mgrade Posted October 16, 2012 Report Share Posted October 16, 2012 Ketamine, Future Antidepressants, Cingulate Cortex http://www.ncbi.nlm....les/PMC3461985/ Schizophrenia and the Cingulate Cortex http://www.ncbi.nlm....les/PMC3458074/ Link to comment Share on other sites More sharing options...
mgrade Posted October 16, 2012 Report Share Posted October 16, 2012 This is a serious boatload of info pertaining to subcortical areas [Cingulate Cortex in particular] and how they relate to disorders with some similar symptoms to comorbid-disorders of HPPD [Try and get to the Full Text versions if you can, Thanks] ..[social Anxiety, Reward System, Mood Disorders, Depression, Schizophrenia, Alzheimer's, Autism, Hallucinogen Use, CREB etc.] http://www.ncbi.nlm....pubmed/23049496 http://www.ncbi.nlm....pubmed/23029036 http://www.ncbi.nlm....pubmed/23028606 http://www.ncbi.nlm....pubmed/23028560 http://www.ncbi.nlm....pubmed/23012487 http://www.ncbi.nlm....pubmed/22986643 http://www.ncbi.nlm....pubmed/22969714 http://www.ncbi.nlm....pubmed/22958533 http://www.ncbi.nlm....pubmed/22952843 http://www.ncbi.nlm....pubmed/22936906 http://www.ncbi.nlm....pubmed/22924012 http://www.ncbi.nlm....pubmed/22922661 http://www.ncbi.nlm....pubmed/22867433 http://www.ncbi.nlm....les/PMC3406317/ http://www.ncbi.nlm....pubmed/22808188 http://www.ncbi.nlm....pubmed/22822396 http://www.ncbi.nlm....pubmed/22832954 http://www.ncbi.nlm....pubmed/22848344 Link to comment Share on other sites More sharing options...
mgrade Posted October 16, 2012 Report Share Posted October 16, 2012 Is treatment-resistance in unipolar melancholic depression characterized by decreased serotonin2A receptors in the dorsal prefrontal – Anterior cingulate cortex? [2012] http://www.sciencedi...028390811003315 Link to comment Share on other sites More sharing options...
mgrade Posted October 16, 2012 Report Share Posted October 16, 2012 Chronic Phenethylamine Hallucinogen Treatment Alters Behavioral Sensitivity to a Metabotropic Glutamate 2/3 Receptor Agonist http://www.nature.co...l/1301600a.html Link to comment Share on other sites More sharing options...
mgrade Posted October 16, 2012 Report Share Posted October 16, 2012 ATP-receptor Agonists α,β-methylene-ATP 2MeSATP 2-methyl-thioATP Link to comment Share on other sites More sharing options...
mgrade Posted October 16, 2012 Report Share Posted October 16, 2012 Intracellular Ca2+ and Extracellular K+: is this what we are looking for? http://www.ncbi.nlm....2-methylene-ATP [edit: i think too, too much of this is not good (not sure)] Link to comment Share on other sites More sharing options...
mgrade Posted October 16, 2012 Report Share Posted October 16, 2012 Drug-Induced Psychosis and Endocannabinoid Receptors CB1: Possible Treatment: CB1 antagonism We have seen that a great deal of knowledge has accumulated concerning drug-induced psychoses over the last 50 years. However, the picture presenting in the clinic, as opposed to that seen in the experimental setting, has not been widely acknowledged as telling us much about schizophrenia itself. Perhaps the main reason for this is that when drug-induced psychoses were first identified, schizophrenia was considered a discrete disease with a likely single genetic cause. Consequently, drug-induced psychoses, even those phenomenologically very similar to schizophrenia, were seen as phenocopies rather than examples of the schizophrenia syndrome consequent upon the operation of a particular cause. However, now that schizophrenia is generally viewed as at the extreme end of a continuum of psychosis where the combined effect of genetic and environmental factors pushes the individual over a threshold into the expression of the disorder. In the light of this new knowledge it is time to re-appraise the drug-induced psychoses. Certainly the major pharmacological theories of schizophrenia have their origins in the effects of drugs of abuse; in chronological order, the effects of LSD initiated the serotonergic model; amphetamines the dopamine hypothesis, PCP, and ketamine the glutamatergic model. Most recently the effects of cannabis have provoked interest in the role of endocannabinoids. None of these models account for the complete picture of schizophrenia, but this is not to be expected if we regard the condition as one with multiple causes and consequent heterogeneity of the clinical picture. Rather the various drugs mimic different aspects of the disorder. Stimulants and THC are particularly likely to induce paranoia beliefs (Javitt and Zukin, 1990), whereas LSD is more closely associated with visual illusions/hallucinations (Smith et al.,2009). The non-competitive NMDA antagonists PCP and ketamine appear to induce negative symptoms, and oneroid states (characterized by perceptual illusions, perplexity, and delusional thinking in the context of clouding of consciousness; Gonzalez-Maeso and Sealfon, 2009). What is common between the different classes of drug is the promotion of a fundamental change in the subject's experience of reality, whether acutely, during drug intoxication (in the case of LSD, ketamine, and THC) or as a result of an adaptive process secondary to repeated use (stimulants and THC). How then is it possible to discriminate between drugs which distort the experience of reality in a way which closely corresponds to aspects of schizophrenia from those that do not? One approach is to postulate that if a drug-model pushes the CNS toward psychosis AND if it is also “true” that a diametrically opposing pharmacological manipulation pulls a schizophrenic psychosis back into reality, then the drug-model in question constitutes a reasonable model of schizophrenic-like psychosis. Some examples may illuminate this idea. Agonists at the 5HT receptor transform reality in a fundamental way; yet 5HT2 