Reply to comments on "Olanzapine treatment of children, adolescents, and adults with pervasive developmental disorders: an open-label pilot study".
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Adolescent↗
Biomedical subjects
M N Potenza
Publications and source records attributed to M N Potenza.
Schizophrenia and pathological gambling.
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Adult↗
Illegal behaviors in problem gambling: analysis of data from a gambling helpline.
Problem gambling behaviors, particularly the most severe form, which is pathological gambling (PG), represent an emerging public health problem. Compared with the general population, individuals with problem gambling are more likely to have reports of legal issues, including commission of crimes, arrest, and incarceration. The goal of the present study is to examine the characteristics of individuals seeking help for gambling problems with regard to reports of illegal behavior secondary to gambling. Individuals with gambling problems were identified through use of a 24-hour gambling helpline, and information regarding the identified problem gambler was investigated with respect to reported presence or absence of gambling-related illegal behaviors. Identified gamblers with reported gambling-related illegal behaviors compared with those without such behaviors appeared to experience more severe gambling-related problems. Despite being on average younger, gamblers with acknowledged gambling-related illegal behaviors were more likely to have reports of having problems with multiple forms of gambling, debts to acquaintances, been suicidal secondary to gambling, used alcohol or drugs excessively, and received mental health treatment. Secondary analyses of the subgroup of gamblers with gambling-related illegal behaviors revealed that those with reports of arrest or incarceration secondary to gambling compared with those with gambling-related illegal behaviors but without arrest or incarceration secondary to gambling were more likely to have features similar to those described for individuals with antisocial personality disorder (ASPD). That is, the gambler with reported arrest or incarceration secondary to gambling was more likely to be male, unemployed, single, and have reports of problems with excessive drug or alcohol use. In contrast, the gamblers acknowledging gambling-related illegal behaviors but not arrest or incarceration secondary to gambling were predominantly female and more likely to have reports of problems with non-strategic forms of gambling (e.g., slot machine), owing money to legitimate sources of borrowing, having filed for bankruptcy, and having family problems related to gambling. The findings indicate: (1) individuals with reported legal problems secondary to gambling represent a more ill subpopulation of problem gamblers; and (2) there exist separate subgroups of gamblers with gambling-related illegal behaviors (i.e., those with or without reported arrest or incarceration secondary to gambling) with strikingly different characteristics and possibly different treatment needs. The results of the present study highlight the importance of the identification and treatment of individuals with gambling problems with respect to legal issues.
Adult↗
Cloning and characterization of RGS9-2: a striatal-enriched alternatively spliced product of the RGS9 gene.
Regulators of G-protein signaling (RGS) proteins act as GTPase-activating proteins (GAPs) for alpha subunits of heterotrimeric G-proteins. Previous in situ hybridization analysis of mRNAs encoding RGS3-RGS11 revealed region-specific expression patterns in rat brain. RGS9 showed a particularly striking pattern of almost exclusive enrichment in striatum. In a parallel study, RGS9 cDNA, here referred to as RGS9-1, was cloned from retinal cDNA libraries, and the encoded protein was identified as a GAP for transducin (Galphat) in rod outer segments. In the present study we identify a novel splice variant of RGS9, RGS9-2, cloned from a mouse forebrain cDNA library, which encodes a striatal-specific isoform of the protein. RGS9-2 is 191 amino acids longer than the retinal isoform, has a unique 3' untranslated region, and is highly enriched in striatum, with much lower levels seen in other brain regions and no expression detectable in retina. Immunohistochemistry showed that RGS9-2 protein is restricted to striatal neuropil and absent in striatal terminal fields. The functional activity of RGS9-2 is supported by the finding that it, but not RGS9-1, dampens the Gi/o-coupled mu-opioid receptor response in vitro. Characterization of a bacterial artificial chromosome genomic clone of approximately 200 kb indicates that these isoforms represent alternatively spliced mRNAs from a single gene and that the RGS domain, conserved among all known RGS members, is encoded over three distinct exons. The distinct C-terminal domains of RGS9-2 and RGS9-1 presumably contribute to unique regulatory properties in the neural and retinal cells in which these proteins are selectively expressed.
