![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 54 to 78 of 98. Go back in thread:
Posted by CrAzYmEd on May 28, 2010, at 6:14:47
In reply to Re: Let's Have Dopamine Pie For Lunch » Brainbeard, posted by Conundrum on May 27, 2010, at 21:02:04
What causes sexual side effects? Lisuride will have PRO sexual effects like all other dopamine agonists by lowering prolactin.
Yes, LSD can increase learning but it does alot more then just 5HT2A agonism (its binding is very simular to lisuride).
LSD: 4.00 5ht1b, 3.77 5ht7, 3.75 5ht6, 3.73 5ht1a, 3.70 5ht1d, 3.64 5ht5a, 3.54 5ht2a, 3.16 D3, 3.11 5ht2b, 3.11 5ht2c, 2.93 Alpha2A, 2.62 5ht1e, 2.55 D2, 2.39 D4, 2.34 D1, 2.05 D5, 1.54 Alpha1A, 1.40 H1, 1.39 Beta1, 1.05 Beta2, 0.65 Alpha1B; 0.00: KOR, DOR, DAT, SERT, MOR, NET; ND: Sigma2, Alpha2B, Alpha2C, Imidazoline1, M1, M2, M3, M4, M5, Sigma1, H2, CB2, CB1, Ca+Channel, NMDA
(4 is best affinity, and under 2 not significant).
Posted by CrAzYmEd on May 28, 2010, at 6:18:27
In reply to Too much dopamine causes anhedonia? » linkadge, posted by Conundrum on May 27, 2010, at 21:18:00
Prozac wont cause a dopamine rebound as it raises dopamine itself: (It can really be anything, its impossible to point a effect of the withdrawal to any receptor)
---------------------------------
http://www.ncbi.nlm.nih.gov/pubmed/15741747
"Twelve patients affected by major depression received a single oral dose of fluoxetine in the morning, 5 mg in the first 5 days, 10 mg from the 6th to the 10th day and 20 mg from the 11th to the 40th day. Twelve healthy subjects received a placebo under identical testing procedures. Blood samples were collected at baseline and 7, 10 and 24 h after drug administration on the 1st day of fluoxetine administration at a dose of 5 mg, and on the 1st and the 30th day of fluoxetine administration at a dose of 20 mg (days 11 and 40 of treatment, respectively). We found that plasma norepinephrine, epinephrine and dopamine levels significantly increased after acute and chronic treatment (p < 0.001), reaching the highest concentrations on the last day. No significant changes of these parameters were observed in control patients."
-------------------------------------
I highly suggest against antipyschotics for the treatment of anxiety or depression, they should only be used to treat psychotic disorders. The risk of tardive dyskinesia and metabolic problems are not wort it.
Posted by Conundrum on May 28, 2010, at 9:23:31
In reply to Re: Too much dopamine causes anhedonia?, posted by CrAzYmEd on May 28, 2010, at 6:18:27
I think that prozac would still have a suppressive effect on dopamine in some areas of the brain though. I believe this is why it is effective in the treatment of OCD.
Interestingly the first 2 years off prozac my memory was bad so I took ginkgo for those first two years. It had a very powerful effect on me and if I took to much I had much more physical endurance and couldn't sleep. Like too much oxygen. Anyway a month after stopping it all the spiritual and loving feelings went away and I was hit with even worse anhedonia. At least then I was able to rid myself of those things. I was never into astrology or numerology before that or believed in conspiracies. I became better at using the logical part of my mind and eliminating unhelpful believes. So I guess in a way its has been helpful. I have no idea the physiology behind any of that though.
I have a similar feeling about atypical APs but it seems like psychiatrists are more comfortable prescribing them than tricyclics!
Posted by CrAzYmEd on May 28, 2010, at 9:47:04
In reply to Re: Too much dopamine causes anhedonia? » CrAzYmEd, posted by Conundrum on May 28, 2010, at 9:23:31
I dont buy the high dopamine OCD theory, this theory only comes from the low D2 bindin in humans and the fact that antipsychotics work for it.
However, there is loads of evidence for glutamate hyperactivity in OCD, glutamate downregulates D2, wich could be the cause of low D2 binding.
Also a good friend of me had moderate succes with pramipexole for OCD (and this isnt due to reduced dopamine, as he's autoreceptors are fully downregulated by now).
While i havent tried a dopamine agonist, i know that drugs that increase dopamine and NMDA antagonists are highly effective for my OCD.
Memantine, is a D2 agonist besides its nmda antagonism and has been found effective for OCD, prozac wich increases dopamine has been found effective for OCD too.
