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  1. #161
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    Quote Originally Posted by bben View Post
    Your right!
    Traditional antipsychotics are the chemical equivalent of a frontal lobotomy.

    They do nothing for the negs, so for someone that rarely ever gets the positives, what's the use? Already sluggish, why add more slug to the sluggish?
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  2. #162
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    alpha(7) Nicotinic acetylcholine receptor activati... [Neuropharmacology. 2009 May-Jun] - PubMed result

    "Here we demonstrate that acute administration of the selective alpha(7) nAChR partial agonist SSR180711 dose-dependently reversed the behavioral impairment induced by PCP."

    I think this should be a potential candidate for the new antipsychotic with mglur agonism.
    Last edited by Psych0; June 5th, 2011 at 09:50 AM.

  3. #163
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    Fluvoxamine as a sigma-1 receptor agonist improved cognitive impairments in a patient with schizophrenia.
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  4. #164
    Senior Member MeDieViL's Avatar
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    Quote Originally Posted by Psych0 View Post
    Fluvoxamine as a sigma-1 receptor agonist improved cognitive impairments in a patient with schizophrenia.
    Damn, antipsychotics and then that shit added to it too, poor fella's. I do admit that mood blunting might make them not care about having tardive dyskinesia.
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  5. #165
    Senior Member MeDieViL's Avatar
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    Quote Originally Posted by Psych0 View Post
    alpha(7) Nicotinic acetylcholine receptor activati... [Neuropharmacology. 2009 May-Jun] - PubMed result

    "Here we demonstrate that acute administration of the selective alpha(7) nAChR partial agonist SSR180711 dose-dependently reversed the behavioral impairment induced by PCP."

    I think this should be a potential candidate for the new antipsychotic with mglur agonism.
    Schizophrenia and the alpha7 Nicotinic Acetylcholine Receptor.


    LF Martin, R Freedman

    In addition to the devastating symptoms of psychosis, many people with schizophrenia also suffer from cognitive impairment. These cognitive symptoms lead to marked dysfunction and can impact employability, treatment adherence, and social skills. Deficits in P50 auditory gating are associated with attentional impairment and may contribute to cognitive symptoms and perceptual disturbances. This nicotinic cholinergic-mediated inhibitory process represents a potential new target for therapeutic intervention in schizophrenia. This chapter will review evidence implicating the nicotinic cholinergic, and specifically, the alpha7 nicotinic receptor system in the pathology of schizophrenia. Impaired auditory sensory gating has been linked to the alpha7 nicotinic receptor gene on the chromosome 15q14 locus. A majority of persons with schizophrenia are heavy smokers. Although nicotine can acutely reverse diminished auditory sensory gating in people with schizophrenia, this effect is lost on a chronic basis due to receptor desensitization. The alpha7 nicotinic agonist 3-(2,4 dimethoxy)benzylidene-anabaseine (DMXBA) can also enhance auditory sensory gating in animal models. DMXBA is well tolerated in humans and a new study in persons with schizophrenia has found that DMXBA enhances both P50 auditory gating and cognition. alpha7 Nicotinic acetylcholine receptor agonists appear to be viable candidates for the treatment of cognitive disturbances in schizophrenia.
    Psychiatry Res. 2011 May 31. [Epub ahead of print]
    Varenicline prevents affective and cognitive exacerbation during smoking abstinence in male patients with schizophrenia.
    Liu ME, Tsai SJ, Jeang SY, Peng SL, Wu SL, Chen MC, Tsai YL, Yang ST.
    Source
    Department of Psychiatry, Long Cyuan Veterans Hospital, Pingtung, Taiwan.
    Abstract
    To explore the effects of varenicline on the psychopathology and cognition of chronic inpatients with schizophrenia, we conducted a non-randomized control group time series investigation between March 2009 and April 2010. In a mandatory smoking cessation intervention, 41 male inpatient smokers were scheduled to undergo either a five-week varenicline treatment (varenicline group) or the use of no drugs (non-treatment group). Depression (HAM-D), anxiety (HAM-A), and psychosis (PANSS) were evaluated at baseline, and at the 2nd, 4th, 8th and 12th week after abstinence; four neuropsychological tests, including Digit Span Forward and Backward (DSF and DSB), and Trail Making Test-A and -B, were evaluated at baseline and at the 4th, 8th and 12th week. .Thirty patients completed the study. Among 15 patients in the non-treatment group, the HAM-D, HAM-A, DSF, and DSB scores were exacerbated during the 2-8weeks of abstinence, but there were no changes in psychotic symptoms and the other two neuropsychological tests. Compared with the non-treatment group, varenicline users experienced less impairment in HAM-D and HAM-A scores at the 2nd and 4th weeks, and in DSF tasks at the 4th week after abstinence. In conclusions, varenicline can attenuate abstinence-induced adverse outcomes and appears to be well-tolerated in smokers with schizophrenia.

