Posted by desolationrower on February 23, 2009, at 12:11:58
for a while, i had been thinking "5-ht2a antagonists are always good (unless you want to trip). 5ht2 is weird, there seems to be a few functional agonism modes (? not sure if this right term - 'agonists' can activate various secondary messagers post-g protein ocupled receptors). other than psylocin for ocd, benefits seem to accrue from antagonists.
but. ECT upregulates 5ht2a. blockade may look like an antidepresant effect but is merely psychomotor activation. most ADs downregulated it: it could be not therapeutic itself, but a compensatory change due to the beneficial increase in 5ht levels.
look at mdma, probably the best pro-social drug. note that 5ht2a releases dopamine in this case (koch galloway 97). and in mice, mdma reduces sociability: it looks like 'anxiety.' so animal models are not working right here.
(Behavioral profile of 3,4-methylenedioxy-methamphetamine (MDMA) in agonistic encounters between male mice.)
also:
Aim: to evaluate the role of serotonin, dopamine and norepinephrine systems in mediating the effect of MDMA on mood, psychomotor behavior and sensorimotor gating in humans. This research used the serotonin uptake inhibitor citalopram, the dopamine D2 antagonist haloperidol and the 5HT2A receptor antagonist ketanserin to investigate the role played by these two neurotransmitters in producing the subjective and physiological effects of MDMA in humans. Citalopram pretreatment attenuated most of the subjective effects of MDMA and reduced MDMA-induced elevation in systolic blood pressure and heart rate. Ketanserin reduced alterations in perception produced by MDMA, and attenuated MDMA-induced elevation in diastolic blood pressure and body temperature. Haloperidol attenuated MDMA-induced positive mood and positive feelings of derealization and increased MDMA-induced anxiety, but did not affect any of the physiological changes produced by MDMA. Citalopram pretreatment also attenuated facilitated pre-pulse inhibition (PPI) seen after MDMA alone. In an ongoing study, the effects of the serotonergic/noradrenerigc drug pindolol on MDMA are investigated in healthy volunteers.note that http://www.heffter.org/review/Review2/chap3.pdf concluded h5t2a modulated the 'percetual'/'hallucinageic' areas of mdma effects
negative: Alterations in responses to LSD in humans associated with chronic administration of tricyclic antidepressants, monoamine oxidase inhibitors or lithium (but: nri/li can be good AD augmentors. what about in anxiety? i posted a few things abotu nri improving OCD response to sris. maybe improved 5ht levels and sensetive 5ht2a receptors is good)
Abstract
This study sought to investigate possible interactions between antidepressant agents and lysergic acid diethylamide (LSD) in humans through the use of retrospective questionnaires. Ten subjects were identified who used LSD during chronic (3 weeks or longer) periods of antidepressant administration. These subjects were asked to desribe the phenomenological effects of self-administered hallucinogens prior to and during antidepressant treatment; a structured, standardized questionnaire was used to evaluate LSD experiences. Chronic tricylic antidepressant administration was associated with subjective increases in physical, hallucinatory and psychological responses to LSD. Similarly, subjects receiving lithium chronically also reported increases in their responses to LSD. In contrast, subjects who had been chronically taking an monoamine oxidase (MAO) inhibitor reported subjective decreases in the effects of LSD. This is similar to a previous report by our group of a decreased response to LSD in individuals who were chronically taking serotonin-selective antidepressants. These altered responses to LSD most likely involve differential changes in central serotonin and dopamine receptor systems and are consistent with other recent data suggesting that the clinical efficacy of different classes of antidepressants may not necessarily rely on a common mechanism of action in the brain.very interesting:
Opposite effects of nefazodone in two human models of anxiety.