Alternative Splicing↗
Olanzapine treatment of children, adolescents, and adults with pervasive developmental disorders: an open-label pilot study.
This pilot study examined the efficacy and tolerability of olanzapine in the treatment of children, adolescents, and adults with pervasive developmental disorders (PDDs). Eight patients with principal diagnoses (DSM-IV) of autistic disorder (N = 5) or PDD not otherwise specified (N = 3) were given olanzapine in an open-label, prospective fashion for 12 weeks. Clinical ratings were obtained at baseline and at the end of weeks (EOWs) 4, 8, and 12. Seven of eight patients completed the 12-week trial, and six of the completers were deemed clinical responders as measured by ratings at the EOW 12 of "much improved" or "very much improved" on the global improvement item of the Clinical Global Impression Scale. Significant improvements in overall symptoms of autism, motor restlessness or hyperactivity, social relatedness, affectual reactions, sensory responses, language usage, self-injurious behavior, aggression, irritability or anger, anxiety, and depression were observed. Significant changes in repetitive behaviors were not observed for the group. The EOW 12 mean +/- SD daily dose of olanzapine was 7.8 +/- 4.7 mg/day. The drug was well tolerated with the most significant adverse effects noted to be increased appetite and weight gain in six patients and sedation in three. With respect to weight gain, the mean +/- SD weight for the group increased from 137.50 +/- 55.81 pounds (62.50 +/- 25.37 kilograms) at baseline to 155.94 +/- 55.13 pounds (70.88 +/- 25.06 kilograms) at EOW 12. No evidence of extrapyramidal side effects or liver function abnormalities was seen. These preliminary results suggest that olanzapine may be an effective and well tolerated drug in targeting core and related symptoms of PDDs in children, adolescents, and adults. Further studies, particularly those that are placebo-controlled and double-blinded, are indicated to better define the clinical use of olanzapine in these patient populations.
Adolescent↗
Olanzapine addition in obsessive-compulsive disorder refractory to selective serotonin reuptake inhibitors: an open-label case series.
BACKGROUND: Despite the efficacy of selective serotonin reuptake inhibitors (SSRIs) in the treatment of obsessive-compulsive disorder, a significant number of patients show no or only partial remission of symptoms. Some evidence exists to suggest that risperidone augmentation can be helpful in treating this refractory group. The efficacy of other atypical antipsychotic agents, such as olanzapine, in augmenting SSRIs in refractory obsessive-compulsive patients has yet to be systematically investigated. METHOD: A series of 10 patients with DSM-IV obsessive-compulsive disorder showing significant residual symptoms following an adequate SSRI trial (12 weeks) were given open-label olanzapine augmentation for a minimum of an additional 8 weeks. Treatment response was assessed using the Yale-Brown Obsessive Compulsive Scale and the Clinical Global Impressions scale. RESULTS: Nine of the 10 patients in this series treated with olanzapine and an SSRI completed the 8-week augmentation trial. Of these, 4 demonstrated a complete remission or major improvement in obsessive-compulsive symptoms, 3 had partial remission, and 2 experienced no benefit. Nine patients experienced minimal adverse effects, primarily sedation, which did not interfere with continuing treatment. One patient discontinued olanzapine owing to excessive sedation. CONCLUSION: The results of this preliminary, open-label trial suggest that olanzapine may be effective in augmenting ongoing SSRI treatment for a portion of patients with obsessive-compulsive disorder refractory to SSRI treatment. Larger, placebo-controlled trials appear warranted to investigate the clinical efficacy and tolerability of olanzapine augmentation of SSRI treatment in SSRI-refractory obsessive-compulsive disorder.