antagonists have no efficacy against schizophrenic psychosis (Zuardi, 2006). Similarly, NMDA channel blockers distort the experience of reality, yet, despite much effort and theoretical support, drugs which enhance NMDA channel opening have not yet been proven to be effective in schizophrenia. In contrast, opposing pharmacological manipulations at D2 receptors can elicit clear bi-directional responses at the psychological level. Drugs which drive D2-mediated signaling to excess have pro-psychotic properties AND D2 blockers are effective against schizophrenic psychosis. On this basis, one can infer that, at a neurochemical level, the DA model psychosis is more akin to reality-distortion in schizophrenia than are either the serotonergic or glutamatergic models. In recent years it has been suggested that excess dopamine synthesis and release in the striatum is the final, common arbiter of positive psychotic symptoms (Broome et al., 2005; Di Forti et al., 2007a; Murray et al., 2008) probably through a pathological dysfunction of the “reward” pathway (Strassman, 1984). Do all of the drugs which induce psychotic symptoms do so via their effects on the dopamine system? Certainly, as we have seen, an argument can be made that they all impact on the dopamine system either directly or indirectly. However, it is not clear that this effect accounts for their propensity to induce the characteristic positive symptoms of schizophrenia. Another caveat is that the dopamine model can probably no longer be considered in isolation from the emerging endocannabinoid model. Earlier we utilized the relatively simple concept of a D2→eCB→CB1 axis to describe the known physiological relations of the two neurochemical systems within the striatum (Kreitzer and Malenka, 2008). Notably, opposing pharmacological manipulations at CB1 receptors can also elicit bi-directional responses, either pro- or antipsychotic. Moreover, CB1 manipulations appear to be effective against dopamine D2 mediated psychoses. http://www.ncbi.nlm....les/PMC3024828/ mGlu5 forms a heterodimer with A2A [atp], which allows endocannabinoids to regulate their own levels, as they inhibit cAMP production, thus increase free adenosine to agonise A2A. This forms a feedback loop between the positive and negative metabotropic receptors, which will can maintain a relatively similar homeostasis with any neuron connected through an electrical synapse. Link to comment Share on other sites More sharing options...
mgrade Posted October 16, 2012 Report Share Posted October 16, 2012 Glutamate Model We know that hypofunctioning glutamate receptors are a contributing factor in developing schizophrenia.(Mechri, A 2001) Alterations in the expression, distribution, autoregulation,(Catapano, L Manji, H, 2006) prevalence of specific heterodimers,(Gonzales, 2012) and relative levels of G proteins, specifically lowered levels of the i isomorph,(F Odaka, T.J Crow, G.W Roberts) all can result in an altered NMDA function. The primary contributor to schizophrenia is a relative deficit of presynaptic glutamate receptors to the postsynaptic receptors. Specifically, group II is indicated in this disorder, given that mGlu2/3 agonists have been found useful in the treatment of both positive and negative symptoms. However, all regulatory neurotransmitters are involved, as every metabotropic receptor has potential to alter glutaminergic function.(Sugai, 2006) Specifically, 5-HT has an extraordinarily wide role in modulatory processes of the brain, as such, it is highly implicated in all CNS function. In addition, CB1 plays a global inhibitory role, serving to inhibit the release of all neurotransmitters. In addition, CB1 is one of the most widely distributed receptors in the brain, thus, downregulation of this receptor will increase global chemical synaptic activity. No difference in expression or distribution is observed, but when the CB1 receptor develops a tolerance, 2-AG(full) cannot exert its full inhibitory effects on GABA and glutamate release. A deficit in endocannobinoid metabolism, or excess catabolism, as well as heavy cannabis use, will deregulate global chemical transmission. This is the key in schizophrenia: the fact this deregulates glutamate carboxylase expression, which acts to downregulate reelin production, the crucial mediator of neurogenesis. Specifically, the reelin expressing cajal-retziu cells are of interest. These cells are a crucial component of corticocorical transmission, due to their long, nearly horizontal axons, multiple synapses, and consistent termination on spiny pyramidal neurons. These allow for interlayer communication over a wider area than those without, e.g. chimpanzees. This is the part of the neurological system which is most different, and the part of the genome which is most "accelerated" vs them. This would indicate that this is a necessary factor for the development of the so called speech centers of the brain, Wernickie's and Broca's areas. Also, a deficit in reelin activity is associated with cortical developmental retardation. These neurons also express 5-HT3 significantly, which is the only serotonergic ligand gated ion channel. Presynaptically, they act to regulate neurotransmitter release, mediating the frequency and strength of tonic firing in connected neurons. This is likely the mechanism through which they mediate long term potentiation. A deficit in this activity would alter plasticity significantly, contributing to the illnesses of bipolar disorder and schizophrenia. This deficit in activation also results in a decrease in activity of 5-HT1A receptors in the raphe nucleus.