    Copyright © 2011 Elsevier Ltd. All rights reserved.
    Neuropsychopharmacology. 2011 Jun;36(7):1366-74. Epub 2011 Mar 2.
    Selective α(4)β(2) Nicotinic Acetylcholine Receptor Agonists Target Epigenetic Mechanisms in Cortical GABAergic Neurons.
    Maloku E, Kadriu B, Zhubi A, Dong E, Pibiri F, Satta R, Guidotti A.
    Source
    The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
    Abstract
    Nicotine improves cognitive performance and attention in both experimental animals and in human subjects, including patients affected by neuropsychiatric disorders. However, the specific molecular mechanisms underlying nicotine-induced behavioral changes remain unclear. We have recently shown in mice that repeated injections of nicotine, which achieve plasma concentrations comparable to those reported in high cigarette smokers, result in an epigenetically induced increase of glutamic acid decarboxylase 67 (GAD(67)) expression. Here we explored the impact of synthetic α(4)β(2) and α(7) nAChR agonists on GABAergic epigenetic parameters. Varenicline (VAR), a high-affinity partial agonist at α(4)β(2) and a lower affinity full agonist at α(7) neuronal nAChR, injected in doses of 1-5 mg/kg/s.c. twice daily for 5 days, elicited a 30-40% decrease of cortical DNA methyltransferase (DNMT)1 mRNA and an increased expression of GAD(67) mRNA and protein. This upregulation of GAD(67) was abolished by the nAChR antagonist mecamylamine. Furthermore, the level of MeCP(2) binding to GAD(67) promoters was significantly reduced following VAR administration. This effect was abolished when VAR was administered with mecamylamine. Similar effects on cortical DNMT1 and GAD(67) expression were obtained after administration of A-85380, an agonist that binds to α(4)β(2) but has negligible affinity for α(3)β(4) or α(7) subtypes containing nAChR. In contrast, PNU-282987, an agonist of the homomeric α(7) nAChR, failed to decrease cortical DNMT1 mRNA or to induce GAD(67) expression. The present study suggests that the α(4)β(2) nAChR agonists may be better suited to control the epigenetic alterations of GABAergic neurons in schizophrenia than the α(7) nAChR agonists.
    Partional agonists? might as well go ride on your bike instead of your car, here's the real shit
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  6. #166
    Senior Member MeDieViL's Avatar
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    J Neuropsychiatry Clin Neurosci. 2009 Winter;21(1):102-3.
    Successful smoking cessation and improvement of negative symptoms with varenicline in a stable schizophrenia patient.
    Anghelescu I.
    Schizophr Res. 2009 May;110(1-3):149-55. Epub 2009 Feb 28.
    Cognitive and antismoking effects of varenicline in patients with schizophrenia or schizoaffective disorder.
    Smith RC, Lindenmayer JP, Davis JM, Cornwell J, Noth K, Gupta S, Sershen H, Lajtha A.
    Source
    Department of Psychiatry, New York University Medical School, NY 11557-0316, United States. robert.smith@med.nyu.edu
    Abstract
    OBJECTIVE:
    Varenicline has been shown to be an effective anti-smoking treatment in smokers without identified psychiatric illness, and the drug's pharmacology suggests possibilities of pro-cognitive effects. However, recent reports suggest varenicline may have the potential for important psychiatric side-effects in some people. We present the first prospective quantitative data on the effects of varenicline on cognitive function, cigarette smoking, and psychopathology in a small sample of schizophrenic patients.

    METHOD:
    Fourteen schizophrenic smokers were enrolled in an open-label study of varenicline with a pre-post design. Measures of cognitive function (RBANS, Virtual Water-Maze Task), cigarette smoking (cotinine levels, CO levels, self-reported smoking and smoking urges), and psychopathology (PANSS) were evaluated prior to and during treatment with varenicline. Data on psychopathology changes among schizophrenic smokers in another drug study, in which patients were not receiving varenicline, were used for comparison.

    RESULTS:
    12 patients completed the study, and 2 patients terminated in the first two weeks of active varenicline because of complaints of nausea or shaking. Varenicline produced significant improvements in some cognitive test scores, primarily associated with verbal learning and memory, but not in scores on visual-spatial learning or memory, or attention. Varenicline significantly decreased all indices of smoking, but did not produce complete smoking abstinence in most patients. During treatment with varenicline there were no significant increases in psychopathology scores and no patient developed signs of clinical depression or suicidal ideation.

