![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 22 to 46 of 46. Go back in thread:
Posted by zeugma on February 26, 2006, at 8:48:11
In reply to Typo...I meant to ask.., posted by mike99 on February 25, 2006, at 21:16:34
>
> if provigil could result in the release of epinephrine and norepinephrine from the adrenals. >>yes, modafinil does.
I experienced a syncopal episode when I switched from 30 mg Ritalin to Provigil 200 mg. I experienced this in the evening (I took Provigil early in the am). I experienced much more profound effects on heart rate on Ritalin (I experience none on Provigil). Neither drug affected my BP.
-z
Posted by SLS on February 26, 2006, at 9:11:37
In reply to Re: provigil discussion » SLS, posted by mike99 on February 25, 2006, at 13:51:04
> Do you have any thoughts then on how provigil stimulates the cardiovascular system,
Not really. Again, I would refer you to structures in the hypothalamus and reticular formation that contain orexinergic (hypocretin) and glutamatergic neurons. The hypothalamus most certainly serves to regulate vital bodily functions.
Regarding modafinil and dopamine, at least one mechanism by which limbic areas rich in DA neurons are stimulated is via the glutamate-releasing properties of modafinil in the thalamus. The GABA-glutamate balance is shifted towards glutamate, thus stimulating (disinhibiting) the nucleus accumbens, a reward center located in the limbic system. I don't believe modafinil affects directly any DA receptor or transporter.
My first guess is that beta blockers would help to mitigate any tachycardia or perhaps even anxiety. The beta blocker probably would not act to antagonize the pharmacology of modafinil, but, rather, to simply compensate for it downstream. Losartan might be an ideal drug as it would also help mitigate the increase in blood pressure seen with modafinil. It would help reduce the effects of the excess plasma NE that modafinil is capable of producing. It should accomplish this by preventing the stimulation of peripheral NE alpha-1 receptors by endogenous NE.
The problem with some of the older studies of modafinil is that they focused almost exclusively on the effects it had on aminergic neurotransmission, particularly NE and DA. Unfortunately, some of the investigators jumped to conclusions prematurely regarding the mechanisms of involvement of these neurotransmitters. Just because a particular pathway must be intact for a drug to produce changes downstream doesn't mean that this pathway is directly affected by the test drug. However, this was the basis by which the original research inferred a direct effect for modafinil on NE receptors.
Modafinil was originally pronounced to be a central alpha-1 adrenergic agonist. No more.
The package label and PDR entries for modafil were written after the NE receptor theories were debunked. The mechanisms by which modafinil produces wakefulness are not well understood, but probably do involve hypocretin. By contrast, the mechanisms by which modafinil improves depression (usually implemented as an augmenting agent) might involve the shifting of thalamic glutamate/GABA balance towards glutamate and the subsequent activation of DA neurons in the nucleus accumbens.Sorry for the redundancies.
- Scott
Posted by zeugma on February 26, 2006, at 12:50:20
In reply to Re: provigil discussion, posted by SLS on February 26, 2006, at 9:11:37
the mechanisms by which modafinil improves depression (usually implemented as an augmenting agent) might involve the shifting of thalamic glutamate/GABA balance towards glutamate and the subsequent activation of DA neurons in the nucleus accumbens.>>
Modafinil also elevates serotonin levels in cortex and dorsal raphe, which is surely relevant to depression.
-z
Posted by SLS on February 26, 2006, at 14:38:46
In reply to Re: provigil discussion » SLS, posted by zeugma on February 26, 2006, at 12:50:20
> the mechanisms by which modafinil improves depression (usually implemented as an augmenting agent) might involve the shifting of thalamic glutamate/GABA balance towards glutamate and the subsequent activation of DA neurons in the nucleus accumbens.>>
>
> Modafinil also elevates serotonin levels in cortex and dorsal raphe, which is surely relevant to depression.
>
> -z
I did not know this. Do you think this is an effect secondary to another mechanism of action of modafinil, or does the molecule affect 5-HT neurons directly? In other words, are the outflows of 5-HT in these areas secondary to increases in the releases of hypocretin or glutamate produced elsewhere by modafinil?Again, we see hypocretin:
I found this interesting:
Here, modafinil seems to act as an amplifier. By itself, though, it does not elicit 5-HT increase. I noticed some other work by these same authors suggesting otherwise, but at concentrations too high to be relevant to those in clinical use.
- Scott
Posted by tessellated on February 26, 2006, at 14:48:22
In reply to Re: provigil discussion » zeugma, posted by SLS on February 26, 2006, at 14:38:46
OK, now I've gotta question.
What are your guys' thoughts on combining MAOI's with modafinil?