(Bantick, Deakin, Grasby 2001) This serves to increase global serotonin levels, as 5-HT1A serves as an autoreceptor The 5-HT1B receptor, also acting as an autoreceptor, specifically within the striatum, but also parts of basal ganglia then will inhibit serotonin release. This disinhibits frontal dopamine release. The local deficit of 5HT within the striatum, basal ganglia, and prefrontal cortexcauses a deficit of excitatory 5-HT6 signalling. This receptor is primarily GABAergic, as such, it causes an excess of glutamatergic, norepinephrinic, dopaminergic, and cholinergic activity within the prefrontal cortex and the striatum. An excess of 5-HT7 signaling within the thalamus also creates too much excitatory transmission to the prefrontal cortex. Combined with another critical abnormality observed in schizoid patients: 5-HT2A dysfunction, this altered signalling cascade creates cortical, thus cognitive abnormalities. 5-HT2A allows a link between cortical, thus conscious, and the basal ganglia,unconscious. Axons from 5-HT2A neurons in layer V of thecerebral cortex reach the basal ganglia, forming a feedback loop, allowing us to condition ourselves. Signalling from layer V of the cerebral cortex to the basal ganglia alters 5-HT2C signalling. This feedback loop with 5HT2C is how the outer cortex layers can exert some control over our neurochemicals, specifically oxytocin and vasopressin. This alteration in this limbic-layer five axis creates the profound change in social cognition, and sometimes cognition as a whole that is observed in schizoid patients. However, genesis of the actual alterations is a much more complex phenomena. [edit]The role of inhibitory transmission The cortico-striatal-thalamic loop, is the source of the ordered input necessary for a higher level upper cortical loop. Feedback is controlled by the inhibitory potential of the cortices. Through 5-HT2A efferents from layer V, transmission, processed, from layer III through the interneuron layer reaches the basal ganglia and brain stem. The core thalamic input to layer I is combined with the ordered matrix input to VI. A process happens with layer III/I and II/III efferents: these circuits are where our self/other perception, and the mechanisms for logic lie.(anteriorly) Also, it is how, through the entorhinal cortex, which almost completely lacks layer IV, can control orbitofrontal and thalamic output from the hippocampus, as well as (indirectly) provide a pathway for hippocampal communication to the other cortices. This is opposed by the frontal lobes, which have much larger granular areas, thus inhibitory potential,from input to the striatum. Another modulatory factor is the corpus callosum, providing a direct inhibitory connection, interhemispherical, to the cortical layer VI, thus indirectly to layer V. As such, the halves of the brain exert some control over basal input of the other side, but can only inhibit due to the GABAergic nature of the corpus callosum. The root of this control is an extraordinarily complex dihemispherical beat frequency in layer IV between layer V and layers II/III. One might say qualia happens here. How the other side can (indirectly) inhibit the 5-HT2A signal cascade, is crucial for the development of language. It requires highly structured left side structures allowing for the imagination of the formants, and the mouth movements that correspond to them. It also needs a more distributed, contextual, reality based side, to integrate the naturally nonsensical medium of language back to intuitive sensory/spatial analogies. Again, thalamic input from layer V is a cruical factor in the functionality of the human brain. It allows the two sides to receive similar inputs, thus be able to perceive the same world. In psychosis, thalamic input loses much of its integrated character: hyperactive core feedback loops overwhelm the ordered output. This is due to excessive D2 and 5-HT2A activity. This alteration in input to the top and bottom of the cortex. The altered 5-HT signal cascade enhances the strength of excitatory thalamic input from layer V. This abnormality, enhancing the thalamic-cortical transmission cascade versus the corticostriratal control, creates a feedback loop, resulting in abnormally strong basal ganglic output. The root of psychosis(experiences that cannot be explained, even within their own mind) is when basal ganglic input to layer V overwhelms the inhibitory potential of the higher cortexies resulting from striatal transmission. When combined with the excess prefrontal, specifically orbitofrontal transmission, from the hippocampus, this creates a brain prone to falling into self reinforcing belief. However, given a specific environment, a person with this kind of brain(a human) can create a self-reinforcing pattern of maladaptive behavior, from the altered the layer II/III and III/I axises, from the disinhibited thalamic output. Rationality is impaired, primarily as response to the deficit of oxytocin and excess of vasopressin from the abnormal 5HT2C activity. An altered HPA axis, perhaps from xenohormones, drug use, or a genetic predisposition to altered adregenic and norepineprine signalling. An altered HPA axis, in the direction of more activation and stress, is the primary pathological trait in all social disorders. Frontal cortex activity will be impaired, when combined with excess DA activity: the basis for the advancement of schizophrenia, but it is also the neurologic mechanism behind many other psychotic diseases as well. Only with a specific psychosocial perception of the world will a patient with a high risk of psychosis will develop it. Heredity of schizophrenia may even be a result of specific parenting techniques passed on though generations, and not just genetics. However, the genetic component is the primary source of the neurological abnormalities which leave one prone to psychological disorders. Specifically, there is much overlap between bipolar disorder and schizophrenia, and other psychotic disorders. They all are linked to prenatal trauma, excessive drug use, specifically dissociatives, psychedelics,stimulants, and marijuana, as well as abnormalities in receptor expression. The fact that reduced glutamate function is linked to poor performance on tests requiring frontal lobe and hippocampal function and that glutamate can affectdopamine function, all of which have been implicated in schizophrenia, have suggested an important mediating (and possibly causal) role of glutamate pathways in schizophrenia.