    CONCLUSIONS:
    Our small prospective study suggests that treatment with varenicline appears to have some beneficial cognitive effects which need to be confirmed in larger studies with additional neuropsychological tests. Varenicline appears to have some anti-smoking efficacy in schizophrenia but longer studies are needed to determine whether it will produce rates of smoking abstinence similar to those found in control smokers. Treatment with varenicline may not increase psychopathology or depression in most patients with schizophrenia, but we cannot accurately estimate the absolute risk of a potentially rare side-effect from this small sample.
    Psychiatry Res. 2010 Jan 30;175(1-2):179-80. Epub 2009 Dec 2.
    Varenicline and P50 auditory gating in medicated schizophrenic patients: a pilot study.
    Waldo MC, Woodward L, Adler LE.
    Source
    The Denver VAMC VISN19/MIRECC and UC Denver, School of Medicine, Department of Psychiatry, CO 80220, USA. merilyne.waldo@va.gov
    Abstract
    Most schizophrenic patients have a deficit in auditory sensory gating that appears to be mediated by the alpha-7 nicotinic receptor. This pilot study examines the effects of varenicline, an alpha-7 agonist, on the P50 auditory evoked potential in six schizophrenic patients. The study was canceled because of concerning side effects consistent with those reported by the FDA. However, in this small group of subjects, varenicline did not consistently enhance P50 auditory gating.
    J Psychiatry Neurosci. 2009 May;34(3):E1-2.
    Treatment of comorbid tobacco use in people with serious mental illness.
    Lising-Enriquez K, George TP.
    Source
    Am J Psychiatry. 2007 Aug;164(8):1269.
    Exacerbation of schizophrenia by varenicline.
    Freedman R.
    (bben assuming he is shizo, just kidding bro
    Biochem Pharmacol. 2007 Oct 15;74(8):1092-101. Epub 2007 Jun 26.
    Neuronal nicotinic receptors: a perspective on two decades of drug discovery research.
    Arneric SP, Holladay M, Williams M.
    Source
    Neuromed Pharmaceuticals, Vancouver, BC, Canada. sarneric@neuromed.com
    Abstract
    Neuronal nicotinic acetylcholine receptors (nAChRs) have been a target for drug discovery efforts, primarily for CNS indications, for the past two decades. While nicotine and related natural products have been used for smoking cessation in various formulations (e.g., gum, spray, patches), it was only in 2006 with the launch of varenicline (Chantix) by Pfizer for smoking cessation that a new chemical entity (NCE) originating from a rational medicinal chemistry effort targeting neuronal AChRs was approved. The current overview outlines the chronology of drug discovery efforts in nAChRs from the cloning of the receptor family in the 1980s, to initial research efforts at SIBIA, R.J. Reynolds and Abbott, to the current industry-wide interest in nAChR agonists as novel therapeutics for pain, schizophrenia and Alzheimer's Disease. Key events in the evolution of the nAChR field were the development of high throughput electrophysiological screening tools that provided the means to enable lead optimization efforts in medicinal chemistry and the discovery by John Daly at the NIH of the frog alkaloid, epibatidine, that provided the framework for the discovery of ABT-594, an alpha4beta2 agonist that is 200 times more potent than morphine as an analgesic. Over the next decade, it is anticipated that additional NCEs including antagonists and allosteric modulators (both positive and negative), interacting with various nAChR subtypes, will be advanced to the clinic in areas of high unmet medical need, e.g., pain, neurodegeneration, to provide novel medications with improved efficacy.
    And here comes the good shit
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  7. #167
    Senior Member MeDieViL's Avatar
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    Up-regulation of human alpha7 nicotinic receptors by chronic treatment with activator and antagonist ligands.
    Molinari EJ, Delbono O, Messi ML, Renganathan M, Arneric SP, Sullivan JP, Gopalakrishnan M.
    Source
    Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064-3500, USA.
    Abstract
    This study examined the binding and functional properties of human alpha7 neuronal nicotinic acetylcholine receptors stably expressed in human embryonic kidney (HEK) 293 cells following chronic treatment with nicotinic receptor ligands. Treatment of cells with (-)-nicotine (100 microM) for 120 h increased the Bmax values of [125I]alpha-bungarotoxin binding 2.5-fold over untreated cells. This effect was concentration-dependent (EC50) = 970 microM) and a 6-fold upregulation was observed with the maximal concentration of (-)-nicotine tested. Also, treatment of cells with ligands of varying intrinsic activities including (+/-)-epibatidine, (2,4)-dimethoxybenzylidene anabaseine (GTS-21) and 1,1-dimethyl-4-phenyl piperazinium iodide (DMPP) also upregulated [125I]alpha-bungarotoxin binding. A concentration-dependent upregulation of binding sites was also observed following treatment with the alpha7 nicotinic receptor antagonist, methyllycaconitine (EC50 = 92 microM) with a maximal upregulation of about 7-fold. Functionally, the peak amplitude of the whole-cell currents recorded by fast application of (-)-nicotine after chronic treatment of cells with concentrations of (-)-nicotine (1000 microM) or methyllycaconitine (10 microM) that elicited similar increases in binding levels (3.5-fold) resulted in increases of 2-fold (505 +/- 21 pA) and 6-fold (1820 +/- 137 pA) respectively in whole cell current amplitude compared to untreated cells (267 +/- 24 pA). These studies clearly demonstrate that long-term exposure to both activator and antagonist ligands can increase the density of alpha7 nicotinic receptors and can differentially enhance nicotinic receptor function.
    Nicotine-induced upregulation of human neuronal nicotinic alpha7-receptors is potentiated