The fears are also of potentiating hypertension.
???
Posted by mike99 on February 26, 2006, at 15:28:14
In reply to Re: provigil discussion, posted by SLS on February 26, 2006, at 9:11:37
>>Losartan might be an ideal drug as it would also help mitigate the increase in blood pressure seen with modafinil. It would help reduce the effects of the excess plasma NE that modafinil is capable of producing. It should accomplish this by preventing the stimulation of peripheral NE alpha-1 receptors by endogenous NE.
Hey Scott,
Thanks for the info. Please correct me if I'm mistaken, but I believe losartin is an angiotensin II receptor antagonist.
And while this would lower blood pressure by preventing vasoconstriction and inhibiting aldosterone sectretion from the adrenals, it would not block peripheral NE alpha-1 receptors from endogenous NE (or epinephrine).
I think only an alpha-1 antagonist such as prazosin or a mixed alpha/beta blocker such as labetalol or carvedilol could do this.
Posted by mike99 on February 26, 2006, at 15:31:33
In reply to Re: Typo...I meant to ask.. » mike99, posted by zeugma on February 26, 2006, at 8:48:11
> >
> > if provigil could result in the release of epinephrine and norepinephrine from the adrenals. >>
>
> yes, modafinil does.
>
> I experienced a syncopal episode when I switched from 30 mg Ritalin to Provigil 200 mg. I experienced this in the evening (I took Provigil early in the am). I experienced much more profound effects on heart rate on Ritalin (I experience none on Provigil). Neither drug affected my BP.So you experienced a single episode of syncope and haven't had any problems with it since?
Posted by mike99 on February 26, 2006, at 15:44:04
In reply to Re: provigil discussion, posted by mike99 on February 26, 2006, at 15:28:14
Since it increases plasma epinephrine and norephinephrine, and I'm guessing also direct NE release from sympathetics to the heart.Don't know if anyone really cares about this, so if not please ignore this, but I am very sensitive to sympathomimetics.
I'm hoping provigil may be an alternative since it has less effects on the cardiovascular system. Yet it does seem to have definite sympathomimetic activity.
I've heard of people often combining sympathomimetics with beta blockers to counter the cardiovascular effects. My understanding is this has the potential for "unopposed beta blockade"--where beta receptors are blocked out of proportion with alpha receptors and that this can be very dangerous.
For example, in the ER someone with a cocaine or amphetamine OD should never be treated with a beta blocker solely, but rather a mixed alpha/beta antagonist such as labetalol or carvedilol. This is my understanding.
I don't think many docs are even aware of this.
Anyhow, I am digressing but would be interested in anyone who's switched to provigil due to stimulant intolerance or combined it with an alpha or beta blocker.
Cheers.
Posted by zeugma on February 26, 2006, at 16:10:34
In reply to Re: provigil discussion » zeugma, posted by SLS on February 26, 2006, at 14:38:46
Here, modafinil seems to act as an amplifier. By itself, though, it does not elicit 5-HT increase. I noticed some other work by these same authors suggesting otherwise, but at concentrations too high to be relevant to those in clinical use.>>
I believe you're referring to this:
Doses of modafinil administered to rats are much higher than those administered to other species, including mice:
So possibly the effect on 5-HT observed by Fuxe et al. is therapeutically relevant to humans, in isolation.