[9] Further support of this theory has come from preliminary trials suggesting the efficacy of coagonists at the NMDA receptor complex in reducing some of the positive symptoms of schizophrenia.[10] Note that the specific mechanisms of this are yet to be elucidated, as it involves a complex interplay between 5-HT1A, 5-HT2A, 5-HT1B, 5-HT2C, 5-HT6, and 5-HT7, D2, D1, the endocannabinoid systsem, including CB2, which regulates glial cell NT release. Particular focus has been placed upon the function of dopamine in the mesolimbic pathway of the brain. This focus largely resulted from the accidental finding that a drug group which blocks dopamine function, known as the phenothiazines, could reduce psychotic symptoms. An influential theory, known as the "dopamine hypothesis of schizophrenia", proposes that a malfunction involving dopamine pathways is therefore the cause of (the positive symptoms of) schizophrenia. Evidence for this theory includes[13] findings that the potency of many antipsychotics is correlated with their affinity to dopamine D2 receptors;[14] and the exacerbatory effects of a dopamine agonist (amphetamine) and a dopamine beta hydroxylase inhibitor (disulfiram) on schizophrenia;[15][16] and post-mortem studies initially suggested increased density of dopamine D2 receptors in the striatum. Such high levels of D2 receptors intensify brain signals and can exacerbate positive symptoms (i.e. hallucinations and paranoia) in schizophrenia. Impaired glutamate (a neurotransmitter which directs neuron to pass along an impulse) activity appears to be another source of schizophrenia symptoms.[17] [edit] [edit] Link to comment Share on other sites More sharing options...
mgrade Posted October 16, 2012 Report Share Posted October 16, 2012 Dopamine Model Some researchers have suggested that dopamine systems in the mesolimbic pathway may contribute to the 'positive symptoms' of schizophrenia (whereas problems with dopamine function in the mesocortical pathway may be responsible for the 'negative symptoms', such as avolition and alogia.) Abnormal expression, thus distribution of the D2 receptor between these areas and the rest of the brain may also be implicated in schizophrenia, specifically in the acute phase. A relative excess of these receptors within the limbic system means Broca's area which can produce illogical language, has an abnormal connection to Wernicke's area, which comprehends language, but does not create it. Note that variation in distribution is observed within individuals, so abnormalities of this characteristic likely play a significant role in all psychological illnesses. Individual alterations are produced by differences within glutaminergic pathways within the limbic system, which are also implicated in other psychotic syndromes. Among the alterations of both synaptic and global structure, the most significant abnormalities are observed in the uncinate fasciculus. (McIntosh, 2008) and the cingulate cortex(Haznedar, 2004). The combination these creates a profound dyssymmetry of prefrontal inhibitory signalling, shifted positively towards the dominant side. Eventually, the cingulate gyrus becomes atrophied towards the anterior, due to long-Term Depression (LTD) and Long-Term Potentiation (LTP) from the abnormally strong signals transversely across the brain.(Shlaug, 2009) This, combined with a relative deficit in GABAergic input to Wernicke's area, shifts the balance of bilateral communication across the corpus callosum posteriorly. (Nakamura,2005) Through this mechanism, hemispherical communication becomes highly shifted towards the left/dominant posterior. As such, spontaneous language from brocca's can propagate through the limbic system to the tertiary auditory cortex. This retrograde signalling to the temporal lobes, results in the parietal lobes not recognizing it as internal, resulting in the auditory hallucinations typical of chronic schizophrenia.(Friston, Karl J, The disconnection hypothesis, 1998) In addition, significant cortical grey matter volume reductions are observed in this disorder. Specifically, the right hemisphere atrophies more, while both sides show a marked decrease in frontal and posterior volume. (Harvey, I, M.A. Ron, G Du Boulay, D Wicks, S.W. Lewis, RM. Murray, Reduction of cortical volume in schizophrenia on magnetic resonance imaging, Psychological Medicine, Cambridge University, 1993). This indicates abnormal synaptic plasticity occurs, where certain feedback loops become so potentiated, others receive little glutaminergic transmission. This is a direct result of the abnormal dopaminergic input to the striatum, thus (indirectly) disinhibition of thalamic activity. The excitatory nature of dopaminergic transmission means the glutamate hypothesis of schizophrenia is inextricably intertwined with this altered functioning. Also, 5-HT, which regulates a wide variety of monoamine neurotransmitters, including dopaminergic transmission. Specifically, 5-HT2A regulates cortical input to the basal ganglia. Many typical and atypical antipsychotics are antagonists at this receptor, as well as 5-HT2C, which is expressed in many parts of the basal ganglia (striatum, prefrontal cortex, nucleus accumbens, amydygalia,and the hippocampus, all structures indicated in this disease). 