    S Nuutinen, E Ekokoski, E Lahdensuo, RK Tuominen

    Chronic nicotine exposure induces upregulation of nicotinic receptors, but the mechanisms underlying this phenomenon are not well understood. The aim of this study was to examine the role of different second messenger systems in the nicotine-induced upregulation of alpha7-nicotinic receptors in SH-EP1-halpha7 human epithelial cells. We show here that chronic exposure to nicotine results in accumulation of cAMP. Furthermore, an enhanced cAMP signalling potentiates nicotine-induced upregulation of alpha7-nicotinic receptors measured by [(3)H]methyllycaconitine ([(3)H]MLA) binding suggesting that cAMP is involved in the alpha7-nicotinic receptor upregulation. Down-regulation of protein kinase C (PKC) with a phorbol ester abolishes the nicotine-induced upregulation of alpha7-nicotinic receptors. Furthermore, overexpression of PKCalpha in SH-EP1-halpha7 cells results in potentiation of nicotine-evoked upregulation indicating that PKC has a role in regulation of alpha7-nicotinic receptor number. The Ca(2+)-calmodulin kinase II (CaMKII) and extracellular signal regulated kinase 1/2 (ERK1/2) appear not to participate in alpha7-nicotinic receptor upregulation since the specific inhibitors of these kinases did not have an effect on the nicotine-induced upregulation. Taken together this study provides evidence that nicotine induces accumulation of cAMP and that the upregulation mechanisms of alpha7-nicotinic receptors are potentiated both by cAMP and PKC. As nicotine-evoked upregulation of heteromeric nicotinic receptors in SH-SY5Y cells was unaffected by the treatment with drugs affecting cAMP signalling or PKC activity, our results suggest that
    Mol Pharmacol. 2010 Aug;78(2):287-96. Epub 2010 May 3.
    A comparative study of the effects of the intravenous self-administration or subcutaneous minipump infusion of nicotine on the expression of brain neuronal nicotinic receptor subtypes.
    Moretti M, Mugnaini M, Tessari M, Zoli M, Gaimarri A, Manfredi I, Pistillo F, Clementi F, Gotti C.
    Source
    Consiglio Nazionale delle Ricerche, Neuroscience Institute-Milano, Cellular and Molecular Pharmacology, Department of Medical Pharmacology, University of Milan, Milan, Italy.
    Abstract
    Long-term nicotine exposure changes neuronal acetylcholine nicotinic receptor (nAChR) subtype expression in the brains of smokers and experimental animals. The aim of this study was to investigate nicotine-induced changes in nAChR expression in two models commonly used to describe the effects of nicotine in animals: operant (two-lever presses) intravenous self-administration (SA) and passive subcutaneous nicotine administration via an osmotic minipump (MP). In the MP group, alpha4beta2 nAChRs were up-regulated in all brain regions, alpha6beta2* nAChRs were down-regulated in the nucleus accumbens (NAc) and caudate-putamen, and alpha7 nAChRs were up-regulated in the caudal cerebral cortex (CCx); the up-regulation of alpha4beta2alpha5 nAChRs in the CCx was also suggested. In the SA group, alpha4beta2 up-regulation was lower and limited to the CCx and NAc; there were no detectable changes in alpha6beta2* or alpha7 nACRs. In the CCx of the MP rats, there was a close correlation between the increase in alpha4beta2 binding and alpha4 and beta2 subunit levels measured by means of Western blotting, demonstrating that the up-regulation was due to an increase in alpha4beta2 proteins. Western blotting also showed that the increase in the beta2 subunit exceeded that of the alpha4 subunit, suggesting that a change in alpha4beta2 stoichiometry may occur in vivo as has been shown in vitro. These results show that nicotine has an area-specific effect on receptor subtypes, regardless of its administration route, but the effect is quantitatively greater in the case of MP administration.
    .... 5 characters more as per requist
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  8. #168
    Senior Member MeDieViL's Avatar
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    Toxicol Appl Pharmacol. 2010 May 1;244(3):344-53. Epub 2010 Feb 2.
    The effects of 3,4-methylenedioxymethamphetamine (MDMA) on nicotinic receptors: intracellular calcium increase, calpain/caspase 3 activation, and functional upregulation.
    Garcia-Ratés S, Camarasa J, Sánchez-García AI, Gandía L, Escubedo E, Pubill D.
    Source
    Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Nucli Universitari de Pedralbes, Universitat de Barcelona, Institut de Biomedicina de la UB (IBUB), Av. Joan XXIII s/n, 08028 Barcelona, Spain.
    Abstract
    Previous work by our group demonstrated that homomeric alpha7 nicotinic acetylcholine receptors (nAChR) play a role in the neurotoxicity induced by 3,4-methylenedioxymethamphetamine (MDMA), as well as the binding affinity of this drug to these receptors. Here we studied the effect of MDMA on the activation of nAChR subtypes, the consequent calcium mobilization, and calpain/caspase 3 activation because prolonged Ca(2+) increase could contribute to cytotoxicity. As techniques, we used fluorimetry in Fluo-4-loaded PC12 cells and electrophysiology in Xenopus oocytes. MDMA produced a rapid and sustained increase in calcium without reaching the maximum effect induced by ACh. It also concentration-dependently inhibited the response induced by ACh, nicotine, and the specific alpha7 agonist PNU 282987 with IC(50) values in the low micromolar range. Similarly, MDMA induced inward currents in Xenopus oocytes transfected with human alpha7 but not with alpha4beta2 nAChR and inhibited ACh-induced currents in both receptors in a concentration-dependent manner. The calcium response was inhibited by methyllycaconitine (MLA) and alpha-bungarotoxin but not by dihydro-beta-erythroidine. These results therefore indicate that MDMA acts as a partial agonist on alpha7 nAChRs and as an antagonist on the heteromeric subtypes. Subsequently, calcium-induced Ca(2+) release from the endoplasmic reticulum and entry through voltage-operated calcium channels are also implicated as proved using specific antagonists. In addition, treatment with MDMA for 24 h significantly increased basal Ca(2+) levels and induced an increase in alpha-spectrin breakdown products, which indicates that calpain and caspase 3 were activated. These effects were inhibited by pretreatment with MLA. Moreover, pretreatment with MDMA induced functional upregulation of calcium responses to specific agonists of both heteromeric and alpha7 nAChR. Sustained calcium entry and calpain activation could favor the activation of Ca(2+)-dependent enzymes such as protein kinase C and nitric oxide synthase, which are involved in the generation of ROS and the blockade of the dopamine transporter. This, together with caspase 3 activation, must play a role in MDMA-induced cytotoxicity.
    BBEN come take a look.

