Evaluating the Role of Neuronal Nitric Oxide Synthase-Containing Striatal Interneurons in Methamphetamine-Induced Dopami
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ORIGINAL ARTICLE
Evaluating the Role of Neuronal Nitric Oxide SynthaseContaining Striatal Interneurons in Methamphetamine-Induced Dopamine Neurotoxicity Ashley N. Fricks-Gleason • Kristen A. Keefe
Received: 16 January 2013 / Revised: 26 March 2013 / Accepted: 1 April 2013 Ó Springer Science+Business Media New York 2013
Abstract Production of nitric oxide (NO) has been implicated in methamphetamine (METH)-induced dopamine (DA) neurotoxicity. The source of this NO has not been clearly delineated, but recent evidence suggests that it arises from activation of neuronal nitric oxide synthase (nNOS), which is selectively expressed in a subpopulation of striatal interneurons. Our objective was to determine whether inhibiting activation of nNOS-containing interneurons in the striatum blocks METH-induced neurotoxicity. These interneurons selectively express the neurokinin-1 (NK-1) receptor, which is activated by substance P. One particular toxin, a conjugate of substance P to the ribosome-inactivating protein saporin (SSP–SAP), selectively destroys neurons expressing the NK-1 receptor. Thus, we examined the extent to which depletion of the nNOScontaining interneurons alters production of NO and attenuates METH-induced neurotoxicity. The SSP–SAP lesions resulted in significant loss of nNOS-containing interneurons throughout striatum. Surprisingly, this marked deletion did not confer resistance to METH-induced DA neurotoxicity, even in areas devoid of nNOS-positive cells. Furthermore, these lesions did not attenuate NO production, even in areas lacking nNOS. These data suggest that nNOS-containing interneurons either are not necessary for
A. N. Fricks-Gleason Department of Pharmacology & Toxicology, University of Utah, 30 South 2000 East, Room 105, Salt Lake City, UT 84112-5820, USA e-mail: [email protected] K. A. Keefe (&) Department of Pharmacology & Toxicology, Interdepartmental Program in Neuroscience, University of Utah, 30 South 2000 East, Room 105, Salt Lake City, UT 84112-5820, USA e-mail: [email protected]
METH-induced DA neurotoxicity or produce NO that can diffuse extensively through striatal tissue and thereby still mediate neurotoxicity. Keywords Methamphetamine Neurotoxicity Nitric oxide synthase Dopamine
Introduction The abuse of methamphetamine (METH) continues to be a major public health concern. As many as 60 million people worldwide report abusing amphetamine-type stimulants, especially METH (Maxwell 2005). The use of METH is highly problematic, not only because of the acute effects of the drug which can include psychosis and aggressive behavior, but also because of the now-documented, longterm consequences on the structure and function of the central nervous system, and concomitant cognitive deficits. It is well established that exposure to multiple high doses of METH produces damage to central monoamine systems, and this toxicity has been modeled in numerous species. In nonhuman primates, decreases in markers of dopamine (DA) innervation have been reported to exist for up to 4 years (Woolverton
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