5-HT2C also regulates dopamine release in response to dopaminerigic drugs as well. More research is needed to explain the exact nature of the altered chemical transmission in this disorder. Recent evidence on a variety of animal models of psychosis, such as sensitization of animal behaviour by amphetamine, or phencyclidine (PCP, Angel Dust),[1] or excess steroids[citation needed], or by removing various genes (COMT, DBH, GPRK6, RGS9, RIIbeta), or making brain lesions in newborn animals, or delivering animals abnormally by Caesarian section, all induce a marked behavioural supersensitivity to dopamine and a marked rise in the number of dopamine D2 receptors in the high-affinity state for dopamine.[2] This latter work implies that there are multiple genes and neuronal pathways that can lead to psychosis and that all these multiple psychosis pathways converge via the high-affinity state of the D2 receptor, the common target for all antipsychotics, typical or atypical. Combined with less inhibitory signalling from the thalamus and other basal ganglic structures, from hyoptrophy (Gur, Bilker 1998) the abnormal activation of the cingulate cortex, specifically around broca's and Wernicke's areas (Haznedar, 2004), abnormal D2 agonism can facilitate the self-reinforcing, illogical patterns of language found in such patients. (Arinami, Gao, Hamaguchi, Toru, 1997) In schizophrenia, this feedback loop has progressed, which produced the widespread neural atrophy characteristic of this disease. Patients on neuroleptic or antipsychotic medication have significantly less atrophy within these crucial areas(Gur, Bilker 1998) As such, early medical intervention is crucial in preventing the advancement of these profound deficits in bilateral communication at the root of all psychotic disorders. (Whitford, 2010) Advanced, chronic schizophrenia can not respond even to clozapine, regarded as the most potent antipsychotic (McEvoy, 2006), as such, a cure for highly advanced schizophrenia is likely impossible, so the value of early intervention cannot be stressed enough. [edit]Discussion [edit]Evidence for the dopamine hypothesis Amphetamine, cocaine and similar drugs increase levels of dopamine in the brain and can cause symptoms which resemble those present in psychosis, particularly after large doses or prolonged use. This is often referred to as "amphetamine psychosis" or "cocaine psychosis," but may produce experiences virtually indistinguishable from the positive symptoms associated with schizophrenia. Similarly, those treated with dopamine enhancing levodopa for Parkinson's disease can experience psychotic side effects mimicking the symptoms of schizophrenia. Up to 75% of patients with schizophrenia have increased signs and symptoms of their psychosis upon challenge with moderate doses of methylphenidate or amphetamine or other dopamine-like compounds, all given at doses at which control normal volunteers do not have any psychologically disturbing effects.[3][4] Some functional neuroimaging studies have also shown that, after taking amphetamine, patients diagnosed with schizophrenia show greater levels of dopamine release (particularly in the striatum) than non-psychotic individuals. However, the acute effects of dopamine stimulants include euphoria, alertness and over-confidence; these symptoms are more reminiscent of mania than schizophrenia.[5] A group of drugs called the phenothiazines, including antipsychotics such as chlorpromazine, has been found to antagonize dopamine binding (particularly at receptorsknown as D2 dopamine receptors) and reduce positive psychotic symptoms. This observation was subsequently extended to other antipsychotic drug classes, such as butyrophenones including haloperidol. The link was strengthened by experiments in 1970s which suggested that the binding affinity of antipsychotic drugs for D2dopamine receptors seemed to be inversely proportional to their therapeutic dose. This correlation, suggesting that receptor binding is causally related to therapeutic potency, was reported by two laboratories in 1976.[6][7] Genetic evidence has suggested that there may be genes, or specific variants of genes, that code for mechanisms involved in dopamine function, which may be more prevalent in people experiencing psychosis or diagnosed with schizophrenia. Dopamine related genes linked to psychosis in this way include COMT, DRD4, andAKT1.[8] Schizophrenics appear to have a high rate of self-medication with nicotine; the therapeutic effect likely occurs through dopamine modulation by nicotinic acetylcholine receptors. [edit]Evidence against the dopamine hypothesis Further experiments, conducted as new methods were developed (particularly the ability to use PET scanning to examine drug action in the brain of living patients) challenged the view that the amount of dopamine blocking was correlated with clinical benefit. These studies showed that some patients had over 90% of their D2receptors blocked by antipsychotic drugs, but showed little reduction in their psychoses. This primarily occurs in patients who have had the psychosis for ten to thirty years. At least 90-95% of first-episode patients, however, respond to antipsychotics at low doses and do so with D2 occupancy of 60-70%. The antipsychoticaripiprazole occupies over 90% of D2 receptors, but this drug is both an agonist and an antagonist at D2 receptors. Furthermore, although dopamine-inhibiting medications modify dopamine levels within minutes, the associated improvement in patient symptoms is usually not visible for at least several days, suggesting that dopamine may be indirectly responsible for the illness.[9] Similarly, a new generation of antipsychotic drugs (called the atypical antipsychotics) were found to be just as effective as older typical antipsychotic drugs in controlling psychosis, but more effective in controlling the negative symptoms, despite the fact that they have lower affinity for dopamine receptors than for various other neurotransmitter receptors.