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.
poster:Larry Hoover
thread:612884
URL: http://www.dr-bob.org/babble/20060227/msgs/613724.html