Posted by Brainbeard on May 28, 2010, at 15:17:55
In reply to Lisuride, incredible potential, posted by CrAzYmEd on May 24, 2010, at 22:41:53
I found a very interesting article on the interplay between unspecific 5HT activation and 5HT2A-activation or blocking as well as 5HT2C-agonism or antagonism:
http://www.nature.com/npp/journal/v28/n2/full/1300057a.html
There is a consesnus based on clinical evidence that 5HT2A-agonism opposes the beneficial effects of unspecific 5HT-activation through serotonin reuptake inhibition (SRI). Thus, 5HT2A-antagonists have been shown to fasten and boost the efficacy of SSRI's. The indirect agonism of 5HT2A receptors by SSRI's is a mechanism that inhibits c.q. defeats the benefits of agonism of other 5HT receptors, probably most notably 5HT1A-receptors.
5HT2A-agonism leads to sexual dysfunction and anxious moods.
In the article mentioned above it's also stated that 5HT2A-agonism promotes glutamate release.5HT2A and 5HT2C receptors have opposing functions in several ways. 5HT2C-agonism has shown to have antidepressant potential. It increases exuality. 5HT2C-antagonism may inhibit the benefits of 5HT2A-antagonism! This is an interesting find since most 5HT2A-antagonists are also 5HT2C-antagonists at least to some degree.
I have become convinced that several of the start-up effects that I typically experience when starting escitalopram are due to 5HT2C-agonism. The first days on escitalopram, and after raising the dose, I have a feeling that resembles my experiences on magic mushrooms. Time is being stretched out immensely: hours last extremely long and I can't believe what the clock is telling me. My appetite is suppressed - a known effect of 5HT2C-agonism. I feel euphoric and hyperseuxal.This must be 5HT2C-agonism!
If lisuride would be an ideal drug, it would at least have to be a 5HT2A-ANTAGONIST and a 5HT2C-agonist. Since it appears to be a stronger 5HT2A-agonist than a 5HT2C-agonist, these two mechanisms will downplay each other's benefits.
Fluoxetine/Prozac, by the way, of course has antidopaminergic properties, like any SSRI. Serotonin puts a brake on dopamine, to put it simply. Prozac causes sexual dysfunction like any other SSRI. It elevates prolactin levels like any other SSRI, which is also an antidopaminergic feature.
Posted by Brainbeard on May 28, 2010, at 15:37:58
In reply to 5HT2A-antagonism + 5HT2C-agonism Would Be Ideal, posted by Brainbeard on May 28, 2010, at 15:17:55
Quotes from mentioned article:
'Interactions have also been observed between 5-HT2A and 5-HT2C receptors at a behavioral level. Opposing effects exist for 5-HT2A and 5-HT2C receptors in modulating hyperlocomotion induced in mice by noncompetitive N-methyl-d-aspartate (NMDA) antagonists (Martin et al, 1997). A recent study has found clear evidence supporting opposing effects of 5-HT2A and 5-HT2C receptors in modulating head shakes in rats (Vickers et al, 2001). Activation of 5-HT2A and 5-HT2C receptors also leads to opposing effects on sexual function in rodents (Berendsen et al, 1990), in a manner suggesting that activation of 5-HT2A receptors could be responsible for the sexual side effects of SSRIs. DRL 72-s behavior also appears to involve reciprocal interactions between 5-HT2A and 5-HT2C receptors, since 5-HT2C agonists, similar to 5-HT2A antagonists, exert antidepressant-like actions in rats performing under this operant paradigm (Marek and Seiden, 1988; Martin et al, 1998; Marek et al, 2001a). In a similar vein, blockade of 5-HT2C receptors may attenuate the antidepressant-like effects observed on the DRL 72-s schedule following administration of drugs that block 5-HT2A receptors (Marek and Seiden, 1994).'
.....
'Activation of 5-HT2C receptors appears to cause effects that functionally oppose the effects resulting from activation of 5-HT2A receptors (see above). These two receptors are differentially regulated by antidepressants in a manner that could have clinical relevance (Berendsen and Broekkamp, 1991). Other preclinical work in rodents has found that 5-HT2C agonists have antidepressant-like action in the forced swim test, the olfactory bulbectomy model, and the DRL 72-s schedule (Martin et al, 1998; Cryan and Lucki, 2000). Moreover, a polymorphism for the 5-HT2C receptor has been linked to mood disorders (Lerer et al, 2001). This might result in an alteration of 5-HT2C function independent of receptor abundance. Alterations in RNA editing of 5-HT2C receptors has been reported in suicide victims (Niswender et al, 2001). Thus, simultaneous blockade of 5-HT2A receptors and activation of 5-HT2C receptors could result in an improved therapeutic benefit over either of these actions in isolation.'