Adult↗
Effects of regulators of G protein-signaling proteins on the functional response of the mu-opioid receptor in a melanophore-based assay.
The goal of the present study was to investigate a possible role for regulators of G protein-signaling (RGS) proteins in opioid receptor (OR) desensitization using cultured Xenopus laevis dermal melanophores. Morphine-induced pigment aggregation in a melanophore cell line stably expressing the murine mu OR (muOR) was quantified over time. Responses of the muOR (a G(i)-linked receptor) exhibited a time-dependent desensitization, which varied with the concentration of morphine used. In contrast, much less desensitization was observed in response to melatonin, effects mediated through the cells' endogenous melatonin receptor (which is also G(i)-linked). To further study OR desensitization, melanophores lacking a muOR were transiently transfected with plasmids encoding the muOR alone or in combination with plasmids encoding one of several RGS subtypes (RGS1, RGS2, RGS3, or RGS4). Overexpression of RGS2, but not the other RGS subtypes, produced a rightward shift in the morphine concentration-response curve. RGS protein overexpression also decreased the magnitude of morphine-induced responses. Finally, the effect of a mutant form of Galpha(i1), which is insensitive to RGS action, was investigated with respect to its ability to alter the response of the muOR to morphine. Expression of the mutant Galpha(i1) prolonged morphine-induced pigment aggregation and produced leftward shifts in concentration-response curves, compared with expression of wild-type Galpha(i1). These results demonstrate that specific RGS proteins can dampen signals initiated by agonist activation of the muOR, and support a possible role for RGS proteins in OR desensitization.
Animals↗
Olanzapine augmentation of fluoxetine in the treatment of refractory obsessive-compulsive disorder.
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Adult↗
Olanzapine augmentation of fluoxetine in the treatment of trichotillomania.
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Adult↗
Characterization of a serotonin receptor endogenous to frog melanophores.
The response of a cell line of Xenopus laevis melanophores to serotonin was examined. Serotonin increased intracellular levels of cAMP and induced pigment dispersion in the cells. The responses depended on both the concentration of serotonin applied and on the time for which the cells were exposed to serotonin. Using a recently described, microtiter-plate-based bioassay, a series of serotonin receptor ligands were evaluated as agonists or antagonists at the melanophore serotonin receptor. The pharmacological profile suggests the presence of a receptor which shares some properties with but appears different from other previously described serotonin receptors.
Animals↗
Functional expression and characterization of human D2 and D3 dopamine receptors.
Functional characteristics of human D2 and D3 receptors (DRs) were examined using a new bioassay suited for the study of Gi-protein-coupled receptors (GiRs). The bioassay utilizes pigment granule aggregation within cultured Xenopus laevis melanophores for the quantitative evaluation of ligands as agonists or antagonists upon particular GiRs. Initial feasibility studies were performed by analyzing a melanocyte receptor endogenous to the melanophores. In dose-dependent manners, melatonin inhibited melatonin-stimulating hormone-induced cAMP accumulation and caused pigment aggregation that could be monitored over time. Next, melanophores were transiently transfected with cDNAs coding for the human D2BR (short form) and D3R. Expression of either receptor conferred upon the cells the ability to aggregate their melanosomes in response to selective dopaminergic agonists. The same ligands also inhibited cAMP accumulation within the transfected melanophores, and the agonist-induced pigment aggregation was shown to be sensitive to pertussis toxin. EC50 and IC50 value determinations revealed that agonists activated the D2R and D3R at similar concentrations, while each of the antagonists displaying an effect was more potent upon the D2R. The results reveal functional similarities and differences between the D2R and D3R.
Animals↗
Pigment dispersion in frog melanophores can be induced by a phorbol ester or stimulation of a recombinant receptor that activates phospholipase C.
