![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 25 of 39. This is the beginning of the thread.
Posted by JohnX2 on March 26, 2002, at 17:48:16
1: Neuropharmacology 2000 Aug 23;39(11):1974-83 Related Articles, Books, LinkOut
Amplification of cortical serotonin release: a further neurochemical action of the vigilance-promoting drug modafinil.Ferraro L, Fuxe K, Tanganelli S, Fernandez M, Rambert FA, Antonelli T.
Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, Ferrara, Italy.
The present in vitro and in vivo studies examined the effects of modafinil on serotonergic transmission in the rat frontal cortex. In the in vitro study modafinil (0.3-30 microM) increased electrically-evoked, but not spontaneous, serotonin ([(3)H]5-HT) efflux from cortical slices in a concentration-dependent manner while the indirect serotonin agonist dl-fenfluramine (1-15 microM) enhanced both spontaneous and evoked [(3)H]5-HT efflux. The effects of modafinil were more pronounced when the 5-HT reuptake was blocked by paroxetine. Contrary to paroxetine (0.3-3 microM) and dl-fenfluramine (1-5 microM), modafinil failed to influence the [(3)H]5-HT uptake. In the in vivo study modafinil (3-100 mg/kg i.p.) increased 5-HT dialysate levels, the maximal effect being already reached at the 30 mg/kg dose. dl-fenfluramine (5 mg/kg) induced an increase in 5-HT levels which was significantly higher than that displayed by modafinil at 30 mg/kg. In the presence of paroxetine (3 microM), the effect of modafinil at 30 mg/kg was higher than that observed in the absence of 5-HT reuptake inhibition. Finally, in the presence of the selective 5-HT(1A) receptor agonist 8-OH-DPAT, modafinil at 100 mg/kg failed to affect 5-HT dialysate levels.These results demonstrate that modafinil regulates cortical serotonergic transmission and suggest that the drug preferentially acts by amplifying the electro-neurosecretory coupling mechanisms and via mechanisms which do not involve the reuptake process.
PMID: 10963741 [PubMed - indexed for MEDLINE]
Posted by JohnX2 on March 26, 2002, at 17:51:07
In reply to modafinil (Provigil) and Serotonin, posted by JohnX2 on March 26, 2002, at 17:48:16
1: Neuropsychopharmacology 1999 Apr;20(4):346-56 Related Articles, Books, LinkOut
The vigilance promoting drug modafinil increases extracellular glutamate levels in the medial preoptic area and the posterior hypothalamus of the conscious rat: prevention by local GABAA receptor blockade.Ferraro L, Antonelli T, Tanganelli S, O'Connor WT, Perez de la Mora M, Mendez-Franco J, Rambert FA, Fuxe K.
Department of Clinical and Experimental Medicine, University of Ferrara, Italy.
The effects of modafinil on glutamatergic and GABAergic transmission in the rat medial preoptic area (MPA) and posterior hypothalamus (PH), are analysed. Modafinil (30-300 mg/kg) increased glutamate and decreased GABA levels in the MPA and PH. Local perfusion with the GABAA agonist muscimol (10 microM), reduced, while the GABAA antagonist bicuculline (1 microM and 10 microM) increased glutamate levels. The modafinil (100 mg/kg)-induced increase of glutamate levels was antagonized by local perfusion with bicuculline (1 microM). When glutamate levels were increased by the local perfusion with the glutamate uptake inhibitor L-trans-PDC (0.5 mM), modafinil produced an additional enhancement of glutamate levels. Modafinil (1-33 microM) failed to affect [3H]glutamate uptake in hypothalamic synaptosomes and slices. These findings show that modafinil increases glutamate and decreases GABA levels in MPA and PH. The evidence that bicuculline counteracts the modafinil-induced increase of glutamate levels strengthens the evidence for an inhibitory GABA/glutamate interaction in the above regions controlling the sleep-wakefulness cycle.
PMID: 10088135 [PubMed - indexed for MEDLINE]
Posted by JohnX2 on March 26, 2002, at 18:09:13
In reply to modafinil (Provigil) and Serotonin, posted by JohnX2 on March 26, 2002, at 17:48:16
1: Neurosci Lett 1999 Jan 15;259(3):181-5 Related Articles, Books, LinkOut
Effects of the vigilance promoting drug modafinil on the synthesis of GABA and glutamate in slices of rat hypothalamus.Perez de la Mora M, Aguilar-Garcia A, Ramon-Frias T, Ramirez-Ramirez R, Mendez-Franco J, Rambert F, Fuxe K.
Department of Biophysics, Instituto de Fisiologia Celular, Universidad Nacional Autonoma de Mexico, Mexico City.