Posted by CrAzYmEd on May 28, 2010, at 15:57:35
In reply to 5HT2A-antagonism + 5HT2C-agonism Would Be Ideal, posted by Brainbeard on May 28, 2010, at 15:17:55
"Fluoxetine/Prozac, by the way, of course has antidopaminergic properties, like any SSRI. Serotonin puts a brake on dopamine, to put it simply. Prozac causes sexual dysfunction like any other SSRI. It elevates prolactin levels like any other SSRI, which is also an antidopaminergic feature."
But whats the end result? I dont say there arent any anti dopaminergic propertie's, but its 5HT2C antagonism may counteract any anti dopaminergic activity, so in the end its not anti dopaminergic anymore.
Like the study i posted points toward INCREASED dopamine and not reduced.
Posted by CrAzYmEd on May 28, 2010, at 16:22:21
In reply to 5HT2A-antagonism + 5HT2C-agonism Would Be Ideal, posted by Brainbeard on May 28, 2010, at 15:17:55
"There is a consesnus based on clinical evidence that 5HT2A-agonism opposes the beneficial effects of unspecific 5HT-activation through serotonin reuptake inhibition (SRI)."
The opposing powers! There's allways a bad boy around counteracting the benefits of mr good guy, but then again there's mr good guy counteracting the problems the bad boys are causing!
It seems that when other receptors are either activated or inhibited, the effects of agonism of a differend receptor could be completely differend, like you say that 5HT2C antagonism could counteract the benefits of 5HT2A antagonism. So id say it depends on the situation wheter 5HT2A antagonism is good.
About your experience with SSRI's, 5HT2A agonism plays a big role in the mushroom experience too , so i wouldnt only point to 5HT2C agonism, its the whole mix, and suprisingly the pharmacological profile of mushrooms is very simular to that of lisuride except that mushrooms seem to be a strong D1 agonist too.
I'm still convinced that 5HT2A agonism is better then 5HT2A antagonism tough (in some situations atleast), 5HT2A can facilate dopamine release togheter with the 5-HT1A, 5-HT1B, 5-HT3 and 5-HT4 receptors. 5HT2A is also crucial for the dopamine release by amphetamine's and opiates while 5HT2C can inhibit it (its a weird one)
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Pharmacol Ther. 2007 Feb;113(2):296-320. Epub 2006 Oct 17.
Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission.
Alex KD, Pehek EA.Department of Neurosciences, Case Western Reserve School of Medicine, Cleveland, OH 44106, USA.
Abstract
The neurotransmitter dopamine (DA) has a long association with normal functions such as motor control, cognition, and reward, as well as a number of syndromes including drug abuse, schizophrenia, and Parkinson's disease. Studies show that serotonin (5-HT) acts through several 5-HT receptors in the brain to modulate DA neurons in all 3 major dopaminergic pathways. There are at least fourteen 5-HT receptor subtypes, many of which have been shown to play some role in mediating 5-HT/DA interactions. Several subtypes, including the 5-HT1A, 5-HT1B, 5-HT2A, 5-HT3 and 5-HT4 receptors, act to facilitate DA release, while the 5-HT2C receptor mediates an inhibitory effect of 5-HT on DA release. Most 5-HT receptor subtypes only modulate DA release when 5-HT and/or DA neurons are stimulated, but the 5-HT2C receptor, characterized by high levels of constitutive activity, inhibits tonic as well as evoked DA release. This review summarizes the anatomical evidence for the presence of each 5-HT receptor subtype in dopaminergic regions of the brain and the neuropharmacological evidence demonstrating regulation of each DA pathway. The relevance of 5-HT receptor modulation of DA systems to the development of therapeutics used to treat schizophrenia, depression, and drug abuse is discussed. Lastly, areas are highlighted in which future research would be maximally beneficial to the treatment of these disorders.--------------------------------
I should take a look at the full paper of that study.
Will take a better look at your post tomorrow, have to get up early today, morgen weer gaan werken:p.
Posted by CrAzYmEd on May 28, 2010, at 16:29:00
In reply to Re: 5HT2A-antagonism + 5HT2C-agonism Would Be Ideal, posted by CrAzYmEd on May 28, 2010, at 16:22:21
But this is about fear tough, not depression, but werent SSRI's also capable of increasing depression when starting the treatment, dont exactly remember, i actually tought that this was also due to 5HT2C agonism, but 5HT2C doesnt appear to be the big gangster as i first tought.
