Neuroscience Letters 469 (2010) 309–313 Contents lists available at ScienceDirect Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet Reduced degeneration of dopaminergic terminals and accentuated astrocyte activation by high dose methamphetamine administration in nociceptin receptor knock out mice Kazuto Sakoori, Niall P. Murphy ∗ Molecular Neuropathology Group, RIKEN Brain Science Institute, 2-1 Hirosawa, Wakoshi, Saitama, 351-0198, Japan article info Article history: Received 6 October 2009 Received in revised form 17 November 2009 Accepted 10 December 2009 Keywords: Opioid Psychostimulant Neurotoxicity Dopamine Glia abstract A major pathology of methamphetamine abuse is loss of dopaminergic function due to destruction of dopaminergic terminals, especially in the striatum. This process is accompanied by gliosis by astrocytes and microglia. Here, we evaluated the function of endogenous nociceptin/orphanin FQ in these events using nociceptin receptor (NOP) knockout mice. Wild-type and knockout mice were injected systemi- cally either saline vehicle or 5 mg/kg methamphetamine four times interspersed by 2 h intervals. Three days later, brains were immunohistochemically processed to visualize methamphetamine-induced loss of tyrosine hydroxylase (as a marker of damage to dopamine terminals), glial fibrillary acidic protein (GFAP, as a marker of astrocytes), and ionized calcium-binding adapter molecule 1 (lba-1, as a marker of microglia) in the striatum. Methamphetamine treatment induced an approximately 80% loss of tyrosine hydroxylase-immunoreactivity, and this effect was mildly attenuated in NOP receptor knockout mice. There was a large increase (approximately 15-fold) in GFAP-immunoreactivity in methamphetamine- treated wild-type mice, which was almost two times larger still in NOP receptor knockout mice. In contrast, Iba-1 immunostaining was only modestly increased (approximately 30%) by methamphetamine treatment, and there were no difference between genotypes. Finally, there were no genotype-dependent differences in hyperthermic responses to methamphetamine. These results indicate that endogenous nociceptin/orphanin FQ exacerbates the neurotoxic effects of methamphetamine on striatal dopamine neurons, and suggests this is due in part to an astrocyte-mediated event. © 2009 Elsevier Ireland Ltd. All rights reserved. The endogenously occurring opioid peptide nociceptin/orphanin FQ (N/OFQ) may be involved in methamphetamine (METH) addic- tion. For example, acquisition of METH-induced conditioned place preference (a model of drug reward) is impaired by N/OFQ [25]. Our own studies show that METH-induced conditioned place preference is enhanced in N/OFQ receptor (NOP) knockout (KO) mice, and METH-induced behavioral sensitization (a behavioral model believed to address some of the plastic processes surround- ing addiction) is impaired [19]. One major pathological change observed in METH abusers is reduction of dopaminergic synaptic terminals in the striatum. For example, positron emission tomog- raphy studies using [11C]d-threo-methylphenidate for dopamine transporters show reduced amounts of dopamine transporters in the striatum of human METH abusers [5,23]. Likewise, in rodent ∗ Corresponding author. Current address: Department of Psychiatry and Biobe- havioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90024-1759, United States. Tel.: +1 310 794 2179. E-mail address: nmurphy@ucla.edu (N.P. Murphy). studies, tyrosine hydroxylase (TH), a marker of dopaminergic ter- minals, in the striatum is reduced by METH administration [13], and the implications of this effect on alterations in reward function and addiction has been widely discussed [11,9]. A single previous study has focused on the involvement of endogenous N/OFQ on neuroprotection of dopamine neurons, by drawing on mice with genetic ablations of the N/OFQ precursor [1]. In this report, the authors showed that 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)-induced toxicity to dopamine neurons was impaired in prepro-N/OFQ KO mice, but METH-induced tox- icity was unchanged. The authors noted that this finding was somewhat surprising, as MPTP and METH are believed to be neuro- toxic to dopamine neurons and terminals by similar mechanisms [1]. Thus, the first objective of the current report was to elaborate understanding of the function of endogenous N/OFQ in METH- induced dopaminergic toxicity. Compared to this previous report, we used a different genetic model, namely NOP receptor KO mice, and a different dose and regimen of METH administration to see if we would observe similar findings. Additionally, we also eval- uated gliosis of astrocyte and microglia by METH administration, because previous reports suggest these are involved in METH- and 0304-3940/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2009.12.014