Quantitative Analysis of the Expression of Dopamine D1 and D2 Receptors in Pyramidal and GABAergic Neurons of the Rat Prefrontal Cortex

Santana, Noemí; Mengod, Guadalupe; Artigas, Francesc

doi:10.1093/cercor/bhn134

Cited by 204 publications

(187 citation statements)

References 64 publications

(83 reference statements)

Supporting

Mentioning

172

Contrasting

Order By: Relevance

“…We would not necessarily expect to detect an overall D2 deficit because neuronal D2 receptors account for only a subset of total PFC D2 expression (32).…”

Section: Discussionmentioning

confidence: 97%

Loss of dendrite stabilization by the Abl-related gene (Arg) kinase regulates behavioral flexibility and sensitivity to cocaine

Gourley

Koleske

Taylor

2009

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Adolescence is characterized by increased vulnerability to developing neuropsychiatric disorders and involves a period of prefrontal cortical dendritic refinement and synaptic pruning that culminates in cytoskeletal stabilization in adulthood. The Abl-related gene (Arg) acts through p190RhoGAP to inhibit the RhoA GTPase and stabilize cortical dendritic arbors beginning in adolescence. Cortical axons, dendrites, and synapses develop normally in Argdeficient (arg ؊/؊ ) mice, but adult dendrites destabilize and regress; thus, arg ؊/؊ mice present a model of adolescent-onset dendritic simplification. We show that arg ؊/؊ mice are impaired in a reversal task and that deficits are grossly exacerbated by low-dose cocaine administration. Although ventral prefrontal dopamine D2 receptor levels predict ''perseverative'' error counts in wild-type mice, no such relationship is found in arg ؊/؊ mice. Moreover, arg ؊/؊ mice are insensitive to the disruptive effects of the D2/D3 antagonist haloperidol in reversal but show normal sensitivity to its locomotor-depressant actions. Arg deficiency and orbitofrontal cortical Arg inhibition via STI-571 infusion also enhance the psychomotor stimulant actions of cocaine. These findings provide evidence that stabilization of dendritic structure beginning in adolescence is critical for the development of adaptive and flexible behavior after cocaine exposure.A dolescence is a critical period of maturation for corticostriatal neurocircuitry and is characterized by increased risk taking, novelty seeking, and vulnerability to addictive drugs that, with repeated use, are associated with cognitive dysfunction in adulthood (1-3). In utero cocaine exposure has limited effects on cognitive performance in adult rodents (4-6), but adolescent and adult cocaine use is associated with poor inhibitory control, inflexible behavior, and drug-related compulsivity. Here, we use an animal model of late-onset dendritic simplification to test the hypothesis that the transition from dendritic refinement and synaptic pruning processes that occur in the adolescent prefrontal cortex (PFC), to the dendrite stabilization processes occurring in the adult PFC, is a period of vulnerability to cocaine.Numerous proteins regulate cortical dendrite development; to date, however, only a few have been implicated in cytoskeletal stability in adolescence and adulthood, serving primarily to antagonize inherent cytoskeletal retraction machinery. For example, activation of the master cytoskeletal regulator, RhoA (Rho), induces neurite retraction, a process required for pruning and refining neuronal connections during development. Rho activation in mature neurons, however, leads to synapse loss and dendritic regression in a wide variety of experimental systems (7-9). Recent studies have identified a Rho inhibitory pathway involving integrin adhesion receptors, the Abl family tyrosine kinase, Arg, and the Rho inhibitor, p190RhoGAP, that acts in dendritic spines of late adolescent mice to maintain synapses and promote dendrite stabi...

show abstract

“…We would not necessarily expect to detect an overall D2 deficit because neuronal D2 receptors account for only a subset of total PFC D2 expression (32).…”

Section: Discussionmentioning

confidence: 97%

Loss of dendrite stabilization by the Abl-related gene (Arg) kinase regulates behavioral flexibility and sensitivity to cocaine

Gourley

Koleske

Taylor

2009

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Dopamine has differentiated effects on dlPFC neuronal physiology in monkeys performing a spatial working memory task: D1/5R, but not D2/3R, stimulation influences Delay cell firing, whereas D2/3R, but not D1/5R, influences Response cell firing (Wang et al, 2004). This contrasts with rodent medial PFC, where certain physiologic studies find layer V neurons responding to both D1/5R and D2/3R manipulations (Parfitt et al, 1990;Zheng et al, 1999;Trantham-Davidson et al, 2004), although in situ hybridization studies have yet to definitively document coexpression within a single rodent PFC neuron (Santana et al, 2009). It is not known if this is a species difference or a regional difference (medial PFC versus dlPFC), because DA effects on medial PFC have yet to be studied in primates.…”

