Phencyclidine-induced increases in striatal neuron firing in behaving rats: reversal by haloperidol and clozapine

White, Ilsun M.; Flory, Graham S.; Hooper, K. C.; Speciale, John; Banks, D. A.; Rebec, George V.

doi:10.1007/bf01276506

Cited by 20 publications

(16 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our studies, a possible mechanism by which these clinically effective antipsychotic agents attenuated the acute inhibitory effects of dizocilpine on miR-219 concentrations is by decreasing the neurochemical and behavioral deficits associated with NMDA receptor hypofunction. Consistent with this hypothesis, it has been shown that haloperidol and clozapine can facilitate NMDA receptor function (44) and counter the inhibitory effects of dizocilpine on NMDA receptor-mediated transmission (45).…”

Section: Discussionsupporting

confidence: 58%

MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction

Kocerha

Faghihi

López‐Toledano

et al. 2009

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

272

218

View full text Add to dashboard Cite

cerebral cortex ͉ glutamatergic signaling ͉ regulatory RNA N MDA receptors (NMDA-R) control many executive brain functions, such as working memory, and their dysfunction is implicated in a host of brain disorders (1-4). Notably, hypofunctional NMDA-R signaling, particularly in the prefrontal cortex (PFC), has been implicated in the cognitive and behavioral disturbances characteristic of schizophrenia (5), autism (6, 7), attention deficit hyperactivity disorder (ADHD) (8, 9), mood disorders (10), and other psychiatric illnesses. The cellular mechanisms by which disrupted NMDA-R transmission drives behavioral pathology are still unclear, although several of the major proteins involved in this pathway, such as calcium/calmodulin-dependent protein kinase II (CaMKII) (11), have been identified. In this study, we examine whether neurobehavioral abnormalities associated with NMDA-R hypofunction can be attributed to a novel class of regulatory RNA molecules, microRNAs (miRNAs).miRNAs have attracted much attention as regulators of neuronal development and synaptic plasticity (12-15). Furthermore, psychiatric disorders such as schizophrenia, autism, and Tourette's syndrome are associated with dysregulated levels of miRNAs (16)(17)(18)(19)(20). miRNAs are small (Ϸ22 nt) noncoding transcripts that can control expression of protein-coding mRNAs at the posttranscriptional level (21). Pleiotropic miRNAs can control gene expression by binding to complementary sequences in the 3Ј untranslated region (3Ј UTR) of target mRNA transcripts to facilitate their degradation and/or inhibit their translation (15,22,23). Understanding this layer of gene regulation therefore promises to enrich our knowledge of brain function and pathology. Dizocilpine is a highly selective phencyclidine-like NMDA-R antagonist that can rapidly produce schizophrenia-like behavioral deficits in humans and rodents (24). We examined whether a psychotomimetic dose of dizocilpine (0.5 mg/kg, i.p.) altered miRNA expression in brain regions of C57BL/6 mice, by using miRNA microarray profiling as an initial screening approach. Our analysis was focused on the PFC because of the considerable evidence linking this brain region with behavioral pathology in psychiatric illnesses (19). We extracted the small RNAs from the PFC of the mice 15 min after administration of a single dose of dizocilpine, i.e., a time-point at which dizocilpine-induced behavioral disturbances such as hyperlocomotion and stereotypy are readily observed (25). Of note, there was a robust reduction of miR-219 out of 182 miRNAs detectable by microarray in PFC tissues (Table S1). miR-219 is a conserved miRNA expressed in both rodent and human brains, but not in other tissues (26,27). These data demonstrate that concentrations of a brain-specific miRNA, which may play a role in regulating NMDA-R function, are altered during states of NMDA-R hypofunction.In support of the microarray data, RT-PCR analyses demonstrated that miR-219 levels were significantly reduced by Ϸ50% (a change from an average cycle th...

show abstract

Section: Discussionsupporting

confidence: 58%

MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction

Kocerha

Faghihi

López‐Toledano

et al. 2009

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

272

218

View full text Add to dashboard Cite

show abstract

“…However, deletion of D2Rs in the STR attenuated the PCP response ( Fig. 3B) compared with controls (Ps < 0.01), consistent with striatal D2R antagonism inhibiting PCP-mediated responses (49,50). These pharmacological and behavioral data suggest distinct roles for D2R signaling in the PFC versus the STR in mediating antipsychotic-like effects.…”

