title: The role of the neuropeptide somatostatin on methamphetamine and glutamate-induced neurotoxicity in the striatum of mice.
abstract: A large body of evidence shows that methamphetamine (METH) causes sustained damage to the brain in animal models and human METH users. In chronic users there are indications of cognitive and motor deficits. Striatal neuropeptides are in a position to modulate the neurochemical effects of METH and consequently striatal neural damage. Somatostatin (SST) is an intrinsic striatal neuropeptide that has been shown to inhibit glutamate transmission; glutamate is integral to METH toxicity and contributes to nitric oxide (NO) synthesis. We hypothesize that SST will protect from METH by inhibition of NO synthesis and thus reducing oxidative stress. To this end, the SST analogue octreotide (OCT) was microinjected into the striatum prior to a systemic injection of METH (30mg/kg). We then assessed 3-nitrotyrosine (3-NT), an indirect index of NO production, tyrosine hydroxylase (TH) protein levels (dopamine terminal marker) and Fluoro-Jade C positive cells (degenerating cells). The SST agonist OCT dose dependently attenuated the METH-induced accumulation of striatal 3-NT. Moreover, pretreatment with OCT effectively mitigated cell death but failed to protect dopamine terminals. Next we co-infused OCT and NMDA and measured 3-NT and Fluoro-Jade C staining. Treatment with OCT had no effect on these parameters. The data demonstrate that SST attenuates the METH-induced production of NO protecting the striatum from the METH-induced cell loss. However, SST failed to prevent the toxicity of the dopamine terminals suggesting that pre- and post-synaptic striatal damage occur via independent mechanisms.
authors.affiliation: Department of Biological Sciences, Hunter College of the City University of New York, 695 Park Avenue, NY 10065, USA.
authors.forename: Lauriaselle
authors.initials: L
authors.lastname: Afanador
authors.forename: Ina
authors.initials: I
authors.lastname: Mexhitaj
authors.forename: Carolyn
authors.initials: C
authors.lastname: Diaz
authors.forename: Dalila
authors.initials: D
authors.lastname: Ordonez
authors.forename: Lisa
authors.initials: L
authors.lastname: Baker
authors.forename: Jesus A
authors.initials: JA
authors.lastname: Angulo
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D005452:Fluoresceins; D018698:Glutamic Acid / Q000633:toxicity*; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008813:Mice, Inbred ICR; D008845:Microinjections; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000473:pathology*; D009498:Neurotoxins / Q000633:toxicity*; D009569:Nitric Oxide / Q000378:metabolism; D015282:Octreotide / Q000494:pharmacology; D013004:Somatostatin / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D005452:Fluoresceins; D009498:Neurotoxins; C534582:fluoro-jade C; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D018698:Glutamic Acid; D014443:Tyrosine; D008694:Methamphetamine; D013004:Somatostatin; D014446:Tyrosine 3-Monooxygenase; D015282:Octreotide