    Psychopharmacology (Berl). 2010 Jan;208(1):143-58. Epub 2009 Nov 21.
    Tobacco smoke exposure induces nicotine dependence in rats.
    Small E, Shah HP, Davenport JJ, Geier JE, Yavarovich KR, Yamada H, Sabarinath SN, Derendorf H, Pauly JR, Gold MS, Bruijnzeel AW.
    Source
    Department of Psychiatry, College of Medicine, McKnight Brain Institute, University of Florida, 100 S. Newell Dr., PO Box 100256, Gainesville, FL 32610, USA.
    Abstract
    RATIONALE:
    Tobacco smoke contains nicotine and many other compounds that act in concert on the brain reward system. Therefore, animal models are needed that allow the investigation of chronic exposure to the full spectrum of tobacco smoke constituents.

    OBJECTIVES:
    The aim of these studies was to investigate if exposure to tobacco smoke leads to nicotine dependence in rats.

    METHODS:
    The intracranial self-stimulation procedure was used to assess the negative affective aspects of nicotine withdrawal. Somatic signs were recorded from a checklist of nicotine abstinence signs. Nicotine self-administration sessions were conducted to investigate if tobacco smoke exposure affects the motivation to self-administer nicotine. Nicotinic receptor autoradiography was used to investigate if exposure to tobacco smoke affects central alpha7 nicotinic acetylcholine receptor (nAChR) and non-alpha7 nAChR levels (primarily alpha4beta2 nAChRs).

