1Psychopharmacology (Berl.) 2001 Feb 154: 105-11
PMID11291999
TitleTyrosine depletion attenuates dopamine function in healthy volunteers.
AbstractTYRosine depletion has been shown to reduce dopamine over activity in animal and human investigations. However, the effects on basal dopamine function have not been explored. Such information could establish TYRosine depletion as an effective probe of dopamine function in healthy volunteers and would also have relevance for future therapeutic applications of this manipulation.
The present study investigated the effect of acute TYRosine depletion on dopamine function in healthy volunteers using a combination of neuroendocrine, neuropsychological and subjective measures.
On one occasion, volunteers received an amino acid drink selectively lacking TYRosine and phenylalanine (TYR-free), whilst on the other they received a balanced (BAL) amino acid drink. Plasma prolactin, amino acid levels and subjective state were monitored over 6 h following the two drinks, and volunteers also completed a battery of tests from the CANTAB, including measures of spatial memory previously found to be sensitive to changes in dopamine function.
Plasma prolactin levels rose following the TYR-free drink relative to the balanced mixture, indicative of decreased dopamine neurotransmission within the hypothalamus. Following the TYR-free drink, volunteers were impaired at spatial recognition memory and spatial working memory. Volunteers also tended to report that they felt less good following the TYR-free than the BAL mixture.
TYRosine depletion in healthy volunteers affected baseline dopamine function on the different measures employed in this study. TYRosine depletion would thereby seem valuable as a probe of dopamine function in human volunteers. Ratings of depression and other aspects of cognitive function were unaffected, suggesting that this manipulation may be free of significant side effects when used as a treatment for conditions characterised by dopamine over activity, such as acute mania and schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
2Mol. Pharmacol. 2005 Apr 67: 1283-90
PMID15644497
TitleTrace amines depress GABA B response in dopaminergic neurons by inhibiting G-betagamma-gated inwardly rectifying potassium channels.
AbstractTrace amines (TAs) are present in the central nervous system in which they up-regulate catecholamine release and are implicated in the pathogenesis of addiction, attention-deficit/hyper-activity disorder, Parkinson's disease, and schizophrenia. By using intracellular and patch-clamp recordings from dopaminergic cells in the rat midbrain slices, we report a depressant postsynaptic action of two TAs, beta-phenylethylamine (beta-PEA) and TYRamine (TYR) on the GABA(B)-mediated slow inhibitory postsynaptic potential and baclofen-activated outward currents. beta-PEA and TYR activated G-proteins, interfering with the coupling between GABA(B) receptors and G-betagamma-gated inwardly rectifying potassium channels. This is the first demonstration that beta-PEA and TYR depress inhibitory synaptic potentials in neurons of the central nervous system, supporting their emerging role as neuromodulators.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
3Mol Biosyst 2009 Dec 5: 1877-88
PMID19763327
TitleMolecular modeling and docking studies of human 5-hydroxytryptamine 2A (5-HT2A) receptor for the identification of hotspots for ligand binding.
AbstractThe serotonergic system has been implicated in emotional and cognitive function. In particular, 5-HT(2A) (5-hydroxytrytamine receptor 2A) is attributed to a number of disorders like schizophrenia, depression, eating disorders and anxiety. 5-HT(2A), being a GPCR (G-protein coupled receptor), is important in the pharmaceutical industry as a proven target for these disorders. Despite their extensive clinical importance, the structural studies of this protein is lacking due to difficulties in determining its crystal structure. We have performed sequence analysis and molecular modeling of 5-HT(2A) that has revealed a set of conserved residues and motifs considered to play an important role in maintaining structural integrity and function of the receptor. The analysis also revealed a set of residues specific to the receptor which distinguishes them from other members of the subclass and their orthologs. Further, starting from the model structure of human 5-HT(2A) receptor, docking studies were attempted to envisage how it might interact with eight of its ligands (such as serotonin, dopamine, DOI, LSD, haloperidol, ketanserin, risperidone and clozapine). The binding studies of dopamine to 5-HT(2A) receptor can bring up better understanding in the etiology of a number of neurological disorders involving both these two receptors. Our sequence analysis and study of interactions of this receptor with other ligands reveal additional residue hotspots such as Asn 363 and TYR 370. The function of these residues can be further analyzed by rational design of site-directed mutagenesis. Two distinct binding sites are identified which could play important roles in ligand binding and signaling.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
4PLoS ONE 2011 -1 6: e27073
PMID22073124
TitleDifferential modulation of Beta-adrenergic receptor signaling by trace amine-associated receptor 1 agonists.
