![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 14 to 38 of 46. Go back in thread:
Posted by mike99 on February 25, 2006, at 15:30:19
In reply to Re: provigil discussion, posted by tessellated on February 25, 2006, at 14:42:49
Hmmm...confusing, confusing.
I'll definitely talk w/ my Dr. about cardio issues related to provigil, but in all likelihood he probably knows less about it than everyone who's posted to this thread (and he's a sharp guy--board-certified in sleep medicine and pulmonology, so he should be quite knowledgeable about provigil).
I'm generally healthy but extremely senstive to/intolerant of stimulants.
I wonder about the sympathomimetic activity of provigil because this might have negative consequences when combined with a beta blocker (as beta blockers "increase pressor affects of sympathomimetics" due to beta receptors being blocked but alpha adrenergic receptors not).
Posted by tessellated on February 25, 2006, at 17:12:33
In reply to Re: provigil discussion, posted by mike99 on February 25, 2006, at 15:30:19
Yeah,
I just cant wait untill its ALL figured out.
Everything would be sooo much easier.
Posted by mike99 on February 25, 2006, at 17:29:01
In reply to Re: provigil discussion, posted by tessellated on February 25, 2006, at 14:42:49
>> As far as the specifics, "direct or indirect alpha-adrenergic agonist" does not necessarily include "auto-adrenergic receptor (modulation)", as these structures are presynaptic and located in the axon not at the synaptic cleft where most neurotransmission occurs.
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.
> Notice they don't even mention beta adrenergic activity.
They sure don't.
Ditto's on wishing there was more to go on.
Posted by zeugma on February 25, 2006, at 17:42:12
In reply to Re: provigil discussion, posted by mike99 on February 25, 2006, at 15:30:19
I have to agree with SLS, Provigil is not an alpha-2 antagonist (antagonist of pre-synaptic NE autoreceptors). If that were the case then depleting an animal of norepinephrine would result in a loss of its effect (similar to the way depleting an individual whose depression has remitted on desipramine results in a relapse), but this seems not to be the case.
On the other hand, animals that lacked dopamine transporters experienced no stimulating effect from either methamphetamine or Provigil, indicating that DA reuptake inhibition is involved. These animals were hypersensitive to caffeine, so it's safe to say that caffeine and Provigil do not share the same mechanisms.
An experiment was also conducted in which Provigil's effect on the ventrolateral proptic nucleus (a major site of sleep regulation) and apparently Provigil blocked the NE transporters in that region:
If Provigil does act as an NE transport blocker it must be extremely localized, because every other NE transport blocker inhibits cataplexy, and Provigil does not do so at all.
The author who comments on the study I cited above theorizes that the combination of weak DA reuptake inhibition, and localized NE reuptake inhibition, may combine to produce its wakefulness effect. Provigil does release orexin, but it has no direct effect on that system (i.e. it is not a ligand for a known orexin receptor). Its effect on GABA inhibition is also well documented:
These effects on GABA and norepinephrine are extremely localized and peculiar, at they seem so to me.
-z
Posted by tessellated on February 25, 2006, at 20:15:32
In reply to Re: provigil discussion, posted by zeugma on February 25, 2006, at 17:42:12
Zuegma,
cool refs, like this serious kinda info.
now are alpha-2 sites presynaptic autoreceptors?
i did not believe this to be the case.
but....
lemme spend time on the refs many thanks,
8edps: antagonizing a presynaptic autoreceptor can result in an increase of NE release. as they modulate NE production; and can infact inhibit NE release/production if agonists/excess NE are present. An antagonist can have post synaptic agonistic affect. Get it? Stimulation can cause inhibition and vice versa.. It's freaking complex....
> I have to agree with SLS, Provigil is not an alpha-2 antagonist (antagonist of pre-synaptic NE autoreceptors). If that were the case then depleting an animal of norepinephrine would result in a loss of its effect (similar to the way depleting an individual whose depression has remitted on desipramine results in a relapse), but this seems not to be the case.
>
> On the other hand, animals that lacked dopamine transporters experienced no stimulating effect from either methamphetamine or Provigil, indicating that DA reuptake inhibition is involved. These animals were hypersensitive to caffeine, so it's safe to say that caffeine and Provigil do not share the same mechanisms.
>
> An experiment was also conducted in which Provigil's effect on the ventrolateral proptic nucleus (a major site of sleep regulation) and apparently Provigil blocked the NE transporters in that region:
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14998233&query_hl=3&itool=pubmed_docsum
>
> If Provigil does act as an NE transport blocker it must be extremely localized, because every other NE transport blocker inhibits cataplexy, and Provigil does not do so at all.
>
> The author who comments on the study I cited above theorizes that the combination of weak DA reuptake inhibition, and localized NE reuptake inhibition, may combine to produce its wakefulness effect. Provigil does release orexin, but it has no direct effect on that system (i.e. it is not a ligand for a known orexin receptor). Its effect on GABA inhibition is also well documented:
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8813612&query_hl=6&itool=pubmed_docsum
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9774168&query_hl=10&itool=pubmed_docsum
>
> These effects on GABA and norepinephrine are extremely localized and peculiar, at they seem so to me.
>
> -z
>
>
Posted by mike99 on February 25, 2006, at 20:55:34
In reply to Re: provigil discussion, posted by tessellated on February 25, 2006, at 20:15:32
..rs
This may likely be to what your doc was referring.
In the CNS alpha-2 receptors are presynaptic autoreceptors.
Stimulating this receptor by NE or drugs such as clonidine or tenex inhibits NE release (presynaptically), which theoretically should result in decreased activation of the corresponding post-synaptic noradrenergic receptors.
Antagonizing the same receptor by a drug like remeron/mirtazapine conversely results in increased NE release.
To the best I could gather, the 2006 PDR still states provigil is not an agonist or antagonist at any "potentially relevant receptors for NE, etc...". I think this would, or at least should include the alpha-2 autoreceptor.
Posted by mike99 on February 25, 2006, at 21:13:55
In reply to Re: provigil mechanism of action?, posted by Racer on February 25, 2006, at 3:22:53
By what mechanism would provigil stimulate the heart/sympathetic nervous system? And how does this compare to the sympathomimetics?
I realize the peripheral stimulation of provigil is supposed to be minimal (one of its advantages), but it does seem to activate the sympathetic system.
Could provigil possibly cause release of epinephrine and epinephrine from the adrenals?
Thanks Zeugma for the excellent references.
Posted by mike99 on February 25, 2006, at 21:16:34
In reply to so how does provigil stimulate the heart?, posted by mike99 on February 25, 2006, at 21:13:55
if provigil could result in the release of epinephrine and norepinephrine from the adrenals.
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.
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