    RESULTS:
    The nAChR antagonist mecamylamine dose-dependently elevated the brain reward thresholds of the rats exposed to tobacco smoke and did not affect the brain reward thresholds of the untreated control rats. Furthermore, mecamylamine induced more somatic withdrawal signs in the smoke-exposed rats than in the control rats. Nicotine self-administration was decreased 1 day after the last tobacco smoke exposure sessions and was returned to control levels 5 days later. Tobacco smoke exposure increased the alpha7 nAChR density in the CA2/3 area and the stratum oriens and increased the non-alpha7 nAChR density in the dentate gyrus.

    CONCLUSION:
    Tobacco smoke exposure leads to nicotine dependence as indicated by precipitated affective and somatic withdrawal signs and induces an upregulation of nAChRs in the hippocampus.
    ALPHA7 upregulation synergy with our above buddy? altough i found study's with a differend conclusion, my stimulant stopped working so someone on amp needs to go trough this clutter (if my stim works im with the girlfriend).
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  9. #169
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    Quote Originally Posted by MeDieViL View Post
    Damn, antipsychotics and then that shit added to it too, poor fella's. I do admit that mood blunting might make them not care about having tardive dyskinesia.
    eheh no, that was just an example how sigma1 agonism can modulate NMDA receptors. sigma1 agonist (E-5842) are in phase II as new antipsychotics too.

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    Senior Member MeDieViL's Avatar
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    In no time wed need to take ketamine to get shizo, cant get any more absurd.
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  11. #171
    Senior Member MeDieViL's Avatar
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    Quote Originally Posted by Psych0 View Post
    eheh no, that was just an example how sigma1 agonism can modulate NMDA receptors. sigma1 agonist (E-5842) are in phase II as new antipsychotics too.
    Nicotine
    Nac
    Varenicline
    Pregnenolone
    Curcumin
    Sigma1 agonist (ton of pharmaceuticals are)

    And we have got a potent anti psychotic stack allready, what do you guys think?
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    Quote Originally Posted by MeDieViL View Post
    Nicotine
    Nac
    Varenicline
    Pregnenolone
    Curcumin
    Sigma1 agonist (ton of pharmaceuticals are)

    And we have got a potent anti psychotic stack allready, what do you guys think?
    I think thats pretty solid. I would add in EPA omega 3 fish oil as well. It has good clinical evidence behind it as possessing antipsychotic activity.

  13. #173
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    also sarcosine, galantamine, cdp-choline, piracetam
    Last edited by Psych0; June 20th, 2011 at 11:09 AM.

  14. #174
    Senior Member MeDieViL's Avatar
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    J Clin Psychopharmacol. 2011 Feb;31(1):86-91.
    Effects of the cannabinoid-1 receptor antagonist rimonabant on psychiatric symptoms in overweight people with schizophrenia: a randomized, double-blind, pilot study.
    Kelly DL, Gorelick DA, Conley RR, Boggs DL, Linthicum J, Liu F, Feldman S, Ball MP, Wehring HJ, McMahon RP, Huestis MA, Heishman SJ, Warren KR, Buchanan RW.
    Source
    Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD 21228, USA. dkelly@mprc.umaryland.edu
    Abstract
    Weight gain is a major adverse effect of several second-generation antipsychotic medications. Rimonabant is a cannabinoid-1 receptor antagonist that promotes weight loss in the general population. We conducted a 16-week, double-blind, placebo-controlled study of rimonabant (20 mg/d) in people with schizophrenia or schizoaffective disorder, based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria, who were clinically stable on second-generation antipsychotics. Participants had a body mass index of 27 kg/m or higher with hyperlipidemia or body mass index of 30 kg/m or higher, and no current substance abuse/dependence (except nicotine), more than weekly cannabis use, or recent depressive symptoms/suicidality. An exercise and dietary counseling group was offered weekly. Target enrollment was 60; the trial was terminated early because of withdrawal of rimonabant from the European market. Fifteen participants were randomized (7 rimonabant, 8 placebo); 5 completed in each group. Rimonabant was associated with a greater reduction in Brief Psychiatric Rating Scale total score versus placebo (mean ± SE difference, -1.9 ± 0.8, P = 0.02), driven by differences in the Brief Psychiatric Rating Scale anxiety/depression (-1.4 ± 0.35, P = 0.0004) and hostility (-0.7 ± 0.3, P = 0.02) factors. Group differences were not significant for the Calgary Depression Scale total score (P = 0.24), Scale for the Assessment of Negative Symptoms total score (P = 0.13), weight, blood pressure, or fasting lipids or glucose. Rimonabant was well tolerated with no significant adverse events. No significant weight loss, metabolic effects, or adverse psychiatric effects were associated with the cannabinoid-1 receptor antagonist rimonabant in this small sample of people with schizophrenia. The endocannabinoid system remains a promising target for pharmacotherapy of schizophrenia and obesity.
    Interesting, shizo's may be free of the reported psychiatric side effects. Riminabant does look like an interesting treatment option.
    One
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    Taurine activates primarily glycine receptors.