Section: Dopamine Influences On Dorsolateral Prefrontal Cortex Phymentioning

confidence: 99%

Dopamine’s Actions in Primate Prefrontal Cortex: Challenges for Treating Cognitive Disorders

2015

View full text Add to dashboard Cite

“…S4 F-H). We have previously shown that the AMPH locomotor response is mediated at least in part by D2Rs in a βarr2-dependent manner (27,29), but D2Rs are expressed in multiple regions of the brain, such as midbrain, STR, and PFC (24,(52)(53)(54)(55)(56)(57). To confirm which D2R+ population of neurons is responsible for the AMPH response, we deleted βarr2 in several distinct neuronal populations; βarr2 f/f mice were crossed with either D2Cre (all D2R+ neurons) or A2aCre (postsynaptic D2R+ striatal neurons) mice as well as the D1Cre (D1R+ neurons) or ChaTCre (cholinergic interneurons) mice as controls.…”

Section: Distinct Striatal Vs Cortical Role Of D2r On Pcp-mediated Bmentioning

confidence: 99%

Distinct cortical and striatal actions of a β-arrestin–biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties

Urs

Gee

Pack

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

118

150

View full text Add to dashboard Cite

The current dopamine (DA) hypothesis of schizophrenia postulates striatal hyperdopaminergia and cortical hypodopaminergia. Although partial agonists at DA D2 receptors (D2Rs), like aripiprazole, were developed to simultaneously target both phenomena, they do not effectively improve cortical dysfunction. In this study, we investigate the potential for newly developed β-arrestin2 (βarr2)-biased D2R partial agonists to simultaneously target hyperand hypodopaminergia. Using neuron-specific βarr2-KO mice, we show that the antipsychotic-like effects of a βarr2-biased D2R ligand are driven through both striatal antagonism and cortical agonism of D2R-βarr2 signaling. Furthermore, βarr2-biased D2R agonism enhances firing of cortical fast-spiking interneurons. This enhanced cortical agonism of the biased ligand can be attributed to a lack of G-protein signaling and elevated expression of βarr2 and G proteincoupled receptor (GPCR) kinase 2 in the cortex versus the striatum. Therefore, we propose that βarr2-biased D2R ligands that exert region-selective actions could provide a path to develop more effective antipsychotic therapies.arrestin | antipsychotics | biased signaling | dopamine D2R | fast-spiking interneurons G protein-coupled receptors (GPCRs) represent the largest family of receptors in the human genome and are one of the most common targets of pharmaceutical drugs (1, 2). Upon ligand binding, GPCRs activate downstream G protein-dependent signaling pathways followed by phosphorylation of the receptor by G protein-coupled receptor kinases (GRKs) (3). Phosphorylation enhances association of the GPCR with β-arrestins (βarrs), and this combined process mediates desensitization of G-protein signaling (4) and internalization of GPCRs (5-7). Two isoforms of βarrs, βarr1 and βarr2, are widely coexpressed in most tissues in mammals and are 80% identical, but they can have either overlapping or distinct functions (8, 9). It is now firmly established that GPCRs activate downstream signaling pathways through not only canonical G-protein pathways but also, the ability of βarrs to scaffold distinct intracellular signaling complexes (10-12). Elucidation of these distinct G-protein and βarr signaling pathways has provided support for the concept of functional selectivity or biased signaling, wherein each signaling pathway has the ability to mediate distinct physiological responses (13). There are now several physiologically relevant examples of selective engagement of signaling pathways or selective GPCR ligands that target these different signaling pathways (13-15). Therefore, leveraging the concept of GPCR functional selectivity holds promise for the development of more selective therapeutic approaches. Dopamine (DA) is a catecholamine neurotransmitter that has been implicated in movement, reward, and cognition (16-19) as well as CNS disorders, such as schizophrenia, attention deficit hyperactivity disorder, Parkinson's disease, and obsessive-compulsive disorder (20-23). DA mediates its effects via GPCRs belonging to two major ...

show abstract

Quantitative Analysis of the Expression of Dopamine D1 and D2 Receptors in Pyramidal and GABAergic Neurons of the Rat Prefrontal Cortex

Cited by 204 publications

References 64 publications

Loss of dendrite stabilization by the Abl-related gene (Arg) kinase regulates behavioral flexibility and sensitivity to cocaine

Loss of dendrite stabilization by the Abl-related gene (Arg) kinase regulates behavioral flexibility and sensitivity to cocaine

Dopamine’s Actions in Primate Prefrontal Cortex: Challenges for Treating Cognitive Disorders

Distinct cortical and striatal actions of a β-arrestin–biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties

Contact Info

Product

Resources

About