What really puzzles me is that modafinil has absolutely no REM-suppressant or anticataleptic effect. This in itself is surprising, since most drugs that work through the alpha-1 adrenoceptor (directly or not) are REM-suppressant and anticataleptic, and I am recovering from my usual Sunday series of REM-distorted sleep episodes that were not a problem when I was on methylphenidate (meaning I could nap on methylphenidate and not experience a sleep-onset REM period that causes immediate, unpleasant waking). Buspirone, too, through stimulation of post-synaptic 5-HT1A receptors or alpha-2 adrenoceptors, blocks REM, making it useful as a quick REM suppressant (but I am trying to stay awake today, so fell asleep involuntarily- but last week I was able to nap during the afternoon after taking buspirone). So I was especially interested in the following passage of the reference you cited:
<<
It has been hypothesized that activation of 5-HT neurons contributes to the function of ascending arousal systems projecting to the forebrain (O'Hearn and Molliver, 1984; McQuade and Sharp, 1995, 1997; Portas et al., 1998). Within the brainstem, serotonergic inputs to REM-sleep active areas in the pedunculopontine tegmental and laterodorsal tegmental nucleus (Honda and Semba, 1994; Vertes and Kocsis, 1994) would tend to suppress REM sleep (Thakkar et al., 1998; Monti and Monti, 2000; Portas et al., 2000). Consistent with this model, in vitro data have shown that 5-HT and 5-HT1A agonists inhibit neurons in those regions (Luebke et al., 1992; Leonard and Llinas, 1994). Furthermore, microinjections of 5-HT into the laterodorsal tegmental nucleus in behaving (unanesthetized) cats and rats have been shown to produce a dose-dependent suppression of REM sleep (Sanford et al., 1994; Horner et al., 1997). In addition, there is direct evidence that suppression of 5-HT neuronal activity in the DRN increases REM sleep (Portas et al., 1996). Thus, direct activation of 5-HT neurons by hcrts could promote wakefulness or suppress sleep states through these and other brainstem and forebrain projections. >>The statement elsewhere in the article that the hypocretin ACTIVATED GABAA signalling in the dorsal raphe is consistent with the fact that both modafinil and clonazepam induce sleep onset REM for me:
<<In the present study, we have found that high concentrations of hcrts can have an indirect inhibitory effect on 5-HT cells by exciting GABAergic interneurons in the DRN area. It remains to be determined how hcrts interact with other transmitters in regulating the GABAergic inputs to the 5-HT cells. Nevertheless, the present results show that the influence of hcrts in the DRN is more complex than simply the direct excitation of 5-HT neurons.>>
Most narcoleptics lack hypocretin in their CSF, but nonetheless they still experience the hypocretinergic effects (increased waking, and aggravation of cataplexy/REM). In fact one physician even speculated (under the sway of earlier thorists who maintained that modafinil worked directly on alpha-1 receptors) that modafinil must be a mixed agonist/antagonist at alpha-1 receptors, since it induced cataplexy and sleep onset REM in his patient.
I would guess that it is hypocretin that is responsible for much of modafinil's effects, from reading the article you cited.
I suppose hypocretin's activation of GABAergic interneurons in the DRN might also be responsible for why modafinil is not especially epileptigenic.
By the way, Karel Fuxe is one of the most illustrious names in neuropharmacology.
-z
Posted by zeugma on February 26, 2006, at 16:15:47
In reply to Re: Typo...I meant to ask.. » zeugma, posted by mike99 on February 26, 2006, at 15:31:33
Posted by zeugma on February 26, 2006, at 16:27:47
In reply to i guess provigil IS an atypical sympathomimetic, posted by mike99 on February 26, 2006, at 15:44:04
Sorry, I can't answer the questions about MAOI's or how to deal with Provigil's sympathomimetic activity, Scott is much more knowledgeable than I am about these matters.
I am probably somewhat tolerant to symapathomimetic activity through years of heavy caffeine use in an attempt to treat my ADHD and sleep disorder.
I do know that an individual has combined MAOI's with Provigil to control narcolepsy and atypical depression, but all I've read is that case study. I don't know about Nardil or other MAOI's.
-z
Posted by ed_uk on February 26, 2006, at 17:07:46
In reply to Re: provigil discussion, posted by mike99 on February 26, 2006, at 15:28:14
........modafinil, it's more relevent to amphetamines and methylphenidate.
Hi Mike
Losartan is, as you say, an angiotensin antagonist.
>it would not block peripheral NE alpha-1 receptors
That's right.
>I think only an alpha-1 antagonist such as prazosin or a mixed alpha/beta blocker such as labetalol or carvedilol could do this.
Among the alpha-1 antagonists, doxazosin (Cardura) is often used in favour of prazosin at the moment, at least it is in the UK. Doxazosin has a longer duration of action than prazosin and provides more consistent anti-hypertensive efficacy across the day. Doxazosin is usually administered once or twice daily, initially as a single dose at bedtime. It can be usefully combined with a beta blocker (such as atenolol or bisoprolol) if necessary. Alpha-1 antagonists do at times cause drowsiness and might theoretically reduce some of the effects of the stimulant. Doxazosin acts as a vasodilator, it reduces BP but not heart rate.
Regards
Ed
Posted by mike99 on February 26, 2006, at 17:18:22
In reply to What I'm about to say is not really relevent to... » mike99, posted by ed_uk on February 26, 2006, at 17:07:46
Posted by SLS on February 26, 2006, at 19:21:29
In reply to What I'm about to say is not really relevent to... » mike99, posted by ed_uk on February 26, 2006, at 17:07:46
Oops.
Sorry.
I was thinking of carvedilol (Coreg).
- Scott
Posted by alohashirt on February 27, 2006, at 0:00:13
In reply to Re: provigil discussion » SLS, posted by mike99 on February 25, 2006, at 13:51:04
>
> Scott,
>
> It does seem the most recent theory is that provigil is not a ligand for any NE receptor as you state.