RATIONALE AND OBJECTIVES: To explore further the role of serotonin (5-HT) in anxiety, the effects of the 5-HT reuptake inhibitor and 5-HT2A receptor antagonist nefazodone (NF) were measured in two human models of anxiety. METHODS: Twenty-nine adult healthy volunteers of both sexes underwent conditioning of skin conductance responses (CSCR) to a tone associated to an aversive white noise. Another 34 subjects performed a simulated public speaking (SPS) task, seemingly related to unconditioned fear. In both tests, subjective states were evaluated through the visual analogue mood scale (VAMS) and a bodily symptoms scale (BSS). In each experiment, subjects were randomly divided into three groups, which received 100 mg NF, 200 mg NF or placebo under double-blind condition. RESULTS: In the CSCR test, NF decreased the number of spontaneous fluctuations of skin conductance (F=4.94; df=2,26; P=0.015). In addition, the increase in VAMS anxiety factor induced by the conditioning task was attenuated by NF (F=11.11; df=2,26; P<0.001). In contrast, the rise of VAMS anxiety induced by SPS was enhanced by NF (F=8.01; df=2,31; P=0.002). CONCLUSIONS: These results indicate that NF decreases conditioned anxiety, while enhancing unconditioned fear. Since the effects of NF may be due to impairment of 5-HT neurotransmission, consequent to overstimulation of autosomic 5-HT1A receptors and blockade of post-synaptic 5-HT2A receptors, the present results support the hypothesis that 5-HT facilitates conditioned anxiety, which may be related to generalised anxiety disorder, while inhibiting unconditioned fear, supposedly related to panic disorder.now, inositol:
The antidepressant activity of inositol in the forced swim test
involves 5-HT2 receptors
study says 5ht2a antagonists block AD effect. and we know inositol doesn't augmnet sris. OTOH, " Effects of myo-Inositol Versus Fluoxetine and Imipramine Pretreatments on Serotonin 5HT2A and Muscarinic Acetylcholine Receptors in Human Neuroblastoma Cells" - Abstract myo-Inositol (mI) is a key metabolic precursor to the phospoinositide (PI) metabolic pathway as a key component of central G-protein coupled receptor signaling systems, including several subtypes of adrenergic, cholinergic, serotonergic and metabotropic glutamatergic receptors. High dose mI has also been shown to be clinically effective in the treatment of obsessive-compulsive disorder, as well as panic and depression, although its mechanism of action remains elusive. The current study aimed to investigate the possible modulatory role of mI versus fluoxetine or imipramine pretreatments on serotonin-2A receptor (5HT2A-R) and muscarinic acetylcholine receptor (mAChR) function and binding in in vitro systems. After pretreating human neuroblastoma cells with different concentrations of mI, fluoxetine, or imipramine, receptor function was measured by second messenger [3H]-IP x accumulation and [35S]-GTPgammaS binding to Gagrq protein. Total [3H]-mI uptake into cells was measured, as well as specific receptor binding to determine receptor binding after the pretreatments. Results suggest that mI reduces 5HT2A-R function at the receptor-G protein level. While fluoxetine also reduced 5HT2A-R function, but to a lesser degree, imipramine increased 5HT2A-R function, which may explain why mI seems to be effective exclusively in selective serotonin reuptake inhibitor-sensitive disorders. In addition mI, and at high concentrations fluoxetine and imipramine, also reduces mAChR function. Furthermore the results suggest that the attenuating effect of mI on mAChRs is partially dependent on the PI metabolic pathway. The data provide novel information on understanding the mechanism of action of mI in depression and related anxiety disorders and added to the evidence suggesting a role for the cholinergic system in the pathophysiology of depression.i've seen it said inositol improves 5ht receptor sensitivity, but i havent' seen any studies sayitn that instead,
Myo-inositol reduces serotonin (5-HT2) receptor induced homologous and heterologous desensitization.
