Fricks-Gleason AN, Keefe KA (2012) Poster: Evaluating the role of neuronal nitric oxide synthase-containing striatal interneurons in methamphetamine-induced dopamine neurotoxicity. Neuroscience 2012 Abstracts 360.06. Society for Neuroscience, New Orleans, LA.
Summary: It is well established that exposure to multiple high doses of methamphetamine (METH) produces damage to central monoamine systems. A number of factors, including the production of nitric oxide (NO), have been implicated in this neurotoxicity. While it is relatively clear that NO contributes to METH-induced neurotoxicity to the dopamine (DA) nerve terminal, the source of this NO has not been clearly delineated. There is considerable evidence suggesting that the generation of NO arises a consequence of the activation of neuronal nitric oxide synthase (nNOS). In striatum, nNOS is located post-synaptic to the DA nerve terminal in a subpopulation of striatal interneurons. Thus, we have hypothesized that DA-mediated activation of the nNOS-containing striatal interneurons is necessary for METH-induced neurotoxicity. These interneurons, along with the cholinergic neurons of striatum, selectively express the neurokinin-1 (NK-1) receptor, which is activated by the neuropeptide Substance P. Consequently, toxins targeted to NK-1 receptor-containing neurons can be used to lesion this population of striatal interneurons. One such toxin, a conjugate of Substance P to the ribosome inactivating protein saporin (SSP-SAP), has been shown to be effective in selectively destroying neurons expressing the NK-1 receptor in striatum. Therefore, using targeted deletion of the nNOS-containing interneurons via SSP-SAP, we examined the extent to which impairing post-synaptic production of NO attenuates METH-induced neurotoxicity. The SSP-SAP lesions resulted in a significant and selective loss of nNOS-containing interneurons throughout the striatum, although it was not possible to completely eliminate all of the neurons. Surprisingly, however, this marked deletion of nNOS-containing interneurons did not confer resistance to METH-induced DA neurotoxicity, even in areas completely devoid of nNOS-positive cell bodies and histochemical detection of NOS activity with NADPH diaphorase histochemical staining. Furthermore, these lesions did not attenuate NO production, as assessed via nitrotyrosine immunohistochemistry, even in areas devoid of nNOS. Taken together, these data suggest that nNOS-containing interneurons either are not necessary for METH-induced DA neurotoxicity, leaving open the potential contribution of other sources of NO, such as endothelial NOS (eNOS), or produce NO/RNS that can diffuse extensively through striatal tissue and thereby still mediate the neurotoxicity.
Related Products: SSP-SAP (Cat. #IT-11)