| 1 | Mol. Cell. Neurosci. 2009 Dec 42: 438-47 |
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| PMID | 19796684 |
| Title | The orphan GPCR, GPR88, modulates function of the striatal dopamine system: a possible therapeutic target for psychiatric disorders? |
| Abstract | In rodents, the orphan G protein-coupled receptor, GPR88, is highly expressed in brain regions implicated in the pathophysiology of and is modulated by treatments for schizophrenia. We compared striatal function of GPR88 knockout mice (GPR88KOs) to wild-type mice using molecular, neurochemical and behavioral tests. GPR88KOs lacked expression of GPR88 in striatum, nucleus accumbens and layer IV of cortex. GPR88KOs had normal striatal dopamine D2 receptor density and affinity and DARPP-32 expression but GPR88KOs had higher basal striatal phosphorylated DARPP-32 Thr-34. In vivo microdialysis detected lower basal dopamine in GPR88KOs while amphetamine-induced dopamine release was normal. Behaviorally, GPR88KOs demonstrated disrupted prepulse inhibition of startle (PPI) and increased sensitivity to apomorphine-induced climbing and stereotypy (AICS) and amphetamine-stimulated locomotor activity. Antipsychotic administration to GPR88KOs normalized the PPI deficit and blocked AICS. The modulatory role of GPR88 in striatal dopamine function suggests it may be a new target for treatments for psychiatric disorders. |
| SCZ Keywords | schizophrenia |
| 2 | Mol Genet Genomic Med 2014 Mar 2: 152-9 |
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| PMID | 24689078 |
| Title | Association study in three different populations between the GPR88 gene and major psychoses. |
| Abstract | GPR88, coding for a G protein-coupled orphan receptor that is highly represented in the striatum, is a strong functional candidate gene for neuropsychiatric disorders and is located at 1p22-p21, a chromosomal region that we have previously linked to bipolar disorder (BD) in the Sardinian population. In order to ascertain the relevance of GPR88 as a risk factor for psychiatric diseases, we performed a genetic association analysis between GPR88 and BD in a sample of triads (patient and both parents) recruited in the Sardinian and the Palestinian population as well as between GPR88 and schizophrenia (SZ) in triads from the Xhosa population in South Africa. We found a positive association between GPR88 and BD in the Sardinian and Palestinian triads. Moreover, we found a positive association between GPR88 and SZ in triads from the Xhosa population in South Africa. When these results were corrected for multiple testing, the association between GPR88 and BD was maintained in the Palestinian population. Thus, these results suggest that GPR88 deserves consideration as a candidate gene for psychiatric diseases and requires to be further investigated in other populations. |
| SCZ Keywords | schizophrenia |
| 3 | Mol. Psychiatry 2015 Aug 20: 951-8 |
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| PMID | 25155879 |
| Title | Local inactivation of Gpr88 in the nucleus accumbens attenuates behavioral deficits elicited by the neonatal administration of phencyclidine in rats. |
| Abstract | GPR88, an orphan G-protein-coupled receptor, is highly and almost exclusively expressed in the medium spiny projection neurons of the striatum, and may thus participate in the control of motor functions and cognitive processing that are impaired in neuropsychiatric disorders such as Parkinson's disease or schizophrenia (SZ). This study investigated the relevance of GPR88 to SZ-associated behavior by knocking down GPR88 gene expression in the ventral striatum (nucleus accumbens) in a neurodevelopmental rat model of SZ, generated by neonatal treatment with phencyclidine (PCP). In this model, we compared the effects of the local inactivation in the adult animal of the expression of GPR88 and of Drd2, a gene strongly implicated in the etiology of SZ and coding for the dopamine receptor type 2 (D2). To inactivate specifically GPR88 and D2 expression, we used the lentiviral vector-mediated microRNA silencing strategy. The neonatal PCP treatment induced in the adult rat hyperlocomotion in response to amphetamine (Amph) and social novelty discrimination (SND) deficits. The inactivation of D2 did not modify the locomotor response to Amph or the cognitive deficits induced by PCP, whereas the silencing of GPR88 inhibited the Amph-induced hyperlocomotion and reduced the impairment of SND elicited by neonatal exposure to PCP. These observations suggest a role for GPR88 in the regulation of cognitive and motor functions, and support its relevance to the pathophysiology and treatment of SZ and other disorders involving dysfunction of the accumbens-striatal complex. |
| SCZ Keywords | schizophrenia |
| 4 | Int J Mol Sci 2015 -1 16: 14109-21 |
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| PMID | 26101869 |
| Title | Novel Therapeutic GPCRs for Psychiatric Disorders. |
| Abstract | G protein-coupled receptors (GPCRs) are the most common targets of the neuropharmacological drugs in the central nervous system (CNS). GPCRs are activated by manifold neurotransmitters, and their activation in turn evokes slow synaptic transmission. They are deeply involved in multiple neurological and psychiatric disorders such as Parkinson's disease and schizophrenia. In the brain, the striatum is strongly innervated by the ventral tegmental area (VTA) and plays a central role in manifestation of psychiatric disorders. Recently, anatomical and comprehensive transcriptome analysis of the non-odorant GPCR superfamily revealed that the orphan GPCRs GPR88, GPR6, and GPR52, as well as dopamine D1 and D2 receptors and the adenosine A2a receptor, are the most highly enriched in the rodent striatum. Genetically engineered animal models and molecular biological studies have suggested that these striatally enriched GPCRs have a potential to be therapeutic psychiatric receptors. This review summarizes the current understanding of the therapeutic GPCR candidates for psychiatric disorders. |
| SCZ Keywords | schizophrenia |
| 5 | Bioorg. Med. Chem. Lett. 2015 Apr 25: 1443-7 |
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| PMID | 25754495 |
| Title | The discovery of potent agonists for GPR88, an orphan GPCR, for the potential treatment of CNS disorders. |
| Abstract | Modulating GPR88 activity is suggested to have therapeutic utility in the treatment of CNS disorders, such as schizophrenia. This Letter will describe the discovery and SAR development of a class of potent GPR88 agonists. |
| SCZ Keywords | schizophrenia |
| 6 | Bioorg. Med. Chem. Lett. 2015 Apr 25: 1448-52 |
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| PMID | 25690789 |
| Title | Design, synthesis, and evaluation of phenylglycinols and phenyl amines as agonists of GPR88. |
| Abstract | Small molecule modulators of GPR88 activity (agonists, antagonists, or modulators) are of interest as potential agents for the treatment of a variety of psychiatric disorders including schizophrenia. A series of phenylglycinol and phenylamine analogs have been prepared and evaluated for their GPR88 agonist activity and pharmacokinetic (PK) properties. |
| SCZ Keywords | schizophrenia |