Psycho-Babble Neurotransmitters Thread 881911

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5ht2A: reėvaluation wrt social anxiet pls comment.

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

 

Re: 5ht2A: reėvaluation wrt social anxiet pls comment. » desolationrower

Posted by SLS on February 23, 2009, at 14:33:02

In reply to 5ht2A: reėvaluation wrt social anxiet pls comment., posted by desolationrower on February 23, 2009, at 12:11:58

That's quite a piece of work you put together.

It is going to take me quite awhile to get through it.

Thanks for the post.


- Scott

 

Re: 5ht2A: reėvaluation wrt social anxiet pls comment.

Posted by desolationrower on February 23, 2009, at 16:11:44

In reply to Re: 5ht2A: reėvaluation wrt social anxiet pls comment. » desolationrower, posted by SLS on February 23, 2009, at 14:33:02

oh i forgot the study that got me thinking of this in the first place. i'm interested if you can put anything together on this.

Serotonergic mechanisms promote dominance acquisition in adult male vervet monkeys.
Author:Raleigh, M J : McGuire, M T : Brammer, G L : Pollack, D B : Yuwiler, A
Citation:Brain-Res. 1991 Sep 20; 559(2): 181-90
Abstract:In a counter-balanced, cross-over study, we examined the contributions of serotonergic systems to the acquisition of social dominance in adult male vervet monkeys. Subjects were members of 12 social groups, each containing 3 adult males, at least 3 adult females, and their offspring. Animals were observed in 5 intervals including a first baseline, a first experimental, a second baseline, a second experimental, and a third baseline period. At the end of the first baseline period, the dominant male was removed from each group. In each group, one of the two remaining subordinate males was selected at random for treatment and during the first experimental period, 6 of the 12 treated males received drugs that enhanced serotonergic activity (3 were given tryptophan 40 mg/kg/day and 3 fluoxetine 2 mg/kg/day). The other 6 treated males received drugs that reduced serotonergic function (3 were given fenfluramine 2 mg/kg/day and 3 cyproheptadine 60 micrograms/kg/day). At the end of the first experimental period, the original dominant male was returned to his group and the second baseline period began. In all instances, the originally dominant male regained his dominant position. The second experimental period began with the dominant male again being removed and, the 12 treated males were given the treatment they had not received in the first experimental period. At the start of the third 12-week baseline period, the original dominant male was returned to his group and resumed his dominant status. When the 12 treated subjects received tryptophan or fluoxetine, they became dominant in all instances. When they received fenfluramine or cyproheptadine, their vehicle-treated cage mates became dominant. The sequence of the behavioral changes shown by the treated males as they acquired dominance status paralleled those seen in naturalistic conditions. These observations support the distinction between dominance and aggression and strongly suggest that when hierarchical relationships are uncertain, serotonergic mechanisms may mediate the behaviors which permit a male to attain high dominance status.

-d/r

 

Re: 5ht2A: reėvaluation wrt social anxiet pls comment. » desolationrower

Posted by SLS on February 24, 2009, at 6:53:37

In reply to Re: 5ht2A: reėvaluation wrt social anxiet pls comment., posted by desolationrower on February 23, 2009, at 16:11:44

I'm afraid I can't focus well enough at the moment in order to understand this stuff. It is unfamiliar territory to me.

Can you perhaps itemize the salient findings you found in the literature and summarize your thoughts on the matter. That would give me a head start.

For now, I can't read more that a few consecutive sentences. I can skim, but this stuff requires word for word reading. Hopefully my doctor will FINALLY listen to me and raise my dosage of desipramine. I have been deteriorating over these last two months.

Oh, while you are here, what do you think of the idea that 5-HT2a antagonism might lead to weight gain?


- Scott

 

Re: 5ht2A: reėvaluation wrt social anxiet pls comment.

Posted by desolationrower on February 24, 2009, at 17:43:09

In reply to Re: 5ht2A: reėvaluation wrt social anxiet pls comment. » desolationrower, posted by SLS on February 24, 2009, at 6:53:37

> I'm afraid I can't focus well enough at the moment in order to understand this stuff. It is unfamiliar territory to me.
>
> Can you perhaps itemize the salient findings you found in the literature and summarize your thoughts on the matter. That would give me a head start.
>
> For now, I can't read more that a few consecutive sentences. I can skim, but this stuff requires word for word reading. Hopefully my doctor will FINALLY listen to me and raise my dosage of desipramine. I have been deteriorating over these last two months.

i'll be reading more next week maybe. i'm taking the bar exam this week so its just stuff i read while being distracted from my final cramming. i think i can sympathise though, trying to study the last month was terrible (only thing my doctor let me change was going from .25 clonazapan to .5 3x week, which i tried a few times and still nothing). i loaded up on nicotine lozenges today, as it helps maintain my focus on a task (although, not selecting a task, so doesn't help outside of soemthing like a test) and nicotine makes me super nauseated and feels like my throat is swollen shut. a tca would be really great. anyway i just wanted to post what i had gotten through so i could get it off my mind. its not organized yet and i have no idea what it means, just some inconsistancies i noticed.


> Oh, while you are here, what do you think of the idea that 5-HT2a antagonism might lead to weight gain?
>

i don't think i've read anything that ties 2a to weight/appetite, other than a lot of antagonists are ligands for both 2a and 2c, and 2c seems to be connected to weight.

-d/r

 

Re: 5ht2A: reėvaluation wrt social anxiet pls comment.

Posted by Sigismund on February 25, 2009, at 15:33:29

In reply to Re: 5ht2A: reėvaluation wrt social anxiet pls comment., posted by desolationrower on February 24, 2009, at 17:43:09

You are talking about 5ht2A, but that often gets mentioned with 5ht2C.

Agomelatine, as a 5ht2C antagonist, may have some positive effect on social anxiety?

 

Re: 5ht2A: reėvaluation wrt social anxiet pls comment. » desolationrower

Posted by Questionmark on March 27, 2009, at 4:24:53

In reply to 5ht2A: reėvaluation wrt social anxiet pls comment., posted by desolationrower on February 23, 2009, at 12:11:58

Nice collection.
It's interesting. I've long felt that the information on 5-HT2 receptor subtypes and their functions was confusing and at least somewhat contradictory. .. I feel like i'm finally getting a decent grasp of 5-HT2C functionality, but i'm still befuddled when it comes to 5-HT2A.
I want to understand.


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