Cerebral microglia mediate sleep/wake and neuroinflammatory effects of methamphetamine

Jonathan P Wisor; Michelle A Schmidt; William C Clegern

doi:10.1016/j.bbi.2011.02.002

► Pharmacological depletion of cerebral microglia attenuates waking effects of methamphetamine. ► Methamphetamine upregulates nitric oxide synthase (NOS) activity in microglia. ► Neuronal NOS knockout abolishes microglial NOS activation by methamphetamine. ► Methamphetamine alters sleep regulatory cytokine synthesis in microglia selectively. Methamphetamine and modafinil exert their wake-promoting effects by elevating monoaminergic tone. The severity of hypersomnolence that occurs subsequent to induced wakefulness differs between these two agents. Microglia detects and modulates CNS reactions to agents such as d-methamphetamine that induce cellular stress. We therefore hypothesized that changes in the sleep/wake cycle that occur subsequent to administration of d-methamphetamine are modulated by cerebral microglia. In CD11b-herpes thymidine kinase transgenic mice (CD11b-TKmt-30), activation of the inducible transgene by intracerebroventricular (icv) ganciclovir results in toxicity to CD11b-positive cells (i.e. microglia), thereby reducing cerebral microglial cell counts. CD11b-TKmt-30and wild type mice were subjected to chronic icv ganciclovir or vehicle administration with subcutaneous mini-osmotic pumps. d-methamphetamine (1 and 2mg/kg), modafinil (30 and 100mg/kg) and vehicle were administered intraperitoneally to these animals. In CD11b-TKmt-30 mice, but not wild type, icv infusion of ganciclovir reduced the duration of wake produced by d-methamphetamine at 2mg/kg by nearly 1h. Nitric oxide synthase (NOS) activity, studied ex vivo, and NOS expression were elevated in CD11b-positive cerebral microglia from wild type mice acutely exposed to d-methamphetamine. Additionally, CD11b-positive microglia, but not other cerebral cell populations, exhibited changes in sleep-regulatory cytokine expression in response to d-METH. Finally, CD11b-positive microglia exposed to d-methamphetamine in vitro exhibited increased NOS activity relative to pharmacologically-naïve cells. CD11b-positive microglia from the brains of neuronal NOS (nNOS)-knockout mice failed to exhibit this effect. We propose that the effects of d-METH on sleep/wake cycles are mediated in part by actions on microglia, including possibly nNOS activity and cytokine synthesis.

Cerebral microglia mediate sleep/wake and neuroinflammatory effects of methamphetamine

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