Author:Rahman, S : Neuman, R S
Citation:Brain-Res. 1993 Dec 24; 631(2): 349-51
Abstract:The effect of myo-inositol was examined on 5-HT2 receptor mediated facilitation of NMDA depolarization of rat neocortical neurons in vitro. Myo-inositol (1-10 mM) potentiated the 5-HT facilitation, the potentiation increasing linearly with log 5-HT concentration. Myo-inositol also eliminated 5-HT induced heterologous desensitization of muscarinic and alpha 1-adrenergic receptor mediated facilitation. Our findings suggest that 5-HT induced homologous and heterologous desensitization results in part from depleting phosphoinositide substrate.Which brings me to the upside point, look at this:
Decreased social behaviour following 3,4-methylenedioxymethamphetamine (MDMA) is accompanied by changes in 5-HT2A receptor responsivity
This study examined the involvement of the 5-HT2A receptor in the long-term anxiogenic effect of a brief exposure of young rats to 3,4-methylenedioxymethamphetamine (MDMA) using the social interaction and elevated plus-maze paradigms. Wistar rats (post-natal day (PND) 28) received either MDMA (5 mg/kg i.p.) or saline (1 ml/kg i.p.) hourly for 4 h on 2 consecutive days. Locomotor activity was measured for 60 min after the first injection and core body temperature was recorded at regular intervals over 4 h. On PND 84, without further drug administration, social interaction was assessed between treatment-matched rat pairs derived from separate litters. On PND 86, rats received either the 5-HT2A/2C receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 1 mg/kg i.p.) or saline and locomotor activity, wet-dog shakes and back muscle contractions were monitored. The change in elevated plus-maze behaviour was assessed following the same injection on PND 87. Acutely, MDMA produced a significant hyperlocomotion and hyperthermia (p<0.01). Following 55 days of abstinence, social interaction was reduced by 27% in MDMA pre-treated rats compared with that in controls (p<0.01). On the elevated plus-maze, pre-treatment with MDMA prevented the anxiogenic effect of DOI. On PND 92, hippocampal, frontal cortical and striatal 5-hydroxytryptamine (5-HT) was significantly reduced in MDMA pre-treated rats by between 16% and 22%, without any accompanying change in [3H]paroxetine binding in cortical homogenates. In conclusion, exposure of young rats to repeated MDMA caused serotonin depletion and induced anxiety-like behaviour in the social interaction test accompanied by a long-lasting reduction in specific 5-HT2A receptor mediated behaviour.Cortical Serotonin 5-HT2A Receptor Binding and Social Communication in Adults With Aspergers Syndrome: An in Vivo SPECT Study
Declan G.M. Murphy, M.R.C.Psych., M.D., Eileen Daly, B.Sc., Nicole Schmitz, Ph.D., Fiona Toal, M.R.C.Psych., Keiran Murphy, F.R.C.Psych., Ph.D., Sarah Curran, M.R.C.Psych., Ph.D., Kjell Erlandsson, Ph.D., Jos Eersels, Ph.D., Robert Kerwin, F.R.C.Psych., Ph.D., Peter Ell, M.D., Ph.D., and Michael Travis, M.R.C.Psych.OBJECTIVE: The cause of autistic spectrum disorder (i.e., autism and Aspergers syndrome) is unknown. The serotonergic (5-HT) system may be especially implicated. However, cortical 5-HT2A receptor density in adults with the disorder has not been examined, to the authors knowledge. METHOD: The authors investigated cortical 5-HT2A receptor binding in eight adults with Aspergers syndrome and in 10 healthy comparison subjects with single photon emission computed tomography and the selective 5-HT2A receptor ligand 123I iodinated 4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]-5-iodo-2-methoxybenzamide (123I-5-I-R91150). RESULTS: People with Aspergers syndrome had a significant reduction in cortical 5-HT2A receptor binding in the total, anterior, and posterior cingulate; bilaterally in the frontal and superior temporal lobes; and in the left parietal lobe. Also, reduced receptor binding was significantly related to abnormal social communication. CONCLUSIONS: The authors findings suggest that adults with Aspergers syndrome have abnormalities in cortical 5-HT2A receptor density and that this deficit may underlie some clinical symptoms.
sorry for the disorganization
-d/r
poster:desolationrower
thread:881911
URL: http://www.dr-bob.org/babble/neuro/20090129/msgs/881911.html