[10] More recent work, however, has shown that atypical antipsychotic drugs such as clozapine and quetiapine bind and unbind rapidly and repeatedly to the dopamine D2 receptor.[11] All of these drugs exhibit inverse agonistic effects at the 5-HT2A/2C receptors, meaning serotonin abnormalites are also involved in the complex constellation of neurologic factors predisposing one to the self reinforcing language-based psychological deficits found in all forms of psychosis. (Williams, Spurlock, 1996), (Berg, Harvey, Sampinato, 2005) The excitatory neurotransmitter glutamate is now also thought to be associated with schizophrenia. Phencyclidine (also known as PCP or "Angel Dust") and ketamine, both of which block glutamate (NMDA) receptors, are known to cause psychosis at least somewhat resembling schizophrenia, further suggesting that psychosis and perhaps schizophrenia cannot fully be explained in terms of dopamine function, but may also involve other neurotransmitters.[12] Similarly, there is now evidence to suggest there may be a number of functional and structural anomalies in the brains of some people diagnosed with schizophrenia, such as changes in grey matter density in the frontal and temporal lobes.[2] It appears, therefore, that there are multiple causes for psychosis and schizophrenia, including gene mutations and anatomical lesions. Link to comment Share on other sites More sharing options...
mgrade Posted October 19, 2012 Report Share Posted October 19, 2012 Winter photoperiods increase CSF turnover. [coffee does also (..perhaps diuretics in general)] <---diuretics raise blood-sugar I think if you come down with HPPD, you should immediately go to Norway or Alaska in December and maybe Cape Horn in June. Link to comment Share on other sites More sharing options...
mgrade Posted October 20, 2012 Report Share Posted October 20, 2012 Back to Visual's idea of broken axons. The scorpion loses its tail. A blown fuse. The Node of Ranvier seems like the point of least resistance. How do we strengthen our myelin, Visual? Strengthen our Nodes of Ranvier? .Where for art thou Visual?, lol Link to comment Share on other sites More sharing options...
mgrade Posted October 20, 2012 Report Share Posted October 20, 2012 [side note: D4 antagonism seems to be very effective in terms of delusions and auditory hallucinations.] Low concentrations of dopamine activate the D2 receptor/pathway. High concentrations of dopamine activate the D1 receptor/pathway. D1 stimulates adenylate cyclase. D2 inhibits adenylate cyclase. ~Wouldn't a selective D1 blocker help us? [Or perhaps D2?]----- http://www.jneurosci...4/47/10652.full Typical Antipsychotic Antagonism D2>5HT2a Atypical Antipsychotic Antagonism 5HT2a>D2 ~But why do most antipsychotics have "across-the-board" quite non-selective DA blockade and 5HT blockade? ~Yet these APs seem to be more effective than more selective drugs? Link to comment Share on other sites More sharing options...
VisualDude Posted October 20, 2012 Report Share Posted October 20, 2012 why do most antipsychotics have "across-the-board" quite non-selective DA blockade... If you dig, it has long been considered that antagonizing D2 (>= 70%) is what is required for treating delusions ("positive" symptoms of schizophrenia). Atypical antipsychotics don't reduce D2 that much but work with some people ... creating a paradox. There are not a lot of dopamine meds developed. Selectivity is hard. And even 'pure' D2 suppression will make a person feel like hell ("negative" symptoms of schizophrenia) [ Note: Careful as you read medical text to differentiate between D2 and D2 ] Low concentrations of dopamine activate the D2 receptor/pathway. High concentrations of dopamine activate the D1 receptor/pathway. Interesting wording here. It is actually more a default reaction - that is, D2 family receptors are inverse so that low dopamine prevents suppression; and D1 family receptors (direct, not inverse) will not properly activate without sufficient dopamine. How do we strengthen our myelin, Visual? Strengthen our Nodes of Ranvier? This is a massive topic, but essentially: Myelin damage is usually fat-soluble molecules (hence the dangers of petroleum products, pesticides, ...). With this kind of molecular binding, there is increased danger of developing auto-immune diseases (like MS) as the body tried to repair. Which causes other kinds of damage. With damage, there is inflammation (the nature of repair). Thus, anti-inflammatory things are important. Phosphatidyl choline (and its cousins) are the principle fats for nerve tissue. Supplying these are important. However they must be free of pesticides and also not something you've developed sensitivity to. For example, most phosphatidyl choline is from soy - but there is so much soy in our diets (at least in USA) that you could increase inflammation with your attempt to help yourself. Therefore one must move slowly. Soporifics are also useful - things that are both water soluble and fat soluble. These must be use very carefully since the body doesn't like to eliminate fats other than burning them. So there is danger of loosening toxins only for them to be deposited in other places. This is a classic, common mistake by 'practitioners' promoting detoxification - very few can actually do it without harming their clients in the long run. The other facet of myelin damage is burnt proteins. Currently there is no known way for these to repair - hence cataracts are not reversible. Again, myelin repair could be a massive thread of it own, as these are just a few bare basics... Link to comment Share on other sites More sharing options...