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

confidence: 65%

“…Although D2R PFC agonism inhibits PCP-induced locomotion, striatal D2R antagonism is thought to be the primary mechanism of action of most APDs (49,50). To broadly explore this paradoxical role of D2R function behaviorally, we selectively deleted D2Rs in either the PFC by injecting an mCherry-Cre adeno-associated virus (AAV) in the previously described D2R floxed (D2 f/f ) mice (51) or the STR by crossing D2 f/f mice with adenosine 2A receptor Cre (A2aCre) mice (Fig.…”

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

“…Thus, inhibitory effects of NMDA antagonists on striatal dopamine release may not be mediated locally within striatum but may require intact striatonigral circuitry. In support of this hypothesis, PCP and MK-801 have both been shown to increase the firing rate of nigrostriatal neurons, an effect that would lead to enhanced striatal dopamine release (White et al 1995).…”

Section: Discussionmentioning

confidence: 88%

Continuous Phencyclidine Treatment Induces Schizophrenia-Like Hyperreactivity of Striatal Dopamine Release

Balla

Koneru

Smiley

et al. 2001

Neuropsychopharmacology

View full text Add to dashboard Cite

Schizophrenia is a widely prevalent neuropsychiatric disorder of unknown etiology. The most widely accepted neurochemical model of schizophrenia, the dopamine model, proposes that schizophrenia is associated with functional hyperactivity of brain dopaminergic systems (Stein and Wise 1971;Davis et al. 1991;Jentsch and Roth 1999). This model is supported by the observations that amphetamine and other dopaminergic agents induce psychotic symptoms that closely resemble those of schizophrenia and that currently available antipsychotic agents function primarily by blocking dopamine (D2) receptors. Mechanisms underlying dopamine dysfunction in schizophrenia, however, remain obscure.Over the past decade, increasing attention has been paid to alternative neurochemical conceptualizations of schizophrenia based upon the phencyclidine/ N -methyl-D -aspartate (PCP/NMDA) model (Javitt 1987;Javitt and Zukin 1991). This hypothesis is based upon the observation that PCP and other dissociative anesthetictype psychotomimetics (e.g., ketamine, MK-801) induce symptoms that closely resemble those of schizophrenia but differ somewhat from the symptoms induced by amphetamine (Luby et al. 1959(Luby et al. , 1962Domino and Luby 1981 Javitt and Zukin 1991;Olney and Farber 1995;Newcomer et al. 1999;Jentsch and Roth 1999).The present study investigates the degree to which continuous treatment with PCP leads to schizophrenialike disturbances in dopamine regulation. This issue has been complicated until recently by the relative paucity of information concerning endogenous dopamine levels in schizophrenia. Over the past several years, however, several studies using in vivo radioreceptor label studies have demonstrated significant striatal hyperreactivity to amphetamine-stimulated dopamine release in schizophrenia (Laruelle et al. 1996(Laruelle et al. , 1999Breier et al. 1997;Abi-Dargham et al. 1998). Enhanced striatal dopamine levels were also observed following ketamine administration in normal volunteers (Breier et al. 1998), supporting a potential role for NMDA receptors in dopamine hyperactivity in schizophrenia. Similar effects of acute administration of NMDA antagonists are observed in rodents (Hiramatsu et al. 1989;Lillrank et al. 1994;Yonezawa et al. 1995).Given that schizophrenia is a chronic condition potentially arising from persistent dysfunction of NMDA receptor-mediated neurotransmission, continuous PCP administration provides a superior dosing paradigm than does acute administration (Sams-Dodd 1999;Jentsch et al. 1998). Further, continuous administration permits amphetamine-induced effects to be measured against a constant background PCP level. For the present study, rats were treated chronically with PCP, and dopamine response to amphetamine was measured in striatum using in vivo microdialysis to investigate the degree to which continuous PCP treatment leads to enhanced responsiveness to amphetamine challenge. PCP was administered by osmotic minipump to maintain as constant a level of PCP as possible, in order to model a persis...

show abstract

Phencyclidine-induced increases in striatal neuron firing in behaving rats: reversal by haloperidol and clozapine

Cited by 20 publications

References 55 publications

MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction

MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction

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

Continuous Phencyclidine Treatment Induces Schizophrenia-Like Hyperreactivity of Striatal Dopamine Release

Contact Info

Product

Resources

About