>
> Do you have any thoughts then on how provigil stimulates the cardiovascular system, (though this is supposed to be minimal)? And if a beta blocker would safely and effectively counter these effects (my guess is it would)?Does it stimulate the cardiovascular system? I couldn't take Adderall, had to take bta blocker to take dexedrine but Provigil did not affect my BP (or my ADHD for that matter) but it helped me stay awake.
Posted by mike99 on February 27, 2006, at 0:45:28
In reply to Re: provigil discussion, posted by alohashirt on February 27, 2006, at 0:00:13
alohashirt,
If you count up 14 threads prior to yours, there is a thread posted by zeugma with a good link regarding your question.
Posted by Larry Hoover on February 27, 2006, at 10:37:25
In reply to provigil mechanism of action?, posted by mike99 on February 24, 2006, at 17:33:54
> Does anyone know provigil's mechanism of action? I've found two contradictory statments on the web:
>
> 1. Pharmacologic Action: alpha-1-adrenoceptor antagonist, dopamine reuptake inhibitor (neurotransmitter.net--future list of drugs...)
>
> 2. Modafanil does not appear to be a direct or indirect alpha-adrenergic agonist (modafanil.com)
>
> Also: "(modafanil) has minimal effects on cardiovascular and hemodynamic parameters". Is this true? If so why caution in patients with cardiovascular conditions?
>
> Thanks for any feedback.
Modafinil sure is an interesting drug. It's supposed to have little or no binding to NE or adrenergic sites, yet its effects are clearly noradrenergic, at least in part.Poking around on Pubmed, I came up with the some interesting clues with respect to the modafinil mechanism. Wisor and Eriksson provide convincing evidence that this is a non-adrenergic dopamine autoreceptor-dependent adrenergic process. Modafinil also somehow exhibits high anatomical specificity of action. Notwithstanding these non-noradrenergic findings, Gallopin et al show convincing evidence of an NE-receptor binding-dependent process (my speculation is non-competitive inhibition?). Willie et al show that the hypothalamus-based neuromodulatory peptide orexin is intimately involved, but strangely, genetically orexin-deficient mice actually had more pronounced responsivity to the drug. And finally, modafinil is shown to have a synergistic effect on serotonin, when combined with classic antidepressant drugs (Ferraro et al).
This is one very mysterious drug. I think there is more than one Ph.D. lurking in the study of this pharmaceutical product.
Lar
Synapse. 2005 Mar 15;55(4):230-41.
Modafinil enhances the increase of extracellular serotonin levels induced by the antidepressant drugs fluoxetine and imipramine: a dual probe microdialysis study in awake rat.Ferraro L, Fuxe K, Agnati L, Tanganelli S, Tomasini MC, Antonelli T.
Department of Clinical and Experimental Medicine, Section of Pharmacology, University of Ferrara, Italy.
In view of a postulated role of the vigilance-promoting drug modafinil in depression, the interaction of modafinil and two classical antidepressant drugs, fluoxetine and imipramine, were studied in 5-HT levels in the dorsal raphe-cortical system using dual-probe microdialysis. Fluoxetine (1-10 mg/kg) dose-dependently increased dorsal raphe-cortical 5-HT levels. Modafinil at a very low dose (3 mg/kg), by itself ineffective, enhanced the fluoxetine (5 mg/kg)-induced increases of 5-HT levels in both brain areas. A synergistic interaction was observed in the prefrontal cortex with fluoxetine (1 mg/kg) in terms of 5-HT release, but not in the dorsal raphe. Imipramine (1.3 mg/kg) increased 5-HT levels in the dorsal raphe, but not in the prefrontal cortex, while the higher doses (10.9-21.8 mg/kg) caused substantial increases in both brain areas. Modafinil (3 mg/kg), injected before imipramine (1.3 mg/kg), which by itself was ineffective on cortical 5-HT levels, increased cortical 5-HT levels. On other hand, modafinil failed to affect the high-dose imipramine (10.9 mg/kg)-induced increase of 5-HT levels in the prefrontal cortex and the imipramine (1.3; 10.9 mg/kg)-induced increase of 5-HT levels in the dorsal raphe nucleus. These results demonstrate that modafinil in low doses enhances the acute effects of fluoxetine and imipramine on 5-HT levels in the dorsal raphe nucleus (fluoxetine only) and especially in the prefrontal cortex of the awake rat. These findings suggest a therapeutic potential of low doses of modafinil in the treatment of depression when combined with low doses of classical antidepressants, especially by increasing 5-HT transmission in cortical regions.
Sleep. 2004 Feb 1;27(1):19-25.
