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Dr. Bob is Robert Hsiung, MD,
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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.
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"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.
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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
Posted by g_g_g_unit on June 6, 2010, at 0:23:25
In reply to Re: My Bloody Regimen » g_g_g_unit, posted by SLS on June 6, 2010, at 0:21:24
>
>
>
> Zoloft is the SSRI that produced the most "brain fog" for me. I was taking 200mg.
>
>
> - Scottoh strange .. did the effect vary at different doses? which produced the least?
Posted by Conundrum on June 6, 2010, at 1:18:10
In reply to Re: My Bloody Regimen » g_g_g_unit, posted by SLS on June 6, 2010, at 0:21:24
Isn't 200mg the highest dose?
Posted by Brainbeard on June 6, 2010, at 1:19:56
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.
>
>Sertraline doesn't produce any cognitive debilitation for me. In a study with elderly folks, it actually improved cognition. The SSRI's usually don't impair cognition much, if at all. When I was starting up fluvoxamine (Luvox), it made me terribly slow at work, but that disappeared once my brain got used to the drug.
Posted by Conundrum on June 6, 2010, at 1:22:11
In reply to Re: My Bloody Regimen, posted by g_g_g_unit on June 6, 2010, at 0:23:25
Other options are effexor and nefazodone for OCD. Might be less dulling.
Posted by g_g_g_unit on June 6, 2010, at 1:41:56
In reply to SSRI's Easy On The Ol' Cognition, posted by Brainbeard on June 6, 2010, at 1:19:56
>
> Sertraline doesn't produce any cognitive debilitation for me. In a study with elderly folks, it actually improved cognition. The SSRI's usually don't impair cognition much, if at all. When I was starting up fluvoxamine (Luvox), it made me terribly slow at work, but that disappeared once my brain got used to the drug.i guess i shouldn't been more patient, though i did give each SRI the requisite 8 weeks. Lexapro and Luvox, in particular, made me feel really foggy; Prozac was neutral, though the sleep disruption at 20mg produced more cognitive s/e's overall.
Posted by Conundrum on June 6, 2010, at 10:46:00
In reply to Re: SSRI's Easy On The Ol' Cognition » Brainbeard, posted by g_g_g_unit on June 6, 2010, at 1:41:56
Maybe 20mg prozac was too high? Many do well at 10 or even 5 mg.
Zoloft, I don't think it is as dulling as lexapro for most ppl.
Posted by SLS on June 8, 2010, at 6:05:52
In reply to Re: My Bloody Regimen, posted by g_g_g_unit on June 6, 2010, at 0:23:25
> >
> >
> >
> > Zoloft is the SSRI that produced the most "brain fog" for me. I was taking 200mg.
> >
> >
> > - Scott
>
> oh strange .. did the effect vary at different doses? which produced the least?
I don't recall the brain fog as being dose-dependent. Perhaps my reaction is atypical.
- Scott
Posted by SLS on June 8, 2010, at 6:10:57
In reply to Re: My Bloody Regimen » SLS, posted by Conundrum on June 6, 2010, at 1:18:10
> Isn't 200mg the highest dose?
Supposedly. I am surprised by how infrequently people reach that dosage. Doctors seem to like 50-100mg. I would continue to increase the dosage of Zoloft to 200mg if it is being tolerated.
- Scott
Posted by Conundrum on June 8, 2010, at 9:33:52
In reply to Re: My Bloody Regimen » Conundrum, posted by SLS on June 8, 2010, at 6:10:57
Perhaps they are aware that too much serotonin is a bad thing and has a flattening effect on mood? Or maybe most patients just do well on 50-100 mg and there is no reason to increase it.
Posted by g_g_g_unit on June 8, 2010, at 10:06:00
In reply to Re: My Bloody Regimen » SLS, posted by Conundrum on June 8, 2010, at 9:33:52
> Perhaps they are aware that too much serotonin is a bad thing and has a flattening effect on mood? Or maybe most patients just do well on 50-100 mg and there is no reason to increase it.
i think you get more DRI at higher doses. im curious about Zoloft. i know someone who is seeing positive gains on just 25mgs. it sounds atypical as far as SSRI's go
Posted by Brainbeard on June 8, 2010, at 11:40:18
In reply to Re: My Bloody Regimen, posted by g_g_g_unit on June 8, 2010, at 10:06:00
The 'S' in 'SSRI' is a bit of a joke.
Prozac is a dopamine and noradrenaline disinhibitor.
Luvox is a potent sigma-1 agonist.
Zoloft is a DRI and also acts on sigma-1 receptors.
Celexa is an antihistaminergic.
Lexapro acts on sigma-1 receptors as well.
Paxil has antihistaminergic and anticholinergic properties and acts on dopamine in higher doses.'RSSRI' would have been a more appropiate name: ' R' for 'Relatively'...
How I love to go off-topic with you guys and gals.
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Dr. Bob is Robert Hsiung, MD,
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