Acute SSRIs Increase Conditioned Fear Expression: Blockade with a 5-HT2C Receptor Antagonist
N.S. Burghardt,1 D.E.A. Bush,1 B.S. McEwen,2 and J.E. LeDoux1Background
SSRIs effectively treat various anxiety disorders, although symptoms of anxiety are often exacerbated during early stages of treatment. We previously reported that acute treatment with the SSRI citalopram enhances the acquisition of auditory fear conditioning, which is consistent with the initial anxiogenic effects reported clinically. Here, we extend our findings by assessing the effects of acute SSRI treatment on the expression of previously acquired conditioned fear.Results
A single pre-testing injection of the SSRIs citalopram or fluoxetine significantly increased fear expression. There was no effect of the antidepressant tianeptine, or the norepinephrine reuptake inhibitor, tomoxetine, indicating that this effect is specific to SSRIs. The SSRI induced enhancement in fear expression was not blocked by tropisetron, a 5-HT3 receptor antagonist, but was blocked by SB 242084, a specific 5-HT2C receptor antagonist.Conclusions
Enhanced activation of 5-HT2C receptors may be a mechanism for the anxiogenic effects of SSRIs observed initially during treatment.
Posted by Brainbeard on May 29, 2010, at 7:37:55
In reply to Re: 5HT2A-antagonism + 5HT2C-agonism Would Be Ideal, posted by CrAzYmEd on May 28, 2010, at 15:57:35
> "Fluoxetine/Prozac, by the way, of course has antidopaminergic properties, like any SSRI. Serotonin puts a brake on dopamine, to put it simply. Prozac causes sexual dysfunction like any other SSRI. It elevates prolactin levels like any other SSRI, which is also an antidopaminergic feature."
>
> But whats the end result? I dont say there arent any anti dopaminergic propertie's, but its 5HT2C antagonism may counteract any anti dopaminergic activity, so in the end its not anti dopaminergic anymore.
>
> Like the study i posted points toward INCREASED dopamine and not reduced.Those studies only show short-term effects. Increase in certain area's of the brain doesn't mean overall increase either.
In fact, 5HT2C-antagonism and SRI are opposing mechanisms. Only in lower doses Prozac's 5HT2C-antagonism may dominate, because of the non-linear dose/response relationship for 5HT2C-antagonism, i.e. only a little is enough for significant effects. On higher (therapeutical) doses however, the benefits of 5HT2C-antagonism will be mostly blown away by indirect 5HT2C-agonism. In accordance with this prediction is the fact that high doses of Prozac are used as an anti-bulimia agent, i.e. to suppress appetite. 5HT2C-antagonism INCREASES appetite, while 5HT2C-agonism suppresses it.
There is a very informative study on the web about Prozac's 5HT2C-antagonism in relation to its SRI here: http://www.pnas.org/content/94/5/2036.full.pdf. Please read the part between starts (***).
A quote: 'So far, the therapeutic effects of fluoxetine have been attributed primarily to its inhibition of 5HT transporters. Interestingly, it has been shown that the therapeutic plasma concentration of fluoxetine is in the micromolar range, and our studies show that, at this concentration range, fluoxetine can potently inhibit the membrane current responses mediated by 5HT2C receptors. Moreover, the affinity of fluoxetine for 5HT2C receptors (Ki 5 65 nM) is close to its affinity for 5HT transporters (Ki 5 33 nM) (29), which is also well below the therapeutic plasma concentration of fluoxetine. Thus, some therapeutic effects of fluoxetine may be a consequence of blocking both 5HT transporters and 5HT2C receptors. ***It should be noted that the blockage of 5HT transporters and that of 5HT2C receptors would have opposing actions on serotonergic synaptic transmission.*** (.....) Because of the highly nonlinear dose/response relationship of 5HT2C receptors the blockage of even a small number of receptors in a cell would lead to very profound changes (.....)'.
You seem to jump to overstatements like 'its 5HT2C antagonism may counteract any anti dopaminergic activity, so in the end its not anti dopaminergic anymore.' That's about as unfounded a prediction as saying that lisuride's 5HT1A-agonism will completely counter its anxiogenic properties. Lisuride probably fosters OCD.
If you look at this interesting study on lisuride that I found on Erowid: http://www.erowid.org/references/refs_view.php?A=ShowDoc1&ID=3705; you see that lisuride induced stereotypical behaviour in rats as well as intensive mounting, i.e. male sexual behaviour. Stereotypical behaviour indicates the potential to exacerbate or induce obsessive compulsive behaviour. And increased libido is not always fun, althoug the accompanying photo of one female rat mounting the other is rather funny.
Anyhow, 5HT2A-agonism inhibits the benefits of both 5HT1A- and 5HT2C-agonism. That's a clinical finding. So if you want to simplify it into good guy vs. bad guy terminology, lisuride does have a bad guy on board, and it's called 5HT2A-agonism. No matter what good things 5HT2A-agonism may do on its own, it's bad news for 5HT1A- and 5HT2C-agonism.