Comment in:
Sleep. 2004 Feb 1;27(1):11-2.Effect of the wake-promoting agent modafinil on sleep-promoting neurons from the ventrolateral preoptic nucleus: an in vitro pharmacologic study.
Gallopin T, Luppi PH, Rambert FA, Frydman A, Fort P.
UMR 5167 CNRS, Physio-Pathologie des Reseaux Neuronaux du Cycle Veille-Sommeil, Institut Federatif des Neurosciences de Lyon (IFNL, IFR19), Universite Claude Bernard Lyon I, Lyon, France.
STUDY OBJECTIVES: The pharmacologic profile of modafinil, an increasingly popular wake-promoting drug for narcolepsy treatment, differs from those of classic psychostimulants such as amphetamine. However, its brain targets are still a matter of debate. We hypothesized that modafinil could increase waking by inhibiting the sleep-promoting neurons from the ventrolateral preoptic nucleus (VLPO). Such action could be direct or indirect via the potentiation of inhibition mediated by waking neurotransmitters. We thus studied the effect of modafinil on the membrane potential and firing rate of VLPO neurons recorded in rat-brain slices. We further determined whether pretreatment with modafinil modifies the effect of noradrenaline, carbachol, serotonin, histamine, dopamine, or clonidine. MEASUREMENTS AND RESULTS: Pretreatment with modafinil specifically increased the inhibition of VLPO neurons induced by noradrenaline but had no effect when applied alone or in combination with other substances. Pretreatment with nisoxetine, a selective noradrenaline reuptake blocker, similarly increased the noradrenaline-induced inhibition of VLPO cells. Further, the potentiation by modafinil was minimized when modafinil and nisoxetine were applied together. CONCLUSIONS: These results suggest that modafinil blocks the reuptake of noradrenaline by the noradrenergic terminals on sleep-promoting neurons from the VLPO. Such a mechanism could be at least partially responsible for the wake-promoting effect of modafinil.
Neuroscience. 2005;130(4):983-95.
Modafinil more effectively induces wakefulness in orexin-null mice than in wild-type littermates.Willie JT, Renthal W, Chemelli RM, Miller MS, Scammell TE, Yanagisawa M, Sinton CM.
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Narcolepsy-cataplexy, a disorder of excessive sleepiness and abnormalities of rapid eye movement (REM) sleep, results from deficiency of the hypothalamic orexin (hypocretin) neuropeptides. Modafinil, an atypical wakefulness-promoting agent with an unknown mechanism of action, is used to treat hypersomnolence in these patients. Fos protein immunohistochemistry has previously demonstrated that orexin neurons are activated after modafinil administration, and it has been hypothesized that the wakefulness-promoting properties of modafinil might therefore be mediated by the neuropeptide. Here we tested this hypothesis by immunohistochemical, electroencephalographic, and behavioral methods using modafinil at doses of 0, 10, 30 and 100 mg/kg i.p. in orexin-/- mice and their wild-type littermates. We found that modafinil produced similar patterns of neuronal activation, as indicated by Fos immunohistochemistry, in both genotypes. Surprisingly, modafinil more effectively increased wakefulness time in orexin-/- mice than in the wild-type mice. This may reflect compensatory facilitation of components of central arousal in the absence of orexin in the null mice. In contrast, the compound did not suppress direct transitions from wakefulness to REM sleep, a sign of narcolepsy-cataplexy in mice. Spectral analysis of the electroencephalogram in awake orexin-/- mice under baseline conditions revealed reduced power in the theta; band frequencies (8-9 Hz), an index of alertness or attention during wakefulness in the rodent. Modafinil administration only partly compensated for this attention deficit in the orexin null mice. We conclude that the presence of orexin is not required for the wakefulness-prolonging action of modafinil, but orexin may mediate some of the alerting effects of the compound.
Neuroscience. 2005;132(4):1027-34.
Dopaminergic-adrenergic interactions in the wake promoting mechanism of modafinil.Wisor JP, Eriksson KS.