The effects of the vigilance promoting drug modafil were studied ex vivo (100 mg/kg; i.p.) and in vitro (10-1000 microM modafinil) on the synthesis of [3H]gamma-aminobutyric acid ([3H]GABA) and [3H]glutamate from [3H]glutamine within the rat hypothalamus. No effects of modafinil were observed on the overall synthesis of these neurotransmitters nor, in vitro (1-33 microM modafinil) on other parameters related to the compartmentalization of their synthesis (glutamate decarboxylase and phosphate-activated glutaminase activities, and [3H]glutamine uptake). It is suggested on these grounds, that the modafinil-induced reductions and increases in regional GABA and glutamate extracellular levels respectively using in vivo microdialysis may be a consequence of an indirect effect of modafinil on these neurons.
PMID: 10025588 [PubMed - indexed for MEDLINE]
Posted by JohnX2 on March 26, 2002, at 18:12:43
In reply to modafinil: glutamate and gaba blockade 2, posted by JohnX2 on March 26, 2002, at 18:09:13
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9376524&dopt=Abstract1: Neuroreport 1997 Sep 8;8(13):2883-7 Related Articles, Books, LinkOut
The antinarcoleptic drug modafinil increases glutamate release in thalamic areas and hippocampus.Ferraro L, Antonelli T, O'Connor WT, Tanganelli S, Rambert F, Fuxe K.
Department of Experimental and Clinical Medicine, University of Ferrara, Italy.
The antinarcoleptic drug modafinil [(diphenyl-methyl)-sulfinyl-2-acetamide; Modiodal] dose-dependently inhibits the activity of GABA neurons in the cerebral cortex and in the nucleus accumbens, as well as in sleep-related brain areas such as the medial preoptic area and the posterior hypothalamus. This study examined the effects of modafinil (30-300 mg/kg, i.p.) on dialysate glutamate and GABA levels in the ventromedial (VMT) and ventrolateral (VLT) thalamus and hippocampal formation (Hip) of the awake rat. The results show a maximal increase in glutamate release in these brain regions at the 100 mg/kg dose, associated with a lack of effect on GABA release. Thus modafinil may increase excitatory glutamatergic transmission in these regions, altering the balance between glutamate and GABA transmission.
PMID: 9376524 [PubMed - indexed for MEDLINE]
Posted by JohnX2 on March 26, 2002, at 18:15:21
In reply to modafinil: glutamate and gaba blockade 3, posted by JohnX2 on March 26, 2002, at 18:12:43
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8977135&dopt=Abstract1: Neurosci Lett 1996 Dec 6;220(1):5-8 Related Articles, Books, LinkOut
The vigilance promoting drug modafinil decreases GABA release in the medial preoptic area and in the posterior hypothalamus of the awake rat: possible involvement of the serotonergic 5-HT3 receptor.Ferraro L, Tanganelli S, O'Connor WT, Antonelli T, Rambert F, Fuxe K.
Institute of Pharmacology, University of Ferrara, Italy.
The effect of modafinil on endogenous gamma-aminobutyric acid (GABA) release in the medial preoptic area (MPA) and posterior hypothalamus (PH) and the role of local 5-HT3 receptors in this effect was investigated in the awake rat using in vivo microdialysis. Modafinil (30-100 mg/kg i.p.) dose-dependently decreased GABA release from the MPA, while only the 100 mg/kg dose markedly reduced GABA release in the PH. The modafinil (100 mg/kg) induced inhibition of GABA release in the MPA and the PH was partially counteracted by the 5-HT3 receptor antagonist MDL72222 (1 microM) when perfused locally alone or together with the non-selective 5-HT receptor antagonist methysergide (1 microM). Thus, the reduction of GABA transmission induced by modafinil in the MPA and in the PH, at least in part, involves local 5-HT3 receptors. The GABA release inhibition by modafinil in the above areas may be relevant for its vigilance promoting action.
PMID: 8977135 [PubMed - indexed for MEDLINE]
Posted by JohnX2 on March 26, 2002, at 18:17:53
In reply to modafinil: 5ht3 interaction with Gaba?, posted by JohnX2 on March 26, 2002, at 18:15:21
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8813612&dopt=Abstract1: Eur J Pharmacol 1996 Jun 13;306(1-3):33-9 Related Articles, Books, LinkOut
The vigilance promoting drug modafinil increases dopamine release in the rat nucleus accumbens via the involvement of a local GABAergic mechanism.Ferraro L, Tanganelli S, O'Connor WT, Antonelli T, Rambert F, Fuxe K.
Institute of Pharmacology, University of Ferrara, Italy.
The present in vivo microdialysis study demonstrated that the subcutaneous injection of modafinil (diphenyl-methyl-sulfinyl-2-acetamide) in doses of 30-300 mg/kg dose dependently increased dopamine release from the intermediate level of the nucleus accumbens along the rostro-caudal axis of the halothane anaesthetized rat. The effect of modafinil in a dose of 100 mg/kg was counteracted by the local perfusion in the nucleus accumbens with the GABAB receptor antagonist phaclofen (beta-p-chlorophenyl-gamma-aminopropyl-phosphonic acid) (50 microM), the GABAA agonist muscimol (3-hydroxy-5-aminomethyl-isoxazolol) (10 microM) and the neuronal GABA reuptake inhibitor SKF89976A (4,4-diphenyl-3-butenyl-nipecotic acid) (0.1 microM), whereas it was increased by the GABAB receptor agonist (-)-baclofen [beta-(p-chlorophenyl-gamma-aminobutyric acid)] (10 microM). In addition, the modafinil-induced increase of dopamine release was associated with a significant reduction of accumbens GABA release. These results suggest that the dopamine releasing action of modafinil in the rat nucleus accumbens is secondary to its ability to reduce local GABAergic transmission, which leads to a reduction of GABAA receptor signaling on the dopamine terminals.