Posted by CrAzYmEd on May 29, 2010, at 8:16:34
In reply to Prozac, 5HT2C And The Trojan Horse In Lisuride, posted by Brainbeard on May 29, 2010, at 7:37:55
"You seem to jump to overstatements like 'its 5HT2C antagonism may counteract any anti dopaminergic activity, so in the end its not anti dopaminergic anymore.' That's about as unfounded a prediction as saying that lisuride's 5HT1A-agonism will completely counter its anxiogenic properties. Lisuride probably fosters OCD."
But its not a overstatement as according to this study it DOES increase dopamine, i never made that conclusion just because prozac is a 5HT2C antagonist, i only made that conclusion on the END result.
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http://www.ncbi.nlm.nih.gov/pubmed/15741747
"Twelve patients affected by major depression received a single oral dose of fluoxetine in the morning, 5 mg in the first 5 days, 10 mg from the 6th to the 10th day and 20 mg from the 11th to the 40th day. Twelve healthy subjects received a placebo under identical testing procedures. Blood samples were collected at baseline and 7, 10 and 24 h after drug administration on the 1st day of fluoxetine administration at a dose of 5 mg, and on the 1st and the 30th day of fluoxetine administration at a dose of 20 mg (days 11 and 40 of treatment, respectively). We found that plasma norepinephrine, epinephrine and dopamine levels significantly increased after acute and chronic treatment (p < 0.001), reaching the highest concentrations on the last day. No significant changes of these parameters were observed in control patients."
------------------------------------------
Plasma increased of dopamine are increased, after acute and chronic dosing, so unless the dopamine increase comes from something else then 5HT2C antagonism, the serotonine does NOT counteract the 5HT2C antagonism.
Posted by CrAzYmEd on May 29, 2010, at 8:44:34
In reply to Prozac, 5HT2C And The Trojan Horse In Lisuride, posted by Brainbeard on May 29, 2010, at 7:37:55
"Anyhow, 5HT2A-agonism inhibits the benefits of both 5HT1A- and 5HT2C-agonism. "
DO you have a source that 5HT2A agonism inhibits the beneficial effect of 5HT1A agonism? While they have opposing effects on dopamine in the frontal cortex this doesnt mean they will counteract eachother benefits completely.
Unless you can show me the source as i'm interested.
---------------------------------------
"If you look at this interesting study on lisuride that I found on Erowid: http://www.erowid.org/references/refs_view.php?A=ShowDoc1&ID=3705; you see that lisuride induced stereotypical behaviour in rats as well as intensive mounting, i.e. male sexual behaviour. Stereotypical behaviour indicates the potential to exacerbate or induce obsessive compulsive behaviour. And increased libido is not always fun, althoug the accompanying photo of one female rat mounting the other is rather funny."
--------------Same with all dopamine agonists in the rats probably, however the human studies regarding pramipexole conclude its well tolerated, while the rats love to have some wild sex on lisuride and walk around on it like a maniac, doesnt mean it will induce streotype behaver in the humans. Like i said a friend with OCD found pramipexole moderately effective for it.
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Stimulation of 5-HT1A or 5-HT2A receptors in the ventrolateral periaqueductal gray causes anxiolytic-, but not panicolytic-like effect in rats.
de Paula Soares V, Zangrossi H Jr.Department of Pharmacology, School of Medicine, University of São Paulo, Av. Bandeirantes 3900, CEP: 14049-900 Ribeirão Preto, Brazil.
Abstract
Evidences from studies using electrical or chemical stimulation of the midbrain periaqueductal gray (PAG) suggest that whereas the dorsal PAG is critical for the regulation of panic-related defensive behaviors, the ventrolateral PAG (vlPAG) modulates generalized anxiety-related responses. In the present study we evaluated whether the activation of 5-HT1A and 5-HT2A/2C receptors in the ventrolateral column of the periaqueductal gray (vlPAG) causes differential effects on an anxiety- and a panic-related defensive behavior, respectively, inhibitory avoidance and escape, in male Wistar rats submitted to the elevated T-maze. Our results showed that intra-vlPAG injection of the endogenous agonist serotonin, the 5-HT1A/7 agonist 8-OH-DPAT or 5-HT2A/2C agonist DOI impaired the acquisition of inhibitory avoidance, without interfering with escape performance. The same selective anxiolytic effect was also observed after local administration of the benzodiazepine receptor agonist midazolam. Moreover, as shown by the results of antagonism studies, 5-HT2A receptors are recruited for the anxiolysis caused by serotonin and DOI, while 5-HT1A receptors account for the effect of 8-OH-DPAT. In conclusion, our data show that the activation of 5-HT1A and 5-HT2A receptors in the vlPAG affects defensive responses related to generalized anxiety, but not panic disorder.So 5HT2A agonism is anxiolytic in the periaqueductal gray area, our bad boy causes some good effects in some brain area's. But yeah in other area's it can cause bad effects like the PAG. Either way i'm still far from convinced that 5HT2A is a bad boy, so id definatly would like to see some studies that it inhibits the positive effects of 5HT1A.
