Effects of Housing on Methamphetamine-Induced Neurotoxicity and

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Effects of housing on methamphetamine-induced neurotoxicity and spatial learning and memory Arnold Gutierrez, Sarah A. Jablonski, Robyn M. Amos-Kroohs, Anna C. Barnes, Michael T. Williams, and Charles V. Vorhees ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.6b00419 • Publication Date (Web): 13 Mar 2017 Downloaded from http://pubs.acs.org on March 15, 2017

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ACS Chemical Neuroscience

Effects of housing on methamphetamine-induced neurotoxicity and spatial learning and memory

Arnold GutierrezA,B, Sarah A. JablonskiA, Robyn M. Amos-KroohsC, Anna C. BarnesA,D, Michael T. WilliamsA,B, and Charles V. VorheesA,B,*

A

Cincinnati Children’s Research Foundation, Dept. of Pediatrics, Div. of Neurology, Cincinnati OH 45229, BUniversity of Cincinnati College of Medicine, Cincinnati OH 45229, CUniversity of North Carolina at Chapel Hill, Nutrition Research Institute, Kannapolis, NC 28081, DUniversity of Cincinnati, College of Arts and Sciences, Cincinnati, Cincinnati OH 45229 D

*Correspondence: Charles V. Vorhees, Ph.D., Professor, Div. of Neurology (MLC 7044), Cincinnati Children’s Research Foundation, 3333 Burnet Ave., Cincinnati, OH 45229. Email: [email protected] Coauthor email: Arnold Gutierrez: [email protected] Sarah Jablonski: [email protected] Robyn Amos-Kroohs: [email protected] Anna Barnes: [email protected] Michael Williams: [email protected]

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Abstract Severe stress potentiates methamphetamine (MA) neurotoxicity. However, whether moderate stress increases or decreases the neurotoxic effects of MA is unknown. We assessed the effects of MA (4 x 10 mg/kg at 2 h intervals) in combination with prior barren-cage housing in adult male Sprague-Dawley rats on monoamines and glial fibrillary acid protein (GFAP) in one cohort and spatial learning and memory in the Morris water maze in another cohort. MA reduced dopamine (DA) and serotonin (5-HT) in the neostriatum and nucleus accumbens, 5-HT in the hippocampus, and increased GFAP in neostriatum and nucleus accumbens compared with saline controls. In neostriatum, barren-cage housing protected against MA-induced increases in GFAP, but it did not prevent DA and 5-HT reductions, although it did increase hippocampal NE. MA impaired spatial learning during acquisition, reversal, and shift phases and impaired reference memory on reversal and shift probe trials. Barren-cage housing enhanced performance during acquisition but not during reversal or shift or on probe trials. The data indicate that prior barren-cage housing moderates MA-induced neostriatal astrogliosis and initial spatial learning, but has no protective effect when the platform is smaller and relocated and therefore requires cognitive flexibility in relearning. Key words: Methamphetamine, barren-cage stress, spatial learning and memory, Morris water maze, monoamines, glial-fibrillary acidic protein


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INTRODUCTION Chronic methamphetamine (MA) abuse results in functional deficits and monoamine changes. Striatal dopamine (DA) and serotonin (5-HT) and hippocampal 5-HT are reduced as are DA and 5-HT transporters (DAT; SERT) 1-4. Chronic MA users also exhibit cognitive impairments in psychomotor ability, explicit and working memory, impulsivity, and inferential reasoning 3, 5-10. Positron emission tomography (PET) studies in chronic users indicate that DAT and SERT gradually recover whereas neuropsychological deficits remain 11. Rodent models of MA-induced neurotoxicity show monoamine changes, including reduced striatal DA and 5-HT, loss of DAT and SERT in the striatum, and reduced 5-HT and SERT in the hippocampus 12-14 similar to those seen in human chronic users by PET or at autopsy 1, 3, 15-18. These changes are associated with several behavioral deficits, including impaired egocentric navigation 19, 20, a form of learning and memory dependent on striatal DA as we have shown for learning in the Cincinnati water maze (CWM) 21-23. This deficit is consistent with the finding that MA primarily affects striatal DA. When it comes to how MA affects allocentric navigation, a hippocampusdependent form of learning and memory, the effects vary. One study 24 in Wistar rats found allocentric acquisition in a 136 cm diameter Morris water maze (MWM) was impaired after 4 injections of 5 mg/kg MA at 2 h intervals and during a probe trial for time in the target quadrant. Another study in Sprague-Dawley rats found no effects on allocentric spatial navigation in a 183 cm diameter maze after 4 injections of 4 mg/kg MA at 2 h intervals. An earlier study in Long-Evans rats 25 found MWM deficits in a 160 3 ACS Paragon Plus Environment


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cm diameter maze on the last day of acquisition and on a probe trial when tested 2 weeks after MA (4 x 10 mg/kg at 2 h intervals) . Herring et al. 35, however, found no effects in Sprague-Dawley rats on MWM spatial navigation in a 210 cm diameter maze two weeks after either a 10 mg/kg x 4 MA at 2 h intervals or after 1.67 mg/kg x 24 MA at 15 min intervals for the same total dose over 6 h. Small effects were also found after 4 injections of 12.5 mg/kg MA at 2 h intervals in a 150 cm maze, 26 but the effects were transient. Chronic variable stress exacerbates the effects of MA on monoamines through neuroinflammation and glutamatergic excitotoxicity 27, 28. However, stress has complex effects depending on the intensity and length of the stressor. For example moderate stress can have positive or negative effects depending on the circumstances. Barrencage housing (BAR) during early brain development results in deficits in the MWM in mice 29-31, in deficits in the MWM and CWM in rats32, and alters corticosterone (CORT) and monoamines in the brain of neonatal rats33-35 compared with standard housed (STD) animals. However, BAR may not have the same effects in adult rats, where its effects are largely unknown. It may even attenuate MA neurotoxicity if it conditions the animal to become more resilient to the stressor. In order to assess the effects of BAR on MA-induced neurotoxicity and cognitive function we exposed adult rats to BAR for three weeks prior to MA or saline administration and tested them two weeks later. To determine the level of stress adaptation induced by BAR, CORT was measured prior to and after MA but prior to MWM testing. Astrogliosis, a marker of neurotoxicity, was assessed by glial fibrillary acidic protein (GFAP) production. We used a MWM but unlike previous studies, we 4 ACS Paragon Plus Environment

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used a larger (244 cm) maze to enhance task difficulty and increase sensitivity 36-38. The design of the experiment is shown in Fig. 1.

Fig. 1: Outline of the design of the experiment. MA=methamphetamine; SAL=Saline; STD=standard housing; BAR=Barren cage housing; MWM=Morris water maze. The numbers under the time line indicate the number of days separating each event.



RESULTS Temperature. Body temperatures for animals were taken once prior to dosing and every 30 min beginning an hour after the first dose (Fig. 1). There was a drug main effect (F(1,101)=142.27, p

Effects of Housing on Methamphetamine-Induced Neurotoxicity and

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