Cortical αl-adrenergic regulation of acute and sensitized morphine locomotor effects

Inserm U.114, Collège de France, 11, Place Marcelin Berthelot, 75231 Paris Cedex 05, France.
Neuroreport (Impact Factor: 1.52). 11/2001; 12(16):3483-3486.


The role of α1-adrenergic transmission was tested on locomotor effects of acute or repeated morphine (5 mg/kg, i.p.) administration. Prazosin, an α1-adrenergic antagonist, administered 30 min before morphine, either systemically (0.5 mg/kg, i.p.) or locally and bilaterally into the prefrontal cortex (200 pmol/side) reduced the stimulatory influence of morphine on locomotion. The progressive increase of the locomotor response induced by repeated morphine injections was blocked by a prazosin pretreatment but not the behavioral sensitization on the test day. These data suggest that blockade of cortical α1-adrenergic receptors reduces the expression of acute and sensitized locomotor responses to morphine, but does not prevent the induction of behavioral sensitization.

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    • "Because Dbh −/− mice have altered responses to other stimulants that are most apparent at low to moderate doses (Weinshenker et al., 2002a; Schank et al., 2006), lower doses of modafinil (6.25 – 50 mg/kg) were selected for these experiments. The dose of prazosin was selected based on published reports that it can block the behavioral effects of stimulants in mice (Drouin et al., 2001; Weinshenker et al., 2002a). The non-selective DA receptor antagonist, cis-(Z)flupenthixol dihydrochloride (0.025 or 0.25 mg/kg; Sigma-Aldrich) was dissolved in 0.9% saline. "
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    ABSTRACT: Modafinil is approved for use in the treatment of excessive daytime sleepiness. The precise mechanism of modafinil action has not been elucidated, although both dopamine (DA) and norepinephrine (NE) systems have been implicated. To explore the roles of DA and NE in the mechanism of modafinil-induced arousal, dopamine beta-hydroxylase knockout (Dbh -/-) mice were examined in behavioral paradigms of arousal (photobeam breaks and behavioral scoring of sleep latency). Dbh -/- mice completely lack NE but have hypersensitive DA signaling. It was hypothesized that Dbh -/- mice would be unresponsive to modafinil if the compound acts primarily via NE, but would be hypersensitive to modafinil if it acts primarily via DA. Dbh -/- mice had increased sensitivity to the locomotor-activating and wake-promoting effects of modafinil. Paradoxically, the alpha1-adrenergic receptor antagonist, prazosin, attenuated the effects of modafinil in control mice, but not in Dbh -/- mice. Blockade of DA receptors with flupenthixol decreased modafinil-induced locomotion and wake in both control and Dbh -/- mice. These results suggest that both NE and DA are involved in the behavioral effects of modafinil in control mice, but the requirement for NE can be bypassed by hypersensitive DA signaling.
    Pharmacology Biochemistry and Behavior 08/2008; 91(2):217-22. DOI:10.1016/j.pbb.2008.07.014 · 2.78 Impact Factor
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    • "Such a stimulation can be attributable to an increased release of NE by D-amphetamine in the prefrontal cortex [21] [22], a structure containing a high density of a1b- adrenergic receptors [17] [22] and possibly responsible for the regulation of DA release in the nucleus accumbens [23]. Our data therefore indicate a critical role of a1b-adrenergic receptors in neurochemical and locomotor effects of psychostimulants ; however, when analyzing the effects of opiates, we found that only part of the morphine-evoked behavioral locomotor response was affected by pharmacological or genetic blockade of a1b-adrenergic receptors [18] [24]. Accordingly, the blockade of a1-adrenergic receptors by prazosin inhibits both the expression and development of behavioral sensitization to moderate doses of D-amphetamine and cocaine, but only reduces the expression of behavioral sensitization to morphine and leaves unaffected its development. "
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    ABSTRACT: A challenge in drug dependence is to delineate long-term behavioral and neurochemical modifications induced by drugs of abuse. In rodents, drugs of abuse induce locomotor hyperactivity, and repeating injections enhance this response. This effect, called behavioral sensitization, persists many months after the last administration, thus mimicking long-term sensitivity to drugs observed in human addicts. Although addictive properties of drugs of abuse are generally considered to be mediated by an increased release of dopamine in the ventral striatum, recent pharmacological and genetic experiments indicate an implication of alpha1b-adrenergic receptors in behavioral and rewarding responses to psychostimulants and opiates. Later on, it was shown that not only noradrenergic but also serotonergic systems, through 5-HT(2A) receptors, were controlling behavioral effects of drugs of abuse. More recently, experiments performed in animals knockout for alpha1b-adrenergic or 5-HT(2A) receptors indicated that noradrenergic and serotonergic neurons, besides their activating effects, inhibit each other by means of the stimulation of alpha1b-adrenergic and 5-HT(2A) receptors and that this mutual inhibition vanishes in wild type mice with repeated injections of psychostimulants, opiates or alcohol. Uncoupling induced by repeated treatments with drugs of abuse installs a stable sensitization of noradrenergic and serotonergic neurons, thus explaining an increased reactivity of dopaminergic neurons and behavioral sensitization. We propose that noradrenergic/serotonergic uncoupling is a common stable neurochemical consequence of repeated drugs of abuse which may also occur during chronic stressful situations and facilitate the onset of mental illness. Drug consumption would facilitate an artificial re-coupling of these neurons, thus bringing a temporary relief.
    Biochemical Pharmacology 02/2008; 75(1):85-97. DOI:10.1016/j.bcp.2007.06.038 · 5.01 Impact Factor
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    • "Nos données indiquent donc le rôle fondamental des récepteurs α1b- adrénergiques dans l'effet neurochimique et comportemental des psychostimulants. Il faut cependant noter que, lorsque nous avons analysé l'effet des opiacés, nous avons trouvé que seule une partie de l'activité locomotrice induite par la morphine était affectée par l'injection de prazosine chez les souris sauvages et qu'une réponse locomotrice à la morphine importante subsistait chez les souris α1b-AR KO [18] [24]. En accord avec cette observation, le blocage des récepteurs α1-adrénergi- ques par la prazosine inhibe l'expression et l'induction de la sensibilisation comportementale à des doses modérées d'amphétamine et de cocaïne alors qu'il ne réduit que l'expression de la sensibilisation comportementale à la morphine sans affecter son induction. "
    Psychotropes 01/2008; 14(3). DOI:10.3917/psyt.143.0011
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