Molecular Neurobiology Laboratory, SRI International, Menlo Park, CA 94025, USA. jonathan.wisor@sri.com
Adrenergic signaling regulates the timing of sleep states and sleep state-dependent changes in muscle tone. Recent studies indicate a possible role for noradrenergic transmission in the wake-promoting action of modafinil, a widely used agent for the treatment of excessive sleepiness. We now report that noradrenergic projections from the locus coeruleus to the forebrain are not necessary for the wake-promoting action of modafinil. The efficacy of modafinil was maintained after treatment of C57BL/6 mice with N-(2-chloroethyl)-N-ethyl 2-bromobenzylamine (DSP-4), which eliminates all noradrenaline transporter-bearing forebrain noradrenergic projections. However, the necessity for adrenergic receptors in the wake-promoting action of modafinil was demonstrated by the observation that the adrenergic antagonist terazosin suppressed the response to modafinil in DSP-4 treated mice. The wake-promoting efficacy of modafinil was also blunted by the dopamine autoreceptor agonist quinpirole. These findings implicate non-noradrenergic, dopamine-dependent adrenergic signaling in the wake-promoting mechanism of modafinil. The anatomical specificity of these dopaminergic-adrenergic interactions, which are present in forebrain areas that regulate sleep timing but not in brain stem areas that regulate sleep state-dependent changes in muscle tone, may explain why modafinil effectively treats excessive daytime sleepiness in narcolepsy but fails to prevent the loss of muscle tone that occurs in narcoleptic patients during cataplexy.
Posted by Larry Hoover on February 27, 2006, at 10:41:03
In reply to Re: provigil discussion, posted by mike99 on February 25, 2006, at 17:29:01
> Good point--the monograph states "At pharmacologic concentrations, modafanil does not bind to MOST POTENTIALLY RELEVANT receptors for norepinephrine, serotonein, dopamine..."
>
> Whatever "most potentially relevant" means. Not very informative IMHO.I always try to keep in the back of my mind that drug monographs are the product of a complex commercial system. Lawyers and accountants and marketing "experts" have all had a crack at the wording. Some monographs are thorough and complete and definitive. Then you get to drugs like modafinil, where no one has a clue. It makes me wonder what they were trying to accomplish when they invented this molecule. Does anyone know that?
Lar
Posted by zeugma on February 27, 2006, at 16:57:26
In reply to Re: provigil discussion » mike99, posted by Larry Hoover on February 27, 2006, at 10:41:03
Then you get to drugs like modafinil, where no one has a clue. It makes me wonder what they were trying to accomplish when they invented this molecule. Does anyone know that?>>
modafinil is a derivative of adrafinil. adrafinil, apparently, is from a series of alpha-1 agonists. The early theories all center on alpha-1 agonism as the mechanism of action, since the actions of both molecules are blocked by prazosin.
Its original use, which remains its major indication, was for narcolepsy.
But from what I have read, investigators were caught off guard by the molecules' properties, e.g.:
Eur J Pharmacol. 1990 May 3;180(1):49-58.
Central alpha 1-adrenergic stimulation in relation to the behaviour stimulating effect of modafinil; studies with experimental animals.Duteil J, Rambert FA, Pessonnier J, Hermant JF, Gombert R, Assous E.
Centre de Recherches du Laboratoire L. Lafon, Maisons-Alfort, France.
Single administration of the new drug modafinil was followed by an increase in locomotor activity in mice and in nocturnal activity in monkeys. Stereotyped behaviour in mice and rats, and potentiation of amphetamine-induced stereotyped behaviour were not observed; however, at the highest dose used, a slight potentiation of apomorphine-induced stereotyped behaviour was observed in rats. The modafinil-induced increase in locomotor activity in mice was prevented by the centrally acting alpha 1-adrenoceptor antagonists, prazosin and phenoxybenzamine, and by reserpine but not by the mixed dopamine D-1/D-2 antagonist, haloperidol, the dopamine D-2 antagonist, sulpiride, the peripherally acting alpha 1-adrenoceptor antagonist, phentolamine, the alpha 2-adrenoceptor antagonist, yohimbine, the beta-adrenoceptor antagonist, propranolol, or by the catecholamine synthesis inhibitor, alpha-methyl-p-tyrosine. Likewise, the modafinil-induced increase in nocturnal activity in monkeys was prevented by prazosin. Interestingly, modafinil did not produce obvious peripheral sympathetic effects in mice and rats (no salivation, no contraction of the pilomotor muscles, slight mydriasis only at high doses). Therefore, modafinil appears to produce a strong stimulating effect in rodents and in primates. These effects could be linked to modulation (stimulation) of central alpha 1-adrenoceptors unaccompanied by peripheral sympathetic effects, which is unexpected.
I wish I were less ADHD-afflicted and could get past the second chapter of my organic chem book, which has been buried beneath books on modal logic and grammatical theory, so I could see what its chemical structure 'looks' like. right now, I can't even tell you what my organic chem book looks like.
oh yes, the drug also attracted the interest of the French military. Modafinil was used by French soldiers during the First Gulf War to improve performance during sleep deprivation.-z
Posted by SLS on February 28, 2006, at 7:11:41
In reply to Re: provigil discussion » Larry Hoover, posted by zeugma on February 27, 2006, at 16:57:26
I don't think adrafinil is a NE alpha-1 receptor agonist either.