PMID: 8813612 [PubMed - indexed for MEDLINE]
Posted by JohnX2 on March 26, 2002, at 18:24:56
In reply to modafinil: increase dopamine by decrease gaba?, posted by JohnX2 on March 26, 2002, at 18:17:53
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1620245&dopt=Abstract1: Naunyn Schmiedebergs Arch Pharmacol 1992 Apr;345(4):461-5 Related Articles, Books, LinkOut
Inhibitory effects of the psychoactive drug modafinil on gamma-aminobutyric acid outflow from the cerebral cortex of the awake freely moving guinea-pig. Possible involvement of 5-hydroxytryptamine mechanisms.Tanganelli S, Fuxe K, Ferraro L, Janson AM, Bianchi C.
Department of Pharmacology, University of Ferrara, Italy.
The effects of modafinil on acetylcholine and GABA outflow from the cerebral cortex of awake freely moving guinea pigs provided with an epidural cup were studied. In the dose range of 3-30 mg/kg s.c. modafinil produced a dose dependent significant inhibition of GABA outflow without influencing cortical acetylcholine release. Methysergide (2 mg/kg, i.p.) and ketanserin (0.5 mg/kg, i.p.) but not prazosin (0.14 mg/kg, i.p.) counteracted the inhibitory action of modafinil on cortical GABA outflow. Modafinil both acutely and chronically in the same dose range increased striatal 5-HIAA levels and 5-HT utilization in the rat (acute) and mouse (chronic). The action on cortical GABA release may be dependent on activity at 5-HT2 receptors, since the action of modafinil in this respect is blocked by the non-selective 5-HT antagonist methysergide and the 5-HT2 antagonist ketanserin. The involvement of 5-HT mechanisms in the inhibitory action of modafinil on cortical GABA release is also suggested by the findings that 5-HT metabolism may become increased by modafinil at least in the striatum. The reduction of cortical GABA outflow via 5-HT2 receptors by modafinil is probably related to some of its actions on the central nervous system including behavioural effects.
PMID: 1620245 [PubMed - indexed for MEDLINE]
Posted by 3 Beer Effect on March 27, 2002, at 4:19:55
In reply to modafinil: glutamate and gaba blockade, posted by JohnX2 on March 26, 2002, at 17:51:07
I know they are not sure exactly how Provigil works but it appears it may work by increasing glutamate & decreasing GABA
I think Lamictal decreases glutamate.
So wouldn't they counteract each other?I started this regimen 2 months ago:
Lamictal 100 mg/day
Provigil 200 mg/day
Klonopin 4 mg/day.The Provigil worked great for a month but then gradually lost duration of action until now where it does absolutely nothing. I wonder if it is because Lamictal takes about a month to work & once it started working it negated the action of the Provigil?
Posted by JohnX2 on March 27, 2002, at 4:57:58
In reply to Do Lamictal Provigil counteract each other?, posted by 3 Beer Effect on March 27, 2002, at 4:19:55
Hi 3be,Did you get a dopamine kick from provigil?
That medicine worked for 2 hrs for me before pooping out! I've looked at this stupid poopout thing inside out. Adderall would poopout in 3 days like clockwork, except when co-administered with Klonopin, a GabaA agonist. Then it was smooth sailing at 40 mg/day (until Klonopin shit on me). I was actually going to ask you if there was a correlation between the Klopopin tolerance and provigil poop out. I've read papers describing how GabaA (specifically Klonopin) and also nmda antagonist alleviate tolerance to amphetamines. Certainly Klonopin worked for me for amphetamine tolerance. I was quite shocked at the effect. Unfortunately when I built up tolerance to klonopin, the amphetamine went KABAM!
But the lamictal observation is interesting. Some people have reported that lamictal helps with Adderall tolerance (which I thought could be through nmda receptor modulation). However, I have found that if I bump Lamictal above 150 mg that weird shit happens that is not really consistent with a simplified NMDA antagonist effect. I think the medicine starts to reuptake monoamines or something, because it starts to give me tension headaches like Zoloft. The Lamictal only works for me in a narrow window of 150-225 mg.
Hmm, need to think about this provigil some more.
Seems as though not protecting those dopamine receptors with Gaba neurons (which are the Gaba A type like Klonopin stimulate) may lead to some sort of (de)sensitization. Just a quick swag.
