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Ferraro L, Tanganelli S, O’Connor WT, Antonelli T, Rambert F, Fuxe K. 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. Neurosci Lett 220: 5-8

Department of Neuroscience, University of Cagliari, Cagliari, Italy
Neuroscience Letters (Impact Factor: 2.03). 01/1997; 220(1):5-8. DOI: 10.1016/S0304-3940(96)13212-2

ABSTRACT

The effect of modafinil on endogenous γ-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 μM) when perfused locally alone or together with the non-selective 5-HT receptor antagonist methysergide (1 μM). 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.

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    • "Hence, it would activate histaminergic neurons in a way distinct from that of tiprolisant. Modafinil reduces the outflow of GABA in the posterior hypothalamus (Tanganelli et al., 1995; Ferraro et al., 1996), thereby diminishing a major inhibitory input from the anterior hypothalamus to the tuberomammillary neurons (Sherin et al., 1998), whereas tiprolisant reverses the constitutive activity of the H 3 -receptors, i.e. of a potent " brake " on HA release (Morisset et al., 2000). In turn, the synergy between the two drugs on noradrenergic neurons may simply reflect the enhanced HA release resulting from their association. "

    Full-text · Dataset · Jul 2014
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    • "This has also been shown with pretreatments of the α1- noradrenergic receptor antagonist prazosin (Tanganelli et al. 1995). MOD's effects on GABA are also influenced by the 5- HT system and can be abolished in the cortex by pretreatment with the 5-HT2 receptor antagonist ketanserin (Tanganelli et al. 1992) and in the hypothalamus by the 5-HT3 antagonist MDL72222, which alone has no effect on GABA levels (Ferraro et al. 1996b). Studies showing that MOD prevented 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP)-induced increases in GABA-A receptor binding in the internal globus pallidus (Zeng et al. 2004) have provided evidence for an interaction at the striatal area level GABAergic system in MPTP-treated marmosets. "
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    ABSTRACT: Modafinil (MOD) and its R-enantiomer (R-MOD) are approved medications for narcolepsy and other sleep disorders. They have also been used, off-label, as cognitive enhancers in populations of patients with mental disorders, including substance abusers that demonstrate impaired cognitive function. A debated nonmedical use of MOD in healthy individuals to improve intellectual performance is raising questions about its potential abuse liability in this population. MOD has low micromolar affinity for the dopamine transporter (DAT). Inhibition of dopamine (DA) reuptake via the DAT explains the enhancement of DA levels in several brain areas, an effect shared with psychostimulants like cocaine, methylphenidate, and the amphetamines. However, its neurochemical effects and anatomical pattern of brain area activation differ from typical psychostimulants and are consistent with its beneficial effects on cognitive performance processes such as attention, learning, and memory. At variance with typical psychostimulants, MOD shows very low, if any, abuse liability, in spite of its use as a cognitive enhancer by otherwise healthy individuals. Finally, recent clinical studies have focused on the potential use of MOD as a medication for treatment of drug abuse, but have not shown consistent outcomes. However, positive trends in several result measures suggest that medications that improve cognitive function, like MOD or R-MOD, may be beneficial for the treatment of substance use disorders in certain patient populations.
    Full-text · Article · Aug 2013 · Psychopharmacology
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    • "Hence, it would activate histaminergic neurons in a way distinct from that of tiprolisant. Modafinil reduces the outflow of GABA in the posterior hypothalamus (Tanganelli et al., 1995; Ferraro et al., 1996), thereby diminishing a major inhibitory input from the anterior hypothalamus to the tuberomammillary neurons (Sherin et al., 1998), whereas tiprolisant reverses the constitutive activity of the H 3 -receptors, i.e. of a potent " brake " on HA release (Morisset et al., 2000). In turn, the synergy between the two drugs on noradrenergic neurons may simply reflect the enhanced HA release resulting from their association. "

    Full-text · Dataset · Jun 2013
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