Pigment dispersion in frog melanophores is classically mediated by receptors that activate protein kinase A via an elevation of intracellular cyclic AMP. Here, 12-O-tetradecanoylphorbol-13-acetate (TPA), an activator of protein kinase C, is found to induce pigment dispersion. To demonstrate that an increase in cAMP is not required for the melanosome movement, a murine bombesin receptor was expressed in the melanophores. When these cells were treated with bombesin, they accumulated intracellular inositol phosphates but not cAMP and dispersed their pigment. Four agonists, one partial agonist, and two antagonists for the bombesin receptor were compared for their ability to induce or block bombesin-induced pigment dispersion. In all cases, the degree of pigment dispersion followed simple equilibrium reactions. The resulting dose-response curves allowed for the determination of the effective concentration for half-maximal pigment dispersion (EC50) or half-maximal inhibition of bombesin-stimulated pigment dispersion (IC50) for the peptides. As the pigment dispersion assay can rapidly evaluate chemicals for their effects on receptors that activate phospholipase C via a functional assay, it has potential utility for investigations of ligand-receptor interactions and for massive drug screening.
Animals↗
A new tool for investigating G protein-coupled receptors.
Vertebrate olfactory receptors are members of the seven-transmembrane-domain G protein-coupled receptor family. They utilize intracellular signal transduction pathways which are activated by stimulation of odorant receptors and use the second messengers cAMP and/or inositol 1,4,5-trisphosphate and diacylglycerol. Studies of how odorants bind to and activate the receptors can be considered part of the more general problem of how chemicals interact with G protein-coupled receptors. This review describes the development of a new technique for assessing functional interactions between chemicals and these receptors in only minutes. Predicted uses of the system include structure-function analyses of both G protein-coupled receptors and their ligands, studies of receptor coupling to G proteins and cloning of cDNAs for these receptors.
Adenylyl Cyclases↗
Functional expression of recombinant G-protein-coupled receptors monitored by video imaging of pigment movement in melanophores.
Xenopus laevis melanophores are capable of functionally expressing recombinant receptors which couple via G-proteins to adenylate cyclase or phospholipase C (PLC). Receptor-mediated stimulation of either of these enzymes causes dispersion of melanosomes while receptor stimulation leading to inhibition of adenylate cyclase induces their aggregation. Translocation of melanosomes within thousands of individual pigment cells was simultaneously tracked by capturing gray scale video images before and after receptor activation. Digital subtraction of poststimulation from prestimulation images was performed on a microcomputer, generating bitplane images containing pixels with nonzero gray scale values wherever melanosome movement had occurred. Movement in both centripetal and centrifugal directions was detectable. The assay was tested using four receptors: a human beta 2-adrenergic receptor which stimulates adenylate cyclase, murine substance P and bombesin receptors which stimulate PLC, and a human D2 dopamine receptor which inhibits adenylate cyclase. Based on melanosome translocation following application of ligands, expression of functional receptors could be consistently detected in melanophores which received only single copies of a plasmid encoding any of the four receptors. By imaging fields containing up to 11,000 melanophores, the presence of a plasmid coding for a receptor could be detected when its frequency was one per 10,000 plasmids transfected. Combining receptor-mediated pigment translocation in melanophores with the rapid data-handling ability of video technology should provide a bioassay useful for investigating the function of G-protein-coupled receptors and for screening cDNA libraries for clones encoding new receptors.
Animals↗
A method for evaluating the effects of ligands upon Gs protein-coupled receptors using a recombinant melanophore-based bioassay.