    http://www.ncbi.nlm.nih.gov/pmc/arti...00274-0137.pdf

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    Glutathione modulates the N-methyl-d-aspartate receptor-activated calcium influx into cultured rat cerebellar granule cells

    Abstract

    Aim: To characterize the effect of combined pre- and postnatal morphine exposure on N-methyl-D-aspartate receptor (NMDA) receptor signaling in hippocampal neurons of the offspring of morphine-addicted female rats. Methods: Cultured hippocampal neurons and synaptosomes were prepared from neonatal and 2- week-old offspring, respectively, of control or morphine-addicted female rats. The increase in the cytosolic Ca2+ concentration ([Ca2+]i) of cultured cells was measured using Fura-2, and glutamate release from synaptosomes was measured enzymatically. Results: Both glutamate and NMDA caused a dose-dependent increase in the [Ca2+]i. The nitric oxide (NO) donor, S-nitrosoglutathione (GSNO), but not 3-morpholinosydnonimine, sodium nitroprusside, and S-nitroso-N-acetylpenicillamine, also induced a [Ca2+]i increase. GSNO and glutathione caused a dose-dependent increase in the [Ca2+]i with respective EC50 values of 56 and 414 μmol/L. Both effects were inhibited by Mg2+ or an NMDA receptor antagonist and were unaffected by the presence of a glutamate scavenger. The other glutathione derivatives, oxidized glutathione, S-methylglutathione, S-ethylglutathione, S-propylglutathione, and S-butylglutathione, the dipeptides, Glu-Cys and Cys- Gly, and the antioxidants, dithiothreitol and mercaptoethanol, failed to induce a [Ca2+]i increase. In addition, glutathione caused a dose-dependent increase in glutamate release from synaptosomes. The maximal responses and the EC50 values for the glutamate-, NMDA-, GSNO-, and glutathione-induced [Ca2+]i increases and the glutathione-induced glutamate release were indistinguishable in the neurons of the offspring from control and morphine-addicted female rats. Conclusion: GSNO and glutathione act as NMDA receptor agonists and, in contrast to hippocampal brain slice, combined pre- and postnatal morphine exposure does not modulate NMDA receptor signaling in the cultured hippocampal neurons.

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    Quote Originally Posted by Psych0 View Post
    Glutathione modulates the N-methyl-d-aspartate receptor-activated calcium influx into cultured rat cerebellar granule cells

    Abstract

    Aim: To characterize the effect of combined pre- and postnatal morphine exposure on N-methyl-D-aspartate receptor (NMDA) receptor signaling in hippocampal neurons of the offspring of morphine-addicted female rats. Methods: Cultured hippocampal neurons and synaptosomes were prepared from neonatal and 2- week-old offspring, respectively, of control or morphine-addicted female rats. The increase in the cytosolic Ca2+ concentration ([Ca2+]i) of cultured cells was measured using Fura-2, and glutamate release from synaptosomes was measured enzymatically. Results: Both glutamate and NMDA caused a dose-dependent increase in the [Ca2+]i. The nitric oxide (NO) donor, S-nitrosoglutathione (GSNO), but not 3-morpholinosydnonimine, sodium nitroprusside, and S-nitroso-N-acetylpenicillamine, also induced a [Ca2+]i increase. GSNO and glutathione caused a dose-dependent increase in the [Ca2+]i with respective EC50 values of 56 and 414 μmol/L. Both effects were inhibited by Mg2+ or an NMDA receptor antagonist and were unaffected by the presence of a glutamate scavenger. The other glutathione derivatives, oxidized glutathione, S-methylglutathione, S-ethylglutathione, S-propylglutathione, and S-butylglutathione, the dipeptides, Glu-Cys and Cys- Gly, and the antioxidants, dithiothreitol and mercaptoethanol, failed to induce a [Ca2+]i increase. In addition, glutathione caused a dose-dependent increase in glutamate release from synaptosomes. The maximal responses and the EC50 values for the glutamate-, NMDA-, GSNO-, and glutathione-induced [Ca2+]i increases and the glutathione-induced glutamate release were indistinguishable in the neurons of the offspring from control and morphine-addicted female rats. Conclusion: GSNO and glutathione act as NMDA receptor agonists and, in contrast to hippocampal brain slice, combined pre- and postnatal morphine exposure does not modulate NMDA receptor signaling in the cultured hippocampal neurons.
    Glutathione as NMDA receptor agonist... a-ha!