Also seems a bit risky in my view to deprotect neurons from Gaba, just my opinion now that I look at the medicine.I also get remarked Wellbutrin poop out, like a response in a few minutes/hours, and then poop out. Go figure. I even tried taking Wellbutrin with dxm (an nmda antagonist) to see if it would prevent tinnitus and poopout and it worked. (except I stopped the experiment because dxm is toxic). A few other posters notably AndrewB used a medication called memantine which just capped hyperglutamate transmission and this purpotedly prevents stimulant poopout (at least for his adderall). I don't know if this would work for Provigil.
Note, I have noticed that if I take Serzone, which is a 5ht-2a antagonist, that I seem to alleviate poop-out to stims. It is also a noradrenanergic alpha-1 antagonist and this helps to produce "pacemaker" firing out of a central pool of dopamine neurons in a area of the brain called the VTA (ventral tegmental area).
I think there is a connection between the serotonin 5ht-2a receptor hyperstimulation, nmda receptor hyperstimulation, and gaba hypostimulation leading to poop out. A genomic cascade which causes dopamine receptor
(de)sensitization. This is still a SWAG on my
behalf. I'll let you know if I figure out more.
My brain may turn to mush in the mean time.Regards,
John> I know they are not sure exactly how Provigil works but it appears it may work by increasing glutamate & decreasing GABA
>
> I think Lamictal decreases glutamate.
> So wouldn't they counteract each other?
>
> I started this regimen 2 months ago:
> Lamictal 100 mg/day
> Provigil 200 mg/day
> Klonopin 4 mg/day.
>
> The Provigil worked great for a month but then gradually lost duration of action until now where it does absolutely nothing. I wonder if it is because Lamictal takes about a month to work & once it started working it negated the action of the Provigil?
Posted by JohnX2 on March 27, 2002, at 5:12:59
In reply to Do Lamictal Provigil counteract each other?, posted by 3 Beer Effect on March 27, 2002, at 4:19:55
3be,When the provigil doesn't work, what does it do?
What it does for me is, it kicks in , gives me a buzz for about 1-2 hrs with increased focus. This poops out (the buzz part) and gives me an enormous headache.
Does the Lamictal make you feel a bit stuporous/confused/dizzy?
(Indicator of hypoglutamatergic activity).Thanks for sharing your experience. I hope it can shed some light on my own. I feel i may have some ADD symptom, but don't know how to treat it.
BTW, I think this whole poop-out thing is a big scam. It could be solved if there was financial interest. But there isn't who has money to be made by addressing this issue? The doctor's make money swizzling the medications. The pharmaceutical makers make money raising the doses. Its all bullshit. I also think TD can be prevented by neuroprotective meds, but who in their right mind would want to fund or even admit that the problem exists? Sorry I rant...
John
> I know they are not sure exactly how Provigil works but it appears it may work by increasing glutamate & decreasing GABA
>
> I think Lamictal decreases glutamate.
> So wouldn't they counteract each other?
>
> I started this regimen 2 months ago:
> Lamictal 100 mg/day
> Provigil 200 mg/day
> Klonopin 4 mg/day.
>
> The Provigil worked great for a month but then gradually lost duration of action until now where it does absolutely nothing. I wonder if it is because Lamictal takes about a month to work & once it started working it negated the action of the Provigil?
Posted by SLS on March 28, 2002, at 8:29:58
In reply to Re: Do Lamictal Provigil counteract each other? » 3 Beer Effect, posted by JohnX2 on March 27, 2002, at 4:57:58
Hi folks.
I wrote this along another thread:
http://www.dr-bob.org/babble/20020327/msgs/100704.html
John, it is almost scary how similarly we react to drugs. I bet Serzone would work for me (partially or otherwise). I am guessing that my positive reaction to Zyprexa, Risperdal, and Geodon were in large part due to their 5-HT2a antagonism.
> Did you get a dopamine kick from provigil?
>
> That medicine worked for 2 hrs for me before pooping out!Me too.
> I've looked at this stupid poopout thing inside out.
> Adderall would poopout in 3 days like clockwork,
Me too with Dexedrine - on several occasions. 3 days.
Scary.
Memantine?
I think there may be some profound significance to the number of days that these responses last - 3. For me, 3 days is exactly how long my transient responses to TCAs, MAOIs, and inoffensive have been. This has been a consistent phenomenon for me over the 20 years that I have been treated.
I have seen the number "3" pop up quite frequently on Psycho-Babble.
It is possible that the number "3" is the key to our doors.
While I'm here, I would like to offer another opportunity for discovery. The existence of a therapeutic window for nortriptyline to the exclusion of all other TCAs might provide for the identification of a specific phenomenon by which depression is both perpetuated and successfully treated.
> except when co-administered with Klonopin, a GabaA agonist. Then it was smooth sailing at 40 mg/day (until Klonopin shit on me).
What about Gabitril? Or perhaps Gabitril + Neurontin (if Neurontin promotes GABA synthesis as some have suggested).