AbstractTrace amine-associated receptors (TAAR) are rhodopsin-like G-protein-coupled receptors (GPCR). TAAR are involved in modulation of neuronal, cardiac and vascular functions and they are potentially linked with neurological disorders like schizophrenia and Parkinson's disease. Subtype TAAR1, the best characterized TAAR so far, is promiscuous for a wide set of ligands and is activated by trace amines TYRamine (TYR), phenylethylamine (PEA), octopamine (OA), but also by thyronamines, dopamine, and psycho-active drugs. Unfortunately, effects of trace amines on signaling of the two homologous ?-adrenergic receptors 1 (ADRB1) and 2 (ADRB2) have not been clarified yet in detail. We, therefore, tested TAAR1 agonists TYR, PEA and OA regarding their effects on ADRB1/2 signaling by co-stimulation studies. Surprisingly, trace amines TYR and PEA are partial allosteric antagonists at ADRB1/2, whereas OA is a partial orthosteric ADRB2-antagonist and ADRB1-agonist. To specify molecular reasons for TAAR1 ligand promiscuity and for observed differences in signaling effects on particular aminergic receptors we compared TAAR, TYRamine (TAR) octopamine (OAR), ADRB1/2 and dopamine receptors at the structural level. We found especially for TAAR1 that the remarkable ligand promiscuity is likely based on high amino acid similarity in the ligand-binding region compared with further aminergic receptors. On the other hand few TAAR specific properties in the ligand-binding site might determine differences in ligand-induced effects compared to ADRB1/2. Taken together, this study points to molecular details of TAAR1-ligand promiscuity and identified specific trace amines as allosteric or orthosteric ligands of particular ?-adrenergic receptor subtypes.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
5J. Neurosci. 2011 Apr 31: 6362-70
PMID21525276
TitleNucleus accumbens ?-opioid receptors mediate social reward.
AbstractPositive social interactions are essential for emotional well-being and proper behavioral development of young individuals. Here, we studied the neural underpinnings of social reward by investigating the involvement of opioid neurotransmission in the nucleus accumbens (NAc) in social play behavior, a highly rewarding social interaction in adolescent rats. Intra-NAc infusion of morphine (0.05-0.1 ?g) increased pinning and pouncing, characteristic elements of social play behavior in rats, and blockade of NAc opioid receptors with naloxone (0.5 ?g) prevented the play-enhancing effects of systemic morphine (1 mg/kg, s.c.) administration. Thus, stimulation of opioid receptors in the NAc was necessary and sufficient for morphine to increase social play. Intra-NAc treatment with the selective ?-opioid receptor agonist [D-Ala(2),N-MePhe(4),Gly(5)-ol]enkephalin (DAMGO) (0.1-10 ng) and the ?-opioid receptor antagonist Cys-TYR-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP) (0.3-3 ?g) increased and decreased social play, respectively. The ?-opioid receptor agonist DPDPE ([D-Pen(2),D-Pen(5)]-enkephalin) (0.3-3 ?g) had no effects, whereas the ?-opioid receptor agonist U69593 (N-methyl-2-phenyl-N-[(5R,7S,8S)-7-(pyrrolidin-1-yl)-1-oxaspiro[4.5]dec-8-yl]acetamide) (0.01-1 ?g) decreased social play. Intra-NAc treatment with ?-endorphin (0.01-1 ?g) increased social play, but met-enkephalin (0.1-5 ?g) and the enkephalinase inhibitor thiorphan (0.1-1 ?g) were ineffective. DAMGO (0.1-10 ng) increased social play after infusion into both the shell and core subregions of the NAc. Last, intra-NAc infusion of CTAP (3 ?g) prevented the development of social play-induced conditioned place preference. These findings identify NAc ?-opioid receptor stimulation as an important neural mechanism for the attribution of positive value to social interactions in adolescent rats. Altered NAc ?-opioid receptor function may underlie social impairments in psychiatric disorders such as autism, schizophrenia, or personality disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
6Neuropsychobiology 2011 -1 64: 202-10
PMID21912188
TitlePolymorphisms of the 5-HT2A receptor gene and clinical response to olanzapine in paranoid schizophrenia.
Abstract5-HT2A receptor is strongly implicated in the mode of action of atypical antipsychotic drugs. The aim of the study was to investigate whether the 5-HT2A receptor gene's polymorphisms (His452TYR and T102C) have an influence on the response to olanzapine in patients with schizophrenia.
We studied 99 Caucasian schizophrenia patients treated with olanzapine. Psychopathology was measured before and after 6 weeks of treatment. Clinical improvement was quantified as change in Positive and Negative Syndrome Scale (PANSS) total scores and subscores as shown by percentage improvement below the baseline score. The clinical response to antipsychotic treatment was defined as 30% improvement from baseline in PANSS scores.
