88 levels are finely regulated by sophisticated mechanisms that depend on the brain area and most likely involve a variety of signaling cascades. Considering the physiological relevance of GPR88, several lines of GPR88 KO mice were created to assess the gene function globally or in specific neuronal populations [ 88 , 89 , 90 , 202 ]. GPR88 has been shown to be densely expressed in the CeA, a brain region that controls emotional processing.…”

“…GPR88 has been shown to be densely expressed in the CeA, a brain region that controls emotional processing. This expression pattern prompted an analysis of anxiety-like related behaviors in global GPR88 KO mice that revealed markedly reduced levels of anxiety [ 88 , 89 , 90 ]. In detail, EPM revealed a longer time spent in the open arms for GPR88 KO mice; similarly, behavioral defensive responses that are sensitive to anxiolytic treatments, such as flat back approaches, stretched attend postures, and head dips, were more frequent in the GPR88 KO mice, suggesting altogether reduced anxiety levels [ 88 ].…”

“…They showed that the A 2A R-GPR88 KO mice replicated the anxiolytic-like phenotype of the global GPR88 KO mice in LDT, MBT, and EPM, while they did not show a greater motivation to explore novel environments in the NFST, as observed in global GPR88 KO [ 89 ]. On the other side, D1-GPR88 KO did not show anxiety-related behaviors in the MBT test [ 90 ]. Furthermore, in a rat model of Parkinson’s disease, the lentiviral shRNA knockdown of GPR88 in the dorsomedial striatum showed an antidepressant-like effect in the FST, while GPR88 knockdown in the dorsomedial or dorsolateral striatum had no impact on SPT [ 91 ].…”

“…Male rats, adult, hypothalamus, microarray, ↓ mRNA by fluoxetine [87]. EPM, male GPR88 KO vs. WT mice, 8-15 week-old, ↑ time in open arms [88], [89], [90] MBT, male GPR88 KO vs. WT mice, 8-15 week-old, ↓ marble buried [88], [89], [90] NSFT, male GPR88 KO vs. WT mice, 8-10 week-old, ↓ latency to feed [88] LDT, male GPR88 KO vs. WT mice, 9-15 week-old, ↑ time in lit box [89] LDT, male A2AR-GPR88 KO vs. GPR88flx/flx mice, 9-15 week-old, ↑ time in lit box [89] EPM, male A2AR-GPR88 KO vs. GPR88flx/flx mice, 9-15 week-old, ↑ time in open arms [89] MBT, male A2AR-GPR88 KO vs. GPR88flx/flx mice, 9-15 week-old, ↓ marble buried [89], [90] NFST, male A2AR-GPR88 KO vs. GPR88flx/flx mice, 9-15 week-old, ↔ latency to feed [89] MBT, male D1R-GPR88 KO vs. GPR88flx/flx mice, 9-15 week-old, ↔ marble buried [90] FST, male GPR88 KD in DMS vs. CNT rats, 7 week-old, ↓ immobility [91] SPT, male GPR88 KD in DMS vs. CNT rats, 7 week-old, ↔ ratio [91] [92] Primary cortical neurons, WB, ↑ levels by chronic corticosterone [92] TST, male GPR158 KO vs. WT mice, 2-4 month-old, ↓ immobility, rescued by viral GPR158 OE in mPFC [92] TST, female GPR158 KO vs. WT mice, 2-4 month-old, ↓ immobility [92] TST, male GPR158 OE in mPFC vs. control mice, 2-4 month-old, ↑ immobility [92] FST, male GPR158 KO vs. WT mice, 2-4 month-old, ↓ immobility, rescued by viral GPR158 OE in mPFC [92] FST, female GPR158 KO vs. WT mice, 2-4 month-old, ↓ immobility [92] FST, male GPR158 OE in mPFC vs. control mice, 2-4 month-old, ↑ immobility [92] EPM, male GPR158 KO vs. WT [92] MBT, male GPR158 KO vs. WT mice, 2-4 month-old, ↓ marble buried [92] MBT, female GPR158 KO vs. WT mice, 2-4 month-old, ↓ marble buried [92] LDT, female GPR158 KO vs. WT mice, 3 month-old, ↓ time in lit box [93] OFT, female GPR158 KO vs. WT mice, 3 month-old, ↓ time in center [93] OFT, male GPR158 KO vs. WT mice, 8-12 week-old, ↔ time in center [94] TST after UCMS, GPR1...…”