mgrade Posted October 20, 2012 Report Share Posted October 20, 2012 Yeah I know the D1/D2 bit [..for those who don't know]: D1 or D1-like type is D1 and D5. D2 or D2-like type is D2, D3, D4. D2 antagonism is obvious classical action of antipsychotics: from sleep/mental illness treatments in India to modern atypical APs. D4 subgroup may be more important in terms of delusions and auditory hallucinations in Schizophrenia. Nevertheless D2 AND 5HT2 are some of the main targets historically, and for the development of newer drugs. ------------------------- The issue that i felt pertinent, involving axon breakage, is, based on logical superficial observations of the immediate physical world, that the breakage point of the axon would happen at the Node of Ranvier rather than in the middle of a Schwann cell. Does that not seem the case? Link to comment Share on other sites More sharing options...
VisualDude Posted October 20, 2012 Report Share Posted October 20, 2012 The issue that i felt pertinent, involving axon breakage, is, based on logical superficial observations of the immediate physical world, that the breakage point of the axon would happen at the Node of Ranvier rather than in the middle of a Schwann cell. Does that not seem the case? Breakage would only be from a physical force ... stretching the axon until it breaks. Peripheral nerves have designs to allow for this some stretch (think of muscles or how about a penis --- don't pull too hard!). However the brain would not be subjected to such forces except physical blows. Demyelination is how axons get damages. Essentially the insulative layer (fat) of neurofilament gets compromized and no longer holds all of the electrical charge. One doc described it as proteins getting velcrowed together. If integrety gets really bad, axon branches can die. If the whole axon dies, then the neuron dies. However, I doubt that most with HPPD have demyelination issues. The bulk would be synaptic changes (burns, plasticity and other alterations). Since there are reports of gene-silencing with LSD (and why not other drugs since even stress can gene silence), then there can be changes in the metabolic functioning of neurons, thus disabling the cell to make some (of many thousands) chemical process. This would ultimately cause the neuron to function differently, even if only it can't keep up to full capacity. If high firing rates are required, the cell can't do it, so the whole balance of the circuit changes. 1 Link to comment Share on other sites More sharing options...
mgrade Posted October 21, 2012 Report Share Posted October 21, 2012 Demyelination, fatty brain insolation deterioration, etc. are problems but not the cause of HPPD. Is there enough voltage, current, amplitude, constant bombardment to burn synapses/neurons? Plasticity mainly means changes in chemicals and action. [Like: reduced DA days after large XTC doses, and reverting back to normal levels 2 weeks later] [The idea that levels/connections change, but are in most cases not permanent] It's a shame that the causes cannot be better pinpointed. Link to comment Share on other sites More sharing options...
VisualDude Posted October 21, 2012 Report Share Posted October 21, 2012 It's a shame that the causes cannot be better pinpointed. When you think of what a person experiences while tripping (with DMT for example), its like vivid dreaming awake with extreme changes/intermixing of perceptions/'consciousness'. Some report experiences similar to near-death-experiences where the brain is oxygen starved. The whole thing is complex. We are complex. Afterall, what is consciousness? Clearly neurotransmitter levels shift the brains operating status. We just try to compensate for what has been changed with HPPD. Looking at DA in the cerebral cortex - the area of all our 'higher' functions [ pun intended ], it isn't simple. The best hopes are DNA doing its job and relearning 'normal'. Link to comment Share on other sites More sharing options...
mgrade Posted October 22, 2012 Report Share Posted October 22, 2012 Is it possible that we are trying to hold on to connections (in the brain) that would otherwise choose new, different routes as a form of normal maintenance? And the same for cell culling and programmed cell death? Link to comment Share on other sites More sharing options...