The His/TYR polymorphism was significantly associated with a percentage improvement in PANSS positive symptom subscore (better response in His/His homozygotes; p<0.05) after treatment with olanzapine. As for the T102C polymorphism, a better response in terms of PANSS positive subscore improvement was observed for C/C homozygotes (p<0.01). A significant association of 5-HT2A genotype distribution of the T102C polymorphism with a categorical measure of response, but only in terms of PANSS positive symptom subscores, was observed (p<0.01).
Variations in the 5-HT2A receptor gene may influence individual and particularly positive symptom response to olanzapine.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
7Brain Res. Bull. 2012 Dec 89: 177-84
PMID22981453
TitleModulation of acetylcholine release by cholecystokinin in striatum: receptor specificity; role of dopaminergic neuronal activity.
AbstractCholecystokinin, a neuroactive peptide functioning as a neurotransmitter and neuromodulator in the central nervous system, mediates a number of processes and is implicated in neurological and psychiatric disorders such as Parkinson's disease, anxiety and schizophrenia. Striatum is one of the brain structures with the highest concentrations of CCK in the brain, rich in CCK receptors as well. The physiological effect of CCK on cholinergic interneurons, which are the major interneurons in striatum and the modulatory interactions which exist between dopamine, acetylcholine and cholecystokinin in this brain structure are still unclear. We studied the effect of cholecystokinin octapeptide (CCK-8) on the release of acetylcholine (ACh) from striatal slices of the rat brain. CCK-8 (0.01-0.1?M) showed no statistically significant effect on the basal but enhanced dose-dependently the electrically (2Hz)-evoked release of [(3)H]ACh. When slices were preperfused with 100?M sulpiride, a selective dopamine D(2) receptor antagonist, the CCK-8 (0.01?M) effect on electrically stimulated ACh release was increased nearly 2-fold. A similar increase was observed after depletion of endogenous dopamine (DA) from nigro-striatal dopaminergic neurons with 6-hydroxydopamine (6-OHDA) (2 250?g/animal, i.c.v.). Furthermore in the presence of dopamine (100?M) or apomorphine (10?M), the prototypical DA receptor agonist, CCK-8 (0.01?M) failed to enhance the stimulation-evoked release of [(3)H]ACh. The D(2) receptor agonist quinpirol (1?M) abolished the CCK-8 effect on electrically stimulated ACh release as well. The increase in electrically induced [(3)H]ACh release produced by 0.01?M CCK-8 was antagonized by d,l loxiglumide (CR 1505), 10?M, a non-peptide CCK-A receptor antagonist and by Suc-TYR-(OSO3)-Met-Gly-Trp-Met-Asp-?-phenethyl-amide (GE-410), 1?M, a peptide CCK-A receptor antagonist. The antagonistic effect of GE-410 on the CCK-8-potentiated, electrically induced release of [(3)H]ACh was studied in striatum for the first time. CAM 1028 (10?M), a CCK-B receptor antagonist, also prevented the potentiating effect of CCK-8 (0.01?M) on electrically stimulated release of [(3)H]ACh. The presented results indicate that (i) CCK-8 is capable of increasing ACh elicited by field electrical stimulation in striatum; (ii) CCK-8 is more effective in its ACh-stimulating effect when dopaminergic activity in striatum is blocked i.e. CCK-8-facilitated release of electrically induced ACh from cholinergic interneurons in the striatum is under the inhibitory control of the tonic activity of dopamine from the nigrostriatal pathway; (iii) the enhancing effect of CCK-8 on electrically evoked ACh release is mediated through both CCK-A and CCK-B cholecystokinin receptors located most likely on the cell bodies of cholinergic interneurons in striatum.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
8Theor Biol Med Model 2013 -1 10: 3
PMID23286827
TitleStructural, phylogenetic and docking studies of D-amino acid oxidase activator (DAOA), a candidate schizophrenia gene.
Abstractschizophrenia is a neurodegenerative disorder that occurs worldwide and can be difficult to diagnose. It is the foremost neurological disorder leading to suicide among patients in both developed and underdeveloped countries. D-amino acid oxidase activator (DAOA), also known as G72, is directly implicated in the glutamateric hypothesis of schizophrenia. It activates D-amino acid oxidase, which oxidizes D-serine, leading to modulation of the N-methyl-D-aspartate receptor.
MODELLER (9v10) was utilized to generate three dimensional structures of the DAOA candidate gene. The HOPE server was used for mutational analysis. The Molecular Evolutionary Genetics Analysis (MEGA5) tool was utilized to reconstruct the evolutionary history of the candidate gene DAOA. AutoDock was used for protein-ligand docking and Gramm-X and PatchDock for protein-protein docking.