Neurontin = Accelerated synthesis of GABA
Gabitril = GABA reuptake inhibitionI am still dubious of the notion that Neurontin increases GABA synthesis. Can you find more information with regard to the pharmacologic properties that Neurontin displays? Although Neurontin can provide me an improvement upon the initiation of treatment, I get all whacked-out and zombie-like within a week or two. I don't know whether this phenomenon is dosage dependant or time-dependant. It occurs at dosages as low as 900mg, and does not appear to mitigate with time.
Oh, and another thing in re poop-out (tachyphylaxis). It almost seems as if the system simply runs out of gas - what little stores of DA that are available are quickly depleted. Here's an observation about my depressed state. It quickly worsens *significantly* upon an attempt to read more than a few paragraphs. It actually "feels" as if I run out of gas. The worsened state most often lasts for hours - or even the balance of the day. I really do think that something is going on presynaptically that prevents an adequate synthesis of dopamine. Have you ever encountered an experiment that attempts to assay tyrosine-hydroxylase activity?
- Scott
Posted by SLS on March 28, 2002, at 10:36:54
In reply to Re: Do Lamictal Provigil counteract each other? ?JohnX2, posted by SLS on March 28, 2002, at 8:29:58
Error:
¡§inoffensive¡¨ should have read ¡§nomifensine¡¨
Nomifensine is an older antidepressant that was marketed briefly as Merital in Europe and the US. It is primarily a reuptake inhibitor of both dopamine (DA) and norepinephrine (NE). Nomifensine was withdrawn from markets worldwide when reports began to surface associating it with fatal hemolytic anemia.
-----------------------------------------------------
> I think there may be some profound significance to the number of days that these responses last - 3. For me, 3 days is exactly how long my transient responses to TCAs, MAOIs, and NOMIFENSINE have been. This has been a consistent phenomenon for me over the 20 years that I have been treated.
I have seen the number "3" pop up quite frequently on Psycho-Babble.> It is possible that the number "3" is the key to our doors.
-----------------------------------------------------
- Scott
Posted by JohnX2 on March 28, 2002, at 13:32:34
In reply to Re: Do Lamictal Provigil counteract each other? » JohnX2, posted by SLS on March 28, 2002, at 8:29:58
> Hi folks.
>
> I wrote this along another thread:
>
> http://www.dr-bob.org/babble/20020327/msgs/100704.html
>
> John, it is almost scary how similarly we react to drugs. I bet Serzone would work for me (partially or otherwise). I am guessing that my positive reaction to Zyprexa, Risperdal, and Geodon were in large part due to their 5-HT2a antagonism.
>
> > Did you get a dopamine kick from provigil?
> >
> > That medicine worked for 2 hrs for me before pooping out!
>
> Me too.
>
> > I've looked at this stupid poopout thing inside out.
>
> > Adderall would poopout in 3 days like clockwork,
>
> Me too with Dexedrine - on several occasions. 3 days.
>
> Scary.
>
> Memantine?I want to give it a run. I think I can get a script. I think the medicine is harmless if it doesn't help. In fact at this point after getting a little dystonia, I wouldn't mind having some neuroprotection. My short silly Wellbutrin trial with dxm worked (The wellbutrin didn't give me tinnitus or poop out). Have you ever thought about trying memantine?
>
> I think there may be some profound significance to the number of days that these responses last - 3. For me, 3 days is exactly how long my transient responses to TCAs, MAOIs, and inoffensive have been. This has been a consistent phenomenon for me over the 20 years that I have been treated.
>
> I have seen the number "3" pop up quite frequently on Psycho-Babble.
>
> It is possible that the number "3" is the key to our doors.
>My feeling is YES! An I personally believe that if I am taking medicines that somehow prevent poopout even on the simple stimulants and correct whatever is malfunctioning (the poopout), then this will open the doors to getting effective AD responses.
My feeling for myself is understanding poop out not which AD, etc (although trying to understand which AD did what is leading up to the same conclusions), will be more key. Personally if I am up and running an an AD (like I am today on Lamictal), but still get poopout on dexedrine, then that leaves a question in my mind that something is still "broken". Frankly I have never gotton back that full wonderfull response I saw on St. John's Wort.
Sorry I refuse to use the hard to remember tachyphylaxism - where do you pick this shit up, and also you seem to know all the cool chemical names, what gives? You have a science background?
> While I'm here, I would like to offer another opportunity for discovery. The existence of a therapeutic window for nortriptyline to the exclusion of all other TCAs might provide for the identification of a specific phenomenon by which depression is both perpetuated and successfully treated.
>That is interesting. I saw your posts with Dr. Goldberg. Are you looking at some extremely sensitive feedback mechanism that requires precision dosing?
That was my point on the stuff I was looking at for TD like treatment, the medicines that intervene seem to brake a chaotic "non-linear" feed back loop. (Mostly by working on Gabaergic and NMDA antagonist paths).
> > except when co-administered with Klonopin, a GabaA agonist. Then it was smooth sailing at 40 mg/day (until Klonopin shit on me).
>
> What about Gabitril? Or perhaps Gabitril + Neurontin (if Neurontin promotes GABA synthesis as some have suggested).
>
> Neurontin = Accelerated synthesis of GABA
> Gabitril = GABA reuptake inhibition
>
> I am still dubious of the notion that Neurontin increases GABA synthesis. Can you find more information with regard to the pharmacologic properties that Neurontin displays? Although Neurontin can provide me an improvement upon the initiation of treatment, I get all whacked-out and zombie-like within a week or two. I don't know whether this phenomenon is dosage dependant or time-dependant. It occurs at dosages as low as 900mg, and does not appear to mitigate with time.
>
Neurontin doesn't doesn't do shit. Topamax helps though. Topamax increases Chloride flux through GabaA neurons much like Klonopin. I believe the addition of Topamax to my cocktail has alleviated some stimulant tolerance (at least shortly after this, pseudoephedrine and caffeine really kicked in). It also precipitated my mania. Topamax also modulates the AMPA gluatamate receptors. You might want to put it on your list of things to try. It didn't make me dumb, which is the main side effect. Perhaps the cascade of AMPA and NMDA glutamate modulation by Topamax and Lamictal is therapeutic. Just a thought.
> Oh, and another thing in re poop-out (tachyphylaxis). It almost seems as if the system simply runs out of gas - what little stores of DA that are available are quickly depleted. Here's an observation about my depressed state. It quickly worsens *significantly* upon an attempt to read more than a few paragraphs. It actually "feels" as if I run out of gas. The worsened state most often lasts for hours - or even the balance of the day. I really do think that something is going on presynaptically that prevents an adequate synthesis of dopamine. Have you ever encountered an experiment that attempts to assay tyrosine-hydroxylase activity?
>
>What do you mean by assay?
I was looking into old schools blood pressure issue, and I found that dosing of bromocriptine *reduces* noradrenaline output for some people (and reduces blood pressure) by somehow indirectly reducing MAO. Food for thought. I should look into this some more, it sound like some interesting shit.
I also was looking into this indirect sensitization pathway to the dopamine D1 receptor by alpha-1 receptors. The D1 receptor is quite involved in amphetamine sensitization.
As far as the Parnate goes, I see that it mainly increases monoamine in the synaptic clept as opposed to upregulating d2 receptors (like the reuptake inhibitors).
I dunno, frankly I think if you and I could figure out why Provigil and Dexedrine, 2 totally different medicines, yet simple, crap out in short order, and how to alleviate this, then we would really be on the right track to getting the ADs to respond robustly.
I hope all my typing is not making you depressed.
I'll look into the tyrosine hydroxylase thing some more. I think there may be something there.
John
> - Scott
Posted by jazzdog on March 28, 2002, at 14:31:17
In reply to Re: Do Lamictal Provigil counteract each other? » SLS, posted by JohnX2 on March 28, 2002, at 13:32:34
I've been trying to figure out this ssri dopamine depletion thing. I read that ssri's exhaust the adrenal glands, which may be the underlying cause. And it turns out that one of the most potent adrenal boosters is glycerhizin, the active ingredient in licorice. Of course, the licorice you buy at the store contains virtually no real licorice - aniseed is substituted. But licorice tea - available at the healthfood store - has met with success in treating chronic fatigue syndrome and is considered one of the most potent drugs in Chinese medicine. I'm going to check it out, and I'll let you know.
- Jane
Posted by jazzdog on March 28, 2002, at 14:36:11
In reply to Licorice tea? No, seriously ..., posted by jazzdog on March 28, 2002, at 14:31:17
Check out:
www.wholehealthmd.com/refshelf/substances_view/0,1525,801,00.html
Posted by JohnX2 on March 28, 2002, at 14:51:10
In reply to Licorice tea? No, seriously ..., posted by jazzdog on March 28, 2002, at 14:31:17
Usually when people are depressed the body has a hyperactive adrenal gland and is producing too much cortisol. Licorice helps to prevent the breakdown of cortisol. There are feedback receptors in the brain called glucocorticoid receptors that are supposed to reduce cortisol production when it is stimulated by excessive glucocorticoids (cortisols, etc).In depressed people, these glucocorticoid receptors are overly downregulated and may not properly feed back and stop the release of cortisol production. Chronic administration of antidepressants often reverses this problem in the HPA axis (hypothalamus-pituitary-adrenal gland). This phenomina may be thought as glucocoritcoid non-suppression. There is a test for this called a dexamethasone (a synthetic steroid) that can be administered to see how your circulating cortisol levels react (maybe your cortisol is too high, and the dexamethasone does not cause a feed back to suppress it).
Now there can be another type of depression that is very backwards that is often associated with PTSD or with Adrenal exhaustion and it has as a trademark of *extremely* low levels of cortisol. This type of depression can be very difficult to treat and give irratic antidepressant responses. In this case there is a hyper-feedback of cortisol administration. The glucorticoid (cortisol detecting) receptors in the brain are overly sensitive (up regulated) and when more glucocorticoid is injected synthetically (say with dexamethasone) then the body will actually do a hyperfeedback and supersupress the cortisol secretion.
I've read that some people believe licorice may be helpful for adrenal exhaustion or ptsd. but it may not be a good idea for vanilla depression (IMO).
You may see an endocrinologist and get your corisol levels checked out 1st.
John
> I've been trying to figure out this ssri dopamine depletion thing. I read that ssri's exhaust the adrenal glands, which may be the underlying cause. And it turns out that one of the most potent adrenal boosters is glycerhizin, the active ingredient in licorice. Of course, the licorice you buy at the store contains virtually no real licorice - aniseed is substituted. But licorice tea - available at the healthfood store - has met with success in treating chronic fatigue syndrome and is considered one of the most potent drugs in Chinese medicine. I'm going to check it out, and I'll let you know.
>
> - Jane
Posted by JohnX2 on March 28, 2002, at 16:11:26
In reply to Re: Do Lamictal Provigil counteract each other? » SLS, posted by JohnX2 on March 28, 2002, at 13:32:34
> I was looking into old schools blood pressure issue, and I found that dosing of bromocriptine *reduces* noradrenaline output for some people (and reduces blood pressure) by somehow indirectly reducing MAO. Food for thought. I should look into this some more, it sound like some interesting shit.
>acutally the bromocriptine at the lower doses hits the presynaptic autorectors and lowers catecholinergic activity. One article suggested *increased* MAO activity.
Purportedly low dose of Pramipexole dose the same.
John
1: Kardiologiia 1991 Apr;31(4):22-4 Related Articles, Books, LinkOut
[Effects of bromocriptine on catecholamine metabolism in subjects with borderline arterial hypertension][Article in Russian]
Merkulova NK, Romaniuk SN, Petunin SN, Temirov AA.
Effects of bromocriptine on hemodynamics and catecholamine exchange were evaluated in patients with borderline arterial hypertension with respect to their family history. The agent was shown to be able to bring down blood pressure and decrease plasma catecholamine levels. With this, platelet monoamine oxidase activity was increased in persons with a family history of hypertensive disease.
PMID: 2067174 [PubMed - indexed for MEDLINE]
Posted by JohnX2 on March 28, 2002, at 17:16:48
In reply to Re: Do Lamictal Provigil counteract each other? » JohnX2, posted by SLS on March 28, 2002, at 8:29:58
>
> Neurontin = Accelerated synthesis of GABA
> Gabitril = GABA reuptake inhibition
>I can look into the Neurontin. I would suggest a Topamax trial if you already know that the Neurontin puts you in a haze. The Gabitril has a worse reputation for tolerability from what I hear. Topamax is a good Gabaergic medicine and I really think that the AMPA glutamate modulation may add a unique therapeutic component to your treatment. Just a thought. Also, Topamax is less sedating. It tends to be more stimulating (but it may give a fog).
Did you get some good leads on Gabatril?
John
Posted by JohnX2 on March 28, 2002, at 20:14:17
In reply to Licorice tea? No, seriously ..., posted by jazzdog on March 28, 2002, at 14:31:17
Hi Jane,
Thanks for the useful information. I also wondered about this matter.
I was once hip-shooting that maybe the body adjusts too far the other way on the AD from a hyperactive HPA (hypothalamus-pituitary-adrenal) axis to a hypoactive HPA.
Can you send any links with information about SSRIs and their connections to the adrenals. I would really appreciate it!
Thanks and best wishes.
John
> I've been trying to figure out this ssri dopamine depletion thing. I read that ssri's exhaust the adrenal glands, which may be the underlying cause. And it turns out that one of the most potent adrenal boosters is glycerhizin, the active ingredient in licorice. Of course, the licorice you buy at the store contains virtually no real licorice - aniseed is substituted. But licorice tea - available at the healthfood store - has met with success in treating chronic fatigue syndrome and is considered one of the most potent drugs in Chinese medicine. I'm going to check it out, and I'll let you know.
>
> - Jane
Posted by jazzdog on March 28, 2002, at 22:20:14
In reply to Re: SSRI, adrenal exhaustion » jazzdog, posted by JohnX2 on March 28, 2002, at 20:14:17
Here's the link:
www.antidepressantsfacts.com/pinealstory.htm
It's a pretty interesting site. The adrenal connection is made in Section 2a, Affecting Mood or Mind.
- Jane
Posted by JohnX2 on March 28, 2002, at 22:50:01
In reply to Re: SSRI, adrenal exhaustion » JohnX2, posted by jazzdog on March 28, 2002, at 22:20:14
Scott/Jane,
I was wondering about the possiblity of getting evaluated for a DST (dexamethasone suppression test)? I have never done this. Do I need to see an endocrinologist?
Scott had indicated a long time ago he was a DST non-suppressor (which is a norm for major depression), I was wondering myself if it was possible to get stuck in a hypocortisolemia state and become a DST super-suppressor. This could give very erratic AD/stimulant poop out.People with MDD who have adrenal exhaustion or perhaps a history of PTSD may have a hypocortisolemia state. I believe detecting this can significantly alter ones treatment strategy.