Posted by CrAzYmEd on May 29, 2010, at 8:49:04
In reply to Re: Prozac, 5HT2C And The Trojan Horse In Lisuride, posted by CrAzYmEd on May 29, 2010, at 8:44:34
DOI isnt exactly the most selective agent, and as lisuride is a PARTIONAL agonist, it may even act as an antagonist, by taking the place of serotonin on those 5HT2A receptors, wich in the results in less 5HT2A activation.
Anyone has its intrinsic activity for the 5HT2A's?
Posted by CrAzYmEd on May 29, 2010, at 9:10:03
In reply to But then again, posted by CrAzYmEd on May 29, 2010, at 8:49:04
5HT2A antagonism alone does NOT increase dopamine, only in combination with D2 antagonism it increases cortical dopamine, also 5HT2A antagonism blocks the dopamine increase by DOI.
5HT2A agonism DOES increase dopamine, 5HT2A is NOT a bad boy!
I copied a few things from the full text, as the paper is really long, but i highly suggest to take a look at it.
------------------
Atypical, but not typical, antipsychotic drugs robustly increase DA release in the PFC. A
common property of these drugs that distinguishes them from the typical agents is high affinity
for the 5-HT2A receptor. Thus, a plausible hypothesis was that 5-HT2A receptor antagonism
increases cortical DA efflux. Earlier studies demonstrated that administration of the nonselective
5-HT2 receptor antagonist ritanserin increased nigrostriatal and mesocorticolimbic
DA efflux (Devaud et al., 1992; Pehek, 1996; Pehek and Bi, 1997). However, subsequent work
has shown that ritanserin may facilitate DA cell activity by antagonizing D2 receptors (Shi et
al., 1995). Multiple subsequent studies have since been performed with the selective 5-HT2A
receptor antagonist M100907 and demonstrate that systemic or intracortical administration
Alex and Pehek Page 11
Pharmacol Ther. Author manuscript; available in PMC 2008 October 7.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
blocks DA release evoked by treatment with the 5-HT2 receptor agonist DOI (Gobert and
Millan, 1999; Pehek et al., 2001).------------------------
In contrast to studies employing the administration of 5-HT2A receptor antagonists alone, the
combined, systemic administration of D2 and 5-HT2A receptor antagonists results in a
potentiation of cortical DA release (Westerink et al., 2001; Liegeois et al., 2002). Evidence
has been provided that this effect may be mediated by actions of released 5-HT interacting
with 5-HT1A receptors (Bonaccorso et al., 2002). In addition, this potentiation may result from
actions of drugs on DA cells in the VTA. It is clear that, as a class, atypical antipsychotic drugs
enhance DA release in the PFC. It is also clear that this effect is not mimicked by selective
antagonism of 5-HT2A receptors. Rather, it may result from a combination of receptor binding
properties including blockade of 5-HT2C receptors (see below).------------------------------
We have
demonstrated that intracortical infusions of the 5-HT2A receptor antagonists M100907 or MDL
11,939 blocked the increases in cortical DA produced by the systemic administration of the 5-
HT2 receptor agonist DOI (Pehek et al., 2001; Pehek et al., 2006).------------------------------
Recent behavioral studies demonstrate that selective 5-HT2A receptor blockade attenuates
DA-mediated behaviors. Administration of the 5-HT2A antagonist SR 46349B (1.0 mg/kg or
less) attenuates hyperactivity induced by either the acute or repeated administration of cocaine
(Filip et al., 2004). Treatment with M100907 reversed behavioral deficits in locomotor activity
and prepulse inhibition of acoustic startle in DAT knockout mice (Barr et al., 2004). In addition
to behavioral abnormalities, these mice display elevated synaptic levels of DA (Gainetdinov
et al., 1999). The authors suggest that 5-HT2A antagonists may be useful in the treatment of
conditions characterized by chronic, elevated dopaminergic tone.------------------------------
Summary
Activation of 5-HT2A receptors stimulates dopaminergic activity in all three pathways
although most work has been performed in the mesocortical system. Investigations into the
circuitry of this regulation indicate that 5-HT2A receptors on corticotegmental projections
regulate DA cellular activity. A functional role for 5-HT2A receptors localized on VTA DA
neurons remains to be determined.For full text, find this abstract (dunno wheter you have journal acces? altough i think this paper was free.
harmacologic mechanisms of serotonergic regulation of dopamine neurotransmission.
Posted by Conundrum on May 29, 2010, at 10:50:27
In reply to 5HT2A is good!, posted by CrAzYmEd on May 29, 2010, at 9:10:03
Interesting thread. Albeit kind of useless. First of all a lot of studies are done with rats, and humans do react different. Second my own experience with prozac reflects what Brainbeard said. At low doses I feel motivated on fluoxetine. As the dose is increased I no longer want to eat. Something has changed with the 5 HT2C receptor. For some people 5 HT2C antagonism is great. However many people don't do well on prozac because for them it causes anxiety. They do better on other SSRIs. So no matter how much you read you won't know how you will react to it.
Third, drugs like nefazodone and protriptyline increase sexual functioning while SSRIs that activate the 5-HT2A receptor cause a decrease in sexual functioning. Another thing is that after chronic use the effect on 5-HT2A receptors changes. Initially 5-HT2A blockade decrease norepinephrine, but after chronic dosing it returns to normal, but is lesshttp://www.askapatient.com/viewrating.asp?drug=16012&name=VIVACTIL
Read the side effects. Increased sexual activation rather than decreased.
http://www.askapatient.com/viewrating.asp?drug=20152&name=SERZONE
So I do believe that 5 HT2A agonism probably increases dopamine in certain areas of the brain, but most people won't be happy with the side effects.
I know that nothing I've said here is particularly scientific but I think its important to look at the actual effect in humans. Also I gotta go.
http://jpet.aspetjournals.org/content/302/3/983.full
Finally, wouldn't a true agonist cause people to hallucinate?
Posted by CrAzYmEd on May 29, 2010, at 11:08:55
In reply to Re: 5HT2A is good! » CrAzYmEd, posted by Conundrum on May 29, 2010, at 10:50:27
"Interesting thread. Albeit kind of useless. First of all a lot of studies are done with rats, and humans do react different. Second my own experience with prozac reflects what Brainbeard said. At low doses I feel motivated on fluoxetine. As the dose is increased I no longer want to eat. Something has changed with the 5 HT2C receptor. "
Sure, more 5HT can cause more 5HT2C agonism, counteracting some antagonism of the 5HT2C receptor, but in HUMANS acute and chronic dosing of prozac increases plasma dopamine levels.
Besides that your own subjective experience doesnt say much about dopamine or serotonine, like i said a higher dose can counteract some 5HT2C antagonism, however that doesnt mean that your dopamine levels are decreased. Just that they MAY be less then on a lower dose, also serotonine can cause emotional blunting and apathy (atleast ssri's can cause that) so this may also overpower any other benefits.
"Finally, wouldn't a true agonist cause people to hallucinate?"
No, lisuride is the proof that this isnt the case, the 5HT2A receptor can be activated in differend ways, there's a differend downstream effect with hallucogenics.Besides, i wouldnt call this thread useless.
Posted by Conundrum on May 29, 2010, at 11:20:32
In reply to Re: 5HT2A is good!, posted by CrAzYmEd on May 29, 2010, at 11:08:55
Well I agree that my subjective experiences are indeed different. When I *first* took prozac years ago it was awesome. I always felt good. If someone I know felt bad I recommended them taking it. I eventually stopped it since I thought I didn't need it. Bad call. Now any increase in serotonin makes me apathetic. So I'd say, yes, in a drug niave person it will probably increase dopamine along with norepinephrine via 5 HT2C antagonism. BTW prozac is a 5 HT2A antagonist according to Lilly's scientists, which about the same binding affinity as the 5HT2C receptor. There may be differences in the actual potency to block electrical signals, since there isn't much written about fluoxetine's actions at the 5HT2a receptor.
http://www.nature.com/npp/journal/v27/n6/full/1395967a.html
Posted by CrAzYmEd on May 29, 2010, at 12:18:06
In reply to Re: 5HT2A is good! » CrAzYmEd, posted by Conundrum on May 29, 2010, at 11:20:32
I want to show you a few things wich i rather dont discuss on the public forum, if you could babblemail me or whatever that thing is called, would be awesome. (dunno if you can even email me, this forum system is weird).
Posted by Brainbeard on May 29, 2010, at 15:04:12
In reply to Re: Prozac, 5HT2C And The Trojan Horse In Lisuride, posted by CrAzYmEd on May 29, 2010, at 8:44:34
> "Anyhow, 5HT2A-agonism inhibits the benefits of both 5HT1A- and 5HT2C-agonism. "
>
> DO you have a source that 5HT2A agonism inhibits the beneficial effect of 5HT1A agonism?>id definatly would like to see some studies that it inhibits the positive effects of 5HT1A.