    No wonder NAC has been really helpful at times for me... at maintaining beneficial 'reconnecting' amph effects for a longer duration (amph effects drop out wayyy too soon for me after dosing, leaving just a dopamine-awake state but no real 'integration' benefits like it does in the initial hour or so of dosing.... this also happens with PEA, but in that case it's followed by a really agitated 'disfocus' feeling after like 20 minutes that resembles a hyperdopaminergic state. It's always a matter of time, too, like the benefits always start out PERFECTLY, but just lose steam way too quickly.

    Thus (and based on a few other finds), I have lately started to suspect a great deal that some type of glutamatergic hypofunction might be behind this oddity of mine, which parallels towards all stimulation I feel in life (w/o supps). Even in terms of sexual 'response,' when supp-naive, I consistently lose the emotion-connectedness to the sensations I'm feeling... every time there is enough built-up (~dopaminergic!) activation. I've tried SARCOSINE, which (@2-7g) seems to provide a great initial benefit towards this, but even THAT is unfortunately not enough to effectively keep this supposed 'NMDA laziness' away for more than a few minutes at a time.


    Sorry to bump an old thread, but now that I'm at it -- any insight as to what might be more specifically implicated in my odd responses, given my assumptions towards glutamatergic function, etc. to narrow it down... would be very helpful!


    PS - What's the deal with having to take ascorbic with NAC, should I be worried about that realistically? I'm currently trying 600mg every 3 hours or so - really noticing benefit in "maintaining connection" for a short while, even in terms of reviving/maintaining amph's "attention/refocusing" effects for longer (making it a lot more like a normal expected duration)... but I was finding that when I'd supp ascorbic acid, the actual amph duration would be like... cut by 2/3'rds :/ probably from acidifying...(?) so I dunno if I can afford to keep doing that, heh.

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    .....

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    Quote Originally Posted by G4D View Post
    I've been looking for anecdotes instead of just theories regarding negative symptoms treatments, and it seems that people suffering from full-blown schizophrenia benefited most from:

    Extremely effective:
    - Minocycline.
    - Sarcosine.

    Moderately effective:
    - Clozapine.
    - Mirtazapine.
    - Pregnenolone.
    - L-methylfolate.
    - Tobacco.

    Mildly effective:
    - Panax Ginseng. (Mixed - probably due to different qualities used?)
    - Glycine. (Surprisingly mild - I think this may be due to very high doses needed?)
    - Resveratrol.
    - NAC.
    - Curcumin.
    - Racetams (Aniracetam, Nefiracetam, Pramiracetam).

    Notable mention:
    - Glutamine: Some people found it helpful for negatives, but followed by a crash characterized by increased positives. This also goes for my own anecdote - it made me paranoid as hell.

    It seems to me that we need not to look further than Minocycline and/or Sarcosine + NAC for negative symptoms, according to anecdotes anyway.
    Very nice - bump. Wish I could contribute more information or commentary on the above with regards to hypotheses etc., but don't want to confound anything since I don't have actual schizo-spectrum symptoms of the sort, and simply find benefit/response to things that properly modulate or re-regulate glutamatergic function in very specific areas (mPFC etc.).

    For instance, lately I've been running guanfacine (0.5mg QID) + memantine adjunct (5mg QID) - finding very good synergy and focus benefits while successfully undoing the NMDA antagonist's "excessive-DA release" issues that characteristically plague its otherwise very beneficial MOA. This has brought about a notable cognitive boost that's coupled with a calm bringing-out of emotional connectedness, empathy and potent anxiolysis, etc. -- however, it is just as likely not to be the case response for many or most people, as it is a personally tailored stack (through several years of on-and-off anecdotal mapping) that's set to address only my own perceived limitations and the stuff I'd like to improve or boost. Etc. etc. etc. - hence the point of this entire redundant post, heheh.. :P


    However, to add at least a bit of something to keep in mind: Any nutritional regimen should really ideally focus on allowing your body to heal itself properly - or just as importantly - allowing YOU to better learn/connect/utilize your mind and will-power to assist your body its naturally-programmed healing. Very many issues that people in our societies face today, including serious mental illnesses, do actually fall "under" this category, as cliche as it might sound. This is simply because the concept itself is actually that broad (but just as proportionately powerful).


    ............
    Best of luck with the continued research, folks. I'll stay tuned and chime in if ever I do have something I can chime in with or recall from studies/ides in relation to this thread. I want to help make an impact in the world in this sense -- at least through this avenue of forums/collective-gathering, there is some very good potential (though also a heavy responsibility for harm reduction!) to do so...

    Namaste,
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