I lost a great deal of information regarding adrafinil and modafinil when my last hard disk crashed. Some of it displayed the molecular differences between the two drugs; a difference that involves the cleaving of a single oxygen atom. I'm not sure if adrafinil is simply acting as a pro-drug in the body where it is quickly metabolized to modafinil or if it carries with it properties that are different from modafinil. A single atom can make a huge difference! In any event, adrafinil was invented in the late 1970s when only a handful of amine receptors had been discovered and assayed. I think most of the talk about adrafinil being a NE alpha-1 agonist relied on a single study using faulty logic. It seems that for adrafinil (and modafinil) to exert its stimulant effect, at least one NE alpha-1 receptor pathway needs to remain intact. They found that to administer a NE alpha-1 antagonist (prazosin?) reversed the stimulant effect of adrafinil. They then proceeded to conclude that adrafinil must therefore be a NE alpha-1 receptor agonist. Of course, this deduction completely ignores the possibility of actions upstream of the NE alpha-1 tracts. The study design was fine. It was the conclusion by the authors that was faulty. Almost every subsequent study cited the faulty one as a platform for their own. The error was perpetuated for many years.
- Scott
Posted by mike99 on February 28, 2006, at 21:18:59
In reply to Re: provigil mechanism of action?, posted by SLS on February 25, 2006, at 6:50:48
> Hi.
>
> Provigil (modafinil) seems to possess at least two properties that can increase wakefulness and vigilence:
>
> 1. Glutamate release
> 2. Orexin (hypocretin) release
>
>>
> - ScottGlutamate toxicity is currently a hot topic in cognitive dysfunction (there are claims that excess glutamate may be neurotoxic and involved in disorders such as ADHD, Dementia, Alzheimer's...) In fact if I'm not mistaken there's a class of drugs in development called ampakines which antagonize the effects of glutamate. They're experimental for ADHD Dementia and many other cognitive disorders.
In fact, memantine/namenda is thought to possibly delay the progression or at least treat symptoms of moderate to severe alzheimers by blocking the actions of glutamate (by acting as an NMDA receptor antagonist).
Just wondering if neurotoxicity would be a potential side effect of provigil and if so whether this would be clinically relevant?
Please feel free to correct any errors of fact I may have made.
Posted by SLS on March 1, 2006, at 7:17:55
In reply to Re: provigil mechanism of action?, posted by mike99 on February 28, 2006, at 21:18:59
> > Hi.
> >
> > Provigil (modafinil) seems to possess at least two properties that can increase wakefulness and vigilence:
> >
> > 1. Glutamate release
> > 2. Orexin (hypocretin) release
> >
> >>
> > - Scott
>
> Glutamate toxicity is currently a hot topic in cognitive dysfunction (there are claims that excess glutamate may be neurotoxic and involved in disorders such as ADHD, Dementia, Alzheimer's...) In fact if I'm not mistaken there's a class of drugs in development called ampakines which antagonize the effects of glutamate. They're experimental for ADHD Dementia and many other cognitive disorders.
>
> In fact, memantine/namenda is thought to possibly delay the progression or at least treat symptoms of moderate to severe alzheimers by blocking the actions of glutamate (by acting as an NMDA receptor antagonist).
>
> Just wondering if neurotoxicity would be a potential side effect of provigil and if so whether this would be clinically relevant?I really don't know. It has been a long time since I looked at that stuff. It might depend on where the glutamate is found and whether the increased levels produce excessive calcium influx.
Most of the excitatory neurons in the brain use glutamate as their neurotransmitter. Glutamate should not be made to look like a scourge. You can't live without it. That a drug like modafinil raises levels of extracellular glutamate might not necessarily translate to neurotoxicity. I haven't really studied this issue well enough to speak with confidence.
Interestingly, some regions of the brain demonstrate overactivity in depression. Perhaps glutamate antagonists help to reduce this.
- Scott
Posted by Larry Hoover on March 1, 2006, at 12:02:15
In reply to Re: provigil mechanism of action?, posted by SLS on March 1, 2006, at 7:17:55
> Most of the excitatory neurons in the brain use glutamate as their neurotransmitter. Glutamate should not be made to look like a scourge. You can't live without it. That a drug like modafinil raises levels of extracellular glutamate might not necessarily translate to neurotoxicity. I haven't really studied this issue well enough to speak with confidence.
>
> Interestingly, some regions of the brain demonstrate overactivity in depression. Perhaps glutamate antagonists help to reduce this.