A suitable template (1ZCA) was selected by employing BLASTp on the basis of 33% query coverage, 27% identity and E-value 4.9. The Rampage evaluation tool showed 91.1% favored region, 4.9% allowed region and 4.1% outlier region in DAOA. ERRAT demonstrated that the predicted model had a 50.909% quality factor. Mutational analysis of DAOA revealed significant effects on hydrogen bonding and correct folding of the DAOA protein, which in turn affect protein conformation. Ciona was inferred as the outgroup. Tetrapods were in their appropriate clusters with bifurcations. Human amino acid sequences are conserved, with chimpanzee and gorilla showing more than 80% homology and bootstrap value based on 1000 replications. Molecular docking analysis was employed to elucidate the binding mode of the reported ligand complex for DAOA. The docking experiment demonstrated that DAOA is involved in major amino acid interactions: the residues that interact most strongly with the ligand C28H28N3O5PS2 are polar but uncharged (Gln36, Asn38, Thr 122) and non-polar hydrophobic (Ile119, Ser171, Ser21, Ala31). Protein-protein docking simulation demonstrated two ionic bonds and one hydrogen bond involving DAOA. Lys-7 of the receptor protein interacted with Lys-163 and Asp-2037. TYR-03 interacted with Arg-286 of the ligand protein and formed a hydrogen bond.
The predicted interactions might serve to inhibit the disease-related allele. It is assumed that current bioinformatics methods will contribute significantly to identifying, analyzing and curing schizophrenia. There is an urgent need to develop effective drugs for schizophrenia, and tools for examining candidate genes more accurately and efficiently are required.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
9Proteins 2014 Jan 82: 103-18
PMID23900790
TitleA common structural scaffold in CTD phosphatases that supports distinct catalytic mechanisms.
AbstractThe phosphorylation and dephosphorylation of the carboxyl-terminal domain (CTD) of the largest RNA polymerase II (RNAPII) subunit is a critical regulatory checkpoint for transcription and mRNA processing. This CTD is unique to eukaryotic organisms and it contains multiple tandem-repeats with the consensus sequence TYR(1) -Ser(2) -Pro(3) -Thr(4) -Ser(5) -Pro(6) -Ser(7) . Traditionally, CTD phosphatases that use metal-ion-independent (cysteine-based) and metal-ion-assisted (aspartate-based) catalytic mechanisms have been considered to belong to two independent groups. However, using structural comparisons we have identified a common structural scaffold in these two groups of CTD phosphatases. This common scaffold accommodates different catalytic processes with the same substrate specificity, in this case phospho-serine/threonine residues flanked by prolines. Furthermore, this scaffold provides a structural connection between two groups of protein TYRosine phosphatases (PTPs): Cys-based (classes I, II, and III) and Asp-based (class IV) PTPs. Redundancy in catalytic mechanisms is not infrequent and may arise in specific biological settings. To better understand the activity of the CTD phosphatases, we combined our structural analyses with data on CTD phosphatase expression in different human and mouse tissues. The results suggest that aspartate- and cysteine-based CTD-dephosphorylation acts in concert during cellular stress, when high levels of reactive oxygen species can inhibit the nucleophilic function of the catalytic cysteine, as occurs in mental and neurodegenerative disorders like schizophrenia, Alzheimer's and Parkinson's diseases. Moreover, these findings have significant implications for the study of the RNAPII-CTD dephosphorylation in eukaryotes.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
10Drug Des Devel Ther 2015 -1 9: 3471-80
PMID26170631
TitleAdaptive evolution and elucidating the potential inhibitor against schizophrenia to target DAOA (G72) isoforms.
Abstractschizophrenia (SZ), a chronic mental and heritable disorder characterized by neurophysiological impairment and neuropsychological abnormalities, is strongly associated with D-amino acid oxidase activator (DAOA, G72). Research studies emphasized that overexpression of DAOA may be responsible for improper functioning of neurotransmitters, resulting in neurological disorders like SZ. In the present study, a hybrid approach of comparative modeling and molecular docking followed by inhibitor identification and structure modeling was employed. Screening was performed by two-dimensional similarity search against selected inhibitor, keeping in view the physiochemical properties of the inhibitor. Here, we report an inhibitor compound which showed maximum binding affinity against four selected isoforms of DAOA. Docking studies revealed that Glu-53, Thr-54, Lys-58, Val-85, Ser-86, TYR-87, Leu-88, Glu-90, Leu-95, Val-98, Ser-100, Glu-112, TYR-116, Lys-120, Asp-121, and Arg-122 are critical residues for receptor-ligand interaction. The C-terminal of selected isoforms is conserved, and binding was observed on the conserved region of isoforms. We propose that selected inhibitor might be more potent on the basis of binding energy values. Further analysis of this inhibitor through site-directed mutagenesis could be helpful for exploring the details of ligand-binding pockets. Overall, the findings of this study may be helpful in designing novel therapeutic targets to cure SZ.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias