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Schlagwörter:
ADHD, mouse models, prefrontal cortex, amphetamine, NMDA receptor, dopamine, GSK3beta
Zusammenfassung:
Psychostimulants show therapeutic efficacy in the treatment of
attention-deficit hyperactivity disorder (ADHD). It is generally assumed
that they ameliorate ADHD symptoms via interfering with monoaminergic
signaling. We combined behavioral pharmacology, neurochemistry and
molecular analyses to identify mechanisms underlying the paradoxical
calming effect of amphetamine in low trait anxiety behavior (LAB) mice,
a novel multigenetic animal model of ADHD. Amphetamine (1 mg/kg) and
methylphenidate (10 mg/kg) elicited similar dopamine and norepinephrine
release in the medial prefrontal cortex (mPFC) and in the striatum of
LAB mice. In contrast, amphetamine decreased, while methylphenidate
increased locomotor activity. This argues against changes in dopamine
and/or norepinephrine release as mediators of amphetamine paradoxical
effects. Instead, the calming activity of amphetamine corresponded to
the inhibition of glycogen synthase kinase 313 (GSK3 beta activity,
specifically in the mPFC. Accordingly, not only systemic administration
of the GSK3 beta inhibitor TDZD-8 (20 mg/kg), but also local
microinjections of TDZD-8 and amphetamine into the mPFC, but not into
the striatum, decreased locomotor activity in LAB mice. Amphetamine
effects seem to depend on NMDA receptor signaling, since pre- or
co-treatment with MK-801 (0.3 mg/kg) abolished the effects of
amphetamine (1 mg/kg) on the locomotion and on the phosphorylation of
GSK3 beta) at the level of the mPFC. Taken together, the paradoxical
calming effect of amphetamine in hyperactive LAB mice concurs with a
decreased GSK3 beta activity in the mPFC. This effect appears to be
independent of dopamine or norepinephrine release, but contingent on
NMDA receptor signaling.