>
>
> - ScottI just want to point out that the most direct antagonist of glutamate is taurine. In every glutaminergic synapse, there are also dedicated taurine reuptake pumps. Taurine is always released with glutamate. Sometimes, though, the balance is not comfortable.
It is blessedly simple to dampen glutamate signalling. Taurine readily crosses the blood/brain barrier. Oral doses are efficacious in minutes.
Lar
Posted by zeugma on March 2, 2006, at 20:21:17
In reply to Re: provigil mechanism of action? » SLS, posted by Larry Hoover on March 1, 2006, at 12:02:15
i am just going to post to make this discussion even more confounding than it's been (I mean discussing modafinil's mode of action, not the discussion itself). Modafinil is classed as a 'neuroprotective agent,' and there have been numerous studies on a so-called 'neuroprotective' effect:
And, especially in view of the well-founded concern about glutamergic toxicity:
Neuroreport. 1998 Dec 21;9(18):4209-13. Related Articles, Links
Modafinil prevents glutamate cytotoxicity in cultured cortical neurons.Antonelli T, Ferraro L, Hillion J, Tomasini MC, Rambert FA, Fuxe K.
Department of Experimental and Clinical Medicine, University of Ferrara, Italy.
The ability of modafinil (Modiodal) to protect cortical neurons from glutamate-induced degeneration was evaluated by measuring electrically evoked [3H]GABA release and [3H]GABA uptake in primary cerebral cortical cultures. In normal cells, electrical stimulation (10 Hz, 2 min) increased [3H]GABA release (FR-NER St1 = 0.77+/-0.14; St2/St1 ratio = 0.94+/-0.02). The exposure of sister cells to glutamate, reduced electrically evoked [3H]GABA release (FR-NER St1 = 0.40+/-0.05; St2/St1 ratio = 0.60+/-0.08). Modafinil (0.3-1 microM) prevented the glutamate-induced reduction of the St2/St1 ratio (0.85+/-0.11; 0.88+/-0.05, respectively). A similar protective effect was observed for [3H]GABA uptake. These findings suggest that modafinil may be neuroprotective in that it attenuates glutamate-induced excitotoxicity in cortical neurons.
I admit to understanding very little of what I've cited, but Pub Med is a beautiful thing.
-z
Posted by SLS on March 2, 2006, at 20:57:02
In reply to Re: provigil mechanism of action?, posted by zeugma on March 2, 2006, at 20:21:17
That's a lot of stuff to consider.
I think excitotoxicity is the result of excessive calcium influx, and not the presence of glutamate per se. Gosh, I would have to do a bunch more research to even pretend that I understand any of this. It might depend on the location(s) of the increased extracellular glutamate as to whether modafinil is neuroprotective or neurotoxic.
'Tis a puzzlement.
- Scott
-----------------------------------------------
> i am just going to post to make this discussion even more confounding than it's been (I mean discussing modafinil's mode of action, not the discussion itself). Modafinil is classed as a 'neuroprotective agent,' and there have been numerous studies on a so-called 'neuroprotective' effect:
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15000882&query_hl=3&itool=pubmed_docsum
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10580713&query_hl=5&itool=pubmed_docsum
>
> And, especially in view of the well-founded concern about glutamergic toxicity:
>
> Neuroreport. 1998 Dec 21;9(18):4209-13. Related Articles, Links
>
>
> Modafinil prevents glutamate cytotoxicity in cultured cortical neurons.
>
> Antonelli T, Ferraro L, Hillion J, Tomasini MC, Rambert FA, Fuxe K.
>
> Department of Experimental and Clinical Medicine, University of Ferrara, Italy.
>
> The ability of modafinil (Modiodal) to protect cortical neurons from glutamate-induced degeneration was evaluated by measuring electrically evoked [3H]GABA release and [3H]GABA uptake in primary cerebral cortical cultures. In normal cells, electrical stimulation (10 Hz, 2 min) increased [3H]GABA release (FR-NER St1 = 0.77+/-0.14; St2/St1 ratio = 0.94+/-0.02). The exposure of sister cells to glutamate, reduced electrically evoked [3H]GABA release (FR-NER St1 = 0.40+/-0.05; St2/St1 ratio = 0.60+/-0.08). Modafinil (0.3-1 microM) prevented the glutamate-induced reduction of the St2/St1 ratio (0.85+/-0.11; 0.88+/-0.05, respectively). A similar protective effect was observed for [3H]GABA uptake. These findings suggest that modafinil may be neuroprotective in that it attenuates glutamate-induced excitotoxicity in cortical neurons.
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9926875&query_hl=9&itool=pubmed_docsum
>
> I admit to understanding very little of what I've cited, but Pub Med is a beautiful thing.
>
> -z
This is the end of the thread.
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