VisualDude Posted October 22, 2012 Report Share Posted October 22, 2012 Is it possible that we are trying to hold on to connections (in the brain) that would otherwise choose new, different routes as a form of normal maintenance? Don't quite understand the question. Existing connections remain until 'enhanced' by learning or change to compensate for functional loss elsewhere (learning by the survivors). HPPD changes things ... essentially new paths. If the old paths get restored (they weren't badly injured), then you now have multiple paths to resolve. [ Spiritual enhancement, lol ] And the same for cell culling and programmed cell death? PCD occurs only from injury or compromized working conditions (injurious functioning environment). It is when a cell is pushed beyond the point of no return. Otherwise, neurons in the brain don't die until you completely die. See Atrophic factors for some reasons for cell death http://en.wikipedia....mmed_cell_death Link to comment Share on other sites More sharing options...
mgrade Posted October 23, 2012 Report Share Posted October 23, 2012 1. When I mean connections, I don't mean physically in-it-of-itself, but the brain living up to its potential, and such that the mind-stuffs are influencing the physical. 2. PCD is something that happens largely in the developing body/brain but not always [and not always from naked-eye perceived injury....But the brain is not totally developed until 25 to 30 years of age in the conversion of a significant amounts of white matter, being substituted with grey matter. Grey matter is more insulating compared to white. Grey matter is less insulating than white. All cells contain genes that program their own death. Link to comment Share on other sites More sharing options...
VisualDude Posted October 23, 2012 Report Share Posted October 23, 2012 brain living up to its potential, and such that the mind-stuffs are influencing the physical From what is known, mind altering drugs work by altering neuron firing usually by increasing neurontramsmitters. The resulting damage afterward is from changes in the system from the high levels. Damage can be in all sorts of ways and is dosage dependant. Theoretically, if the dose is low enough, all drugs are safe. But people push for the effect and this can be cause lasting changes. Take meth as an example, it floods the brain with dopamine so the synapses change to compensate ... this leads to reduced amounts of dopamine when not on the drug ... unfortunately this can be permanent, leaving the person with reduced sense of pleasure for the rest of their life. Now with Parkinson's, there are genetic weaknesses that reduce the ability to clean up metabolic waste during normal activity. The more metabolic activity, the more oxidative stress, and loss of function. The difference between 'normal' and 'parkinsons-prone' is slight. Normal people loose about 1/2% of function per year, PP loose about 1%. If PP lived in an ultra wonderful, low metabolic waste life situations, they won't develop the disorder. Likewise, NP in high metabolic waste life styles loose function more rapidly and can develop Parkinsonism if not actual PD. Take heavy drinking as another example. All binges damage neurons. But it takes about 10 years of binging for the damage to show up - classic cerebellum damage. So with recreational drugs, genetics, amount taken at a time, and frequency of use all influence whether damage is substantial or not. We have folks here that got HPPD with one hit or with 'mild' drugs such as weed. Then there are those who have taken a hundred LSD trips and seem fine. As for brain living up to its potential [ nice pun you gave us ], learning is the healthiest thing to do: music, language, social interaction, exercise, challenges. Along with metabolic support: proper food, rest, clean air and water. Grey matter is more insulating compared to white White matter is more insulating. White is myelin (fat). Grey areas are where the clusters of neuronal bodies are. All cells contain genes that program their own death The mechanism for death is there. The issue is what activates it. The cells in your eyes contain all the info to turn into a giant tongue ... fortunately this doesn't happen. brain is not totally developed until 25 to 30 years of age The last area to mature is the executive center. That is why young people do risky, poor judgement things (aside from inexperience). But the brain isn't growing more neurons. A person is born with the most neurons they will ever have. Over the first few months, millions of cell die (culled). Since growth is about increased synaptic connections, then we never stop growing. But there is a fundamental beginning stage that completes during that time frame. Link to comment Share on other sites More sharing options...
mgrade Posted October 23, 2012 Report Share Posted October 23, 2012 Ooops.......My fault. I confused White with Grey. But I know there is a change. And our points have been made concerning myelin, for sure. I really appreciate it because i think for the most part we do push each other to understand the material better and seek out the mechanisms and possible treatments. But you correcting me about the grey matter kind of proves the point i am making. More connections with less insulation equals possible overexcitation, "short circuits", [bad shit potentially]. Imagine your DVD player with instead of having wire insulation protecting circuits it just is wire. They may not work so well.....esp. in the long run. Link to comment Share on other sites More sharing options...
myrslingerbult Posted October 23, 2012 Report Share Posted October 23, 2012 Is this discussion leading anywhere? I want to be cured more than anything. Link to comment Share on other sites More sharing options...
mgrade Posted October 23, 2012 Report Share Posted October 23, 2012 You ever heard of the saying: You have to learn to walk before you run. Well i think that this discussion has turned into a means or a catalyst to learn and relearn the biological and biochemical structures and mechanisms that have laid the foundation for us finding a treatment for this disorder. Trust me, if it were that easy, there is no doubt in my mind, there would already be a more effective treatment. Link to comment Share on other sites More sharing options...
mgrade Posted October 23, 2012 Report Share Posted October 23, 2012 This seems to push the issue back to the BBB and the glia limitans; proteoglcans, glycoproteins, and back to p-glycoprotein. Link to comment Share on other sites More sharing options...
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