As an increasing number of medically important receptors that couple to stimulatory guanine nucleotide (Gs) proteins are isolated and cloned, there is an equally escalating need for methods to rapidly and reproducibly evaluate potential ligands for their properties as agonists or antagonists. Recently, a bioassay that can quickly and accurately determine the effects of numerous chemicals on a beta 1-like adrenergic receptor (AR) endogenous to melanophores derived from Xenopus laevis was developed. Here, the general utility of the melanophore-based pigment dispersion assay is demonstrated by employing it to evaluate the effects of drugs on a human beta 2 AR. Melanophores were both transiently and stably transfected with a plasmid encoding a beta 2 AR. Stimulation of recombinant cells expressing the beta 2 AR, but not wild-type cells, with beta 2-selective agonists induced pigment dispersion and concomitant elevations in intracellular cAMP. Using a microtiter plate reader, it was straightforward to construct reproducible dose-response curves and rapidly determine rank-order potency and EC50 and IC50 values for agonists and antagonists, respectively. The demonstration of functional expression of a human beta 2 AR in the melanophore-based bioassay suggests that the system may be used for the rapid pharmacological characterization of ligands upon any specific Gs-linked receptor for which a cDNA clone is available.
Animals↗
Structures of zinc(II) with tetradentate N2S2 ligation.
trans-3,3'-(1,2-Cyclohexanediyldinitrilo)-bis(2-methylpropane++ +-2-thiolato )]zinc(II), [Zn(C14H28-N2S2)], Zn(2), Mr = 353.89, monoclinic, C2/c, a = 17.914 (4), b = 9.440 (1), c = 10.877 (2) A, beta = 110.19 (2)degrees, V = 1726 (1) A3, Z = 4, Dm = 1.35 (1), Dx = 1.360 Mg m-3, mu(Mo K alpha, lambda = 0.71073 A) = 0.17 mm-1, F(000) = 752, T = 298 (1) K, RF = 0.026, wRF = 0.037 for 1290 reflections. 3,3'-(1,2-Cyclohexa-1,4- dienediyldinitrilo)bis(2-methylpropane-2-thiolato)] zin c(II), [Zn(C14H24N2S2)], Zn(3), Mr = 349.86, monoclinic, P2(1)/c, a = 9.760 (2), b = 17.326 (3), c = 10.530 (2) A, beta 91.49 (2)degrees, V = 1780 (1) A3, Z = 4, Dm = 1.31 (1), Dx = 1.305 Mg m-3, mu(Mo K alpha, lambda = 0.71073 A) = 0.16 mm-1, F(000) = 736, T = 297 (1) K, RF = 0.050, wRF = 0.062 for 1723 reflections. The structures consist of discrete complexes with distorted-tetrahedral ZnS2(thiolate)N2(amine) coordination geometries. Zn--S [2.2533 (6) A for Zn(2); 2.259 (1), 2.253 (1) A for Zn(3)] and Zn--N [2.101 (2) A for Zn(2); 2.088 (4), 2.128 (4) A for Zn(3)] distances are close to those reported for similar structures with bidentate N(amine)S(thiolate) ligands. The N,S chelate rings in both structures exhibit the envelope conformation with the tetrasubstituted C atoms comprising the flaps. In Zn(3), the central N,N chelate ring adopts the envelope conformation, while in Zn(2), the corresponding ring is gauche.(ABSTRACT TRUNCATED AT 250 WORDS)
Chemical Phenomena↗
A rapid quantitative bioassay for evaluating the effects of ligands upon receptors that modulate cAMP levels in a melanophore cell line.
A new method for rapidly evaluating the effects of drugs on receptors that regulate intracellular cAMP in a cell line derived from Xenopus laevis melanophores has been developed. Melanophores were plated into sterile 96 well microtiter plates, and 3 days later the cells were treated with melatonin for 30 min to induce melanosome aggregation. Subsequent exposure to MSH or adrenergic agonists caused dose dependent pigment dispersion that peaked within 30 min. The cumulative pigment displacement from cells could be quantitated by using a microplate reader to measure changes in transmittance of light through the wells. The acquired data enabled detailed and reproducible dose response curves and time course analyses to be generated. In addition, the assay followed for the rapid characterization of the effects of antagonists upon the beta adrenergic receptor (beta AR). The assay has the potential to test the effects of ligands upon any receptor capable of mediating pigment translocation in the melanophore cell line.
Animals↗