John
Posted by Bekka H. on March 28, 2002, at 23:26:21
In reply to Re: SSRI, adrenal exhaustion, posted by JohnX2 on March 28, 2002, at 22:50:01
Hi John,
I think that an endocrinologist would be the best person to see, but I imagine some internists could do it, too. Some internists have dual specialties in endocrinology and internal medicine. I've had two Dexamethasone suppression tests in my life. They are used to test for certain endocrine abnormalities as well as for the psychiatric disturbances. Actually, the DST for psychiatric use is highly controversial and somewhat unreliable. I have had highly elevated corticosteroid levels for many years, yet both of my DST's were normal (i.e., I DID suppress cortisol). If I'm not mistaken, I believe it was Peter Stokes, M.D., at the Weill Medical College of Cornell University, who "gave birth to" the use of the Dexamethasone Suppression Test for depression.
Perhaps your psychiatrist could refer you to an endocrinologist. That would probably be the best route.
I don't know what part of the country you live in. If you're in NY, I could recommend some people, but most Manhattan doctors charge too much and most do not participate in managed care, so you have to foot the bill yourself and then submit the bill to your insurance company.
P.S. This weekend I will rent "Planes, Trains and Automobiles."
Bekka
Posted by JohnX2 on March 28, 2002, at 23:27:04
In reply to Re: SSRI, adrenal exhaustion » JohnX2, posted by jazzdog on March 28, 2002, at 22:20:14
Hi Jane,Most conventional psychiatry would disagree with the information presented on that web site.
If I am reading that paragraph correct, the website implies that the SSRIs increase the output of cortisol and adrenaline to produce a euphoric state. Best I understand, this is simply not the case according to conventional thought.
What is generally thought to be the case is that a depressed person may have excessive levels of cortisol circulating through the body, and the feedback mechanisms to control this are not in check. One may also find enlarged adrenal glands in a depressive. An effective antidepressant would correct the hypercortisolemia, which could be protective in many ways to ones health, contrary to the statement made in the web site.
John
> Here's the link:
>
> www.antidepressantsfacts.com/pinealstory.htm
>
> It's a pretty interesting site. The adrenal connection is made in Section 2a, Affecting Mood or Mind.
>
> - Jane
Posted by JohnX2 on March 28, 2002, at 23:38:36
In reply to Re: SSRI, adrenal exhaustionJohnx2, posted by Bekka H. on March 28, 2002, at 23:26:21
> Hi John,
>
> I think that an endocrinologist would be the best person to see, but I imagine some internists could do it, too. Some internists have dual specialties in endocrinology and internal medicine. I've had two Dexamethasone suppression tests in my life. They are used to test for certain endocrine abnormalities as well as for the psychiatric disturbances. Actually, the DST for psychiatric use is highly controversial and somewhat unreliable. I have had highly elevated corticosteroid levels for many years, yet both of my DST's were normal (i.e., I DID suppress cortisol). If I'm not mistaken, I believe it was Peter Stokes, M.D., at the Weill Medical College of Cornell University, who "gave birth to" the use of the Dexamethasone Suppression Test for depression.
>Hi Bekka,
Can I pick your brain...
Thanks, I have read that the DST is not a very accurate marker, just a proxy. Were you depressed when you were marked a DST suppressor?
I've heard of people with certain flavors of disorders being able to get their cortisol levels down, but never suppressing cortisol after AD administration.
Also have you had your cortisol levels measured "normal" after a depression lift?
I'm pretty sure I have immune system dysfunction associated with my problems as I have this Raynaud's problem that flares up.
Regards,
John
> Perhaps your psychiatrist could refer you to an endocrinologist. That would probably be the best route.
>
> I don't know what part of the country you live in. If you're in NY, I could recommend some people, but most Manhattan doctors charge too much and most do not participate in managed care, so you have to foot the bill yourself and then submit the bill to your insurance company.
>
> P.S. This weekend I will rent "Planes, Trains and Automobiles."
>
> Bekka
Posted by Bekka H. on March 29, 2002, at 0:31:50
In reply to Re: SSRI, adrenal exhaustionJohnx2 » Bekka H., posted by JohnX2 on March 28, 2002, at 23:38:36
Hi John,
Yes, I was depressed when I was a DST suppressor. I think I've been depressed most of my life, but the two DST tests were done in 1996 and 2000. Both were "normal." My corticosteroid levels, however, have been consistently elevated for YEARS, regardless of whatever antidepressant I've been on - or off. I'm convinced that my hippocampus must be all shriveled up by now. Earlier this year, I tried Tianeptine, because I heard that it might reverse some hippocampal damage caused by excess cortisol. Unfortunately, I was unable to give the Tianeptine a long enough trial. I did try it for about a month, but I wasn't up to the therapeutic dose during most of that time, and I did not see much improvement in my mood during that brief trial. I might try it again some day, but not for a while.
Do you see a rheumatologist for your Raynaud's?
Bekka
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