It's given in the study mentioned above (Gerard J Marek, Linda L Carpenter, Christopher J McDougle and Lawrence H Price: 'Synergistic Action of 5-HT2A Antagonists and Selective Serotonin Reuptake Inhibitors in Neuropsychiatric Disorders', in: Neuropsychopharmacology (2003) 28, 402412, link: http://www.nature.com/npp/journal/v28/n2/full/1300057a.html). Quote:
'INTERACTIONS BETWEEN 5-HT2A AND 5-HT1A RECEPTORS
At a cellular level, activation of 5-HT2A and 5-HT1A receptors exerts depolarizing and hyperpolarizing effects, respectively, on cortical pyramidal cells (Araneda and Andrade, 1991; Tanaka and North, 1993; Ashby et al, 1994; Aghajanian and Marek, 1997). These interactions have been observed both under in vitro conditions and during in vivo recordings from the rodent medial prefrontal cortex. Similar interactions have also been observed at a behavioral level. For example, stimulation of 5-HT1A receptors suppresses head shakes in rats induced by hallucinogenic drugs, which activate 5-HT2A receptors (Arnt and Hyttel, 1989; Schreiber et al, 1995). Previous studies have demonstrated that systemic administration of 5-HT1A agonists can block head shakes induced by direct infusion of the hallucinogen 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) into the medial prefrontal cortex (Granhoff et al, 1992; Willins and Meltzer, 1997).
Evidence for opposing effects of activation of 5-HT2A and 5-HT1A receptors has also been obtained from a behavioral screen for antidepressant drugs, rats performing on a differential reinforcement of low rate 72-s (DRL 72-s) schedule (Marek et al, 1989a,1989b; Marek and Seiden, 1994; Jolly et al, 1999). This behavioral screen measures a cardinal feature of prefrontal cortical 'executive function,' that is, withholding inappropriate responses (Fuster, 1997). At an operational level, water-deprived animals in this paradigm must wait at least 72 s following the previous response in order to receive a reinforcer (water) for making a response. The efficacy of 5-HT antagonists in exerting an antidepressant-like response on this screen (increased reinforcement rate, decreased response rate, and a cohesive rightward shift in the inter-response time (IRT) histogram) is related to the selectivity of the antagonists for 5-HT2A relative to 5-HT1A receptors (Marek et al, 1989a; Marek and Seiden, 1994).'
There are no 'good guys' and 'bad guys'; there are several complex and intertwined mechanisms striving for a delicate balance.
Posted by Brainbeard on May 29, 2010, at 15:10:44
In reply to Brainbeard, babblemail me!, posted by CrAzYmEd on May 29, 2010, at 12:18:06
> I want to show you a few things wich i rather dont discuss on the public forum, if you could babblemail me or whatever that thing is called, would be awesome. (dunno if you can even email me, this forum system is weird).
Dude, have you got babblemail on? Your name doesn't have the babblemail link. You can email me at brainbeard [at] gmx.com (without the spaces, obviously).
Posted by Brainbeard on June 2, 2010, at 2:47:03
In reply to Re: Brainbeard, babblemail me!, posted by Brainbeard on May 29, 2010, at 15:10:44
Posted by CrAzYmEd on June 2, 2010, at 8:58:02
In reply to I have ordered lisuride (nm), posted by Brainbeard on June 2, 2010, at 2:47:03
Nice man! Keep us updated!
What other meds are on again? (that used to be in your sig i think but i accidenly turned that off).
Posted by Brainbeard on June 2, 2010, at 13:10:17
In reply to Re: I have ordered lisuride, posted by CrAzYmEd on June 2, 2010, at 8:58:02
> Nice man! Keep us updated!
> What other meds are on again? (that used to be in your sig i think but i accidenly turned that off).Erm, 125mg of sertraline (obn Zoloft), 20mg of pipamperone (Dipiperone), one quarter of a Deanxit pill (10mg melitracene + 0.5mg flupentixol), 0.3mg melatonin. Occasionally: methylphenidate (obn Ritalin) 10mg, 5-10mg oxazepam, 2.5-5mg diazepam.
Posted by g_g_g_unit on June 5, 2010, at 20:49:38
In reply to My Bloody Regimen, posted by Brainbeard on June 2, 2010, at 13:10:17
> Erm, 125mg of sertraline (obn Zoloft)this is the only SSRI i'm still interested in trying. are you finding that it has a more favourable side-effect profile to the others as far as cognition goes? i've read it's the least likely to have an impact on memory, etc.
Posted by SLS on June 6, 2010, at 0:21:24
In reply to Re: My Bloody Regimen » Brainbeard, posted by g_g_g_unit on June 5, 2010, at 20:49:38
>
> > Erm, 125mg of sertraline (obn Zoloft)
>
> this is the only SSRI i'm still interested in trying. are you finding that it has a more favourable side-effect profile to the others as far as cognition goes? i've read it's the least likely to have an impact on memory, etc.
Zoloft is the SSRI that produced the most "brain fog" for me. I was taking 200mg.
- Scott
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