Chronic wheel running reduces maladaptive patterns of methamphetamine intake: regulation by attenuation of methamphetamine-induced neuronal nitric oxide synthase - PubMed (original) (raw)

Chronic wheel running reduces maladaptive patterns of methamphetamine intake: regulation by attenuation of methamphetamine-induced neuronal nitric oxide synthase

Alexander J Engelmann et al. Brain Struct Funct. 2014 Mar.

Abstract

We investigated whether prior exposure to chronic wheel running (WR) alters maladaptive patterns of excessive and escalating methamphetamine intake under extended access conditions, and intravenous methamphetamine self-administration-induced neurotoxicity. Adult rats were given access to WR or no wheel (sedentary) in their home cage for 6 weeks. A set of WR rats were injected with 5-bromo-2'-deoxyuridine (BrdU) to determine WR-induced changes in proliferation (2-h old) and survival (28-day old) of hippocampal progenitors. Another set of WR rats were withdrawn (WRw) or continued (WRc) to have access to running wheels in their home cages during self-administration days. Following self-administration [6 h/day], rats were tested on the progressive ratio (PR) schedule. Following PR, BrdU was injected to determine levels of proliferating progenitors (2-h old). WRc rats self-administered significantly less methamphetamine than sedentary rats during acquisition and escalation sessions, and demonstrated reduced motivation for methamphetamine seeking. Methamphetamine reduced daily running activity of WRc rats compared with that of pre-methamphetamine days. WRw rats self-administered significantly more methamphetamine than sedentary rats during acquisition, an effect that was not observed during escalation and PR sessions. WR-induced beneficial effects on methamphetamine self-administration were not attributable to neuroplasticity effects in the hippocampus and medial prefrontal cortex, but were attributable to WR-induced inhibition of methamphetamine-induced increases in the number of neuronal nitric oxide synthase expressing neurons and apoptosis in the nucleus accumbens shell. Our results demonstrate that WR prevents methamphetamine-induced damage to forebrain neurons to provide a beneficial effect on drug-taking behavior. Importantly, WR-induced neuroprotective effects are transient and continued WR activity is necessary to prevent compulsive methamphetamine intake.

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Conflict of interest statement

Conflict of interest The authors report no biomedical financial interests or potential conflict of interest.

Figures

Fig. 1

Wheel running increases proliferation and survival of newly born progenitors in the dentate gyrus of the hippocampus, and increases neuronal activation of hippocampal granule cell neurons in the dentate gyrus. a Schematic of experimental procedure and BrdU injections during a 6-week chronic running activity paradigm; BrdU injections are indicated by a syringe. b Total number of revolutions per hour during week 6 during a 24-h period. c Total number of revolutions per week (left y-axis); total miles run per week (right y-axis) during the 6 week running period. d Quantitative analysis of the number of BrdU labeled cells in the subgranular zone (2-h BrdU, left y-axis) or granule cell layer (28-day BrdU, right y-axis) of the hippocampal dentate gyrus in sedentary and wheel running (WRc) rats. e Quantitative analysis of 2-h-old BrdU cells in the subgranular zone from sedentary, WRc and WRw rats. f Stereological estimates of the number of Fos cells in the granule cell layer of the dentate gyrus of the hippocampus. Data are expressed as mean ± SEM; n = 18 in b and c; n = 6 in each group in d and e; n = 6–12 in each group in f. *p < 0.05 vs. sedentary rats; #p < 0.05 vs. WRc rats

Fig. 2

Wheel running decreases methamphetamine self-administration. a Schematic of methamphetamine self-administration behavior (0.05 mg/kg/inj, FR1 schedule) and BrdU injections (indicated by syringes). b–f Active and inactive lever responses for methamphetamine during acquisition sessions (b); methamphetamine intake (mg/ kg) during acquisition sessions (c); during escalation sessions (d, e), and during PR sessions (f). Data are expressed as mean ± SEM. n = 9 sedentary group; n = 9 WRw; n = 6 WRc. *p < 0.05 vs. sedentary methamphetamine rats in (b); vs. session 1 in (c–d); $p < 0.05 vs. WRc in (b, e); #p < 0.05 vs. WRw in (e)

Fig. 3

Running output before methamphetamine experience positively correlates with the amount of methamphetamine self-administered (a). Exercise output in revolutions per day (x_-axis) plotted against amount of methamphetamine consumed; left y_-axis represents acquisition in mg/kg and right y_-axis represents escalation in mg/kg. b–c Weekly running output from WRc rats before surgery (SUR), after SUR and after initiation of methamphetamine self-administration (Meth) (b) and daily running output before and after methamphetamine self-administration (c). Data are expressed as mean ± SEM. n = 9 sedentary group; n = 9 WRw; n = 6 WRc. 1_p < 0.05 vs. week 1; 2_p < 0.05 vs. week 2; 6_p < 0.05 vs. week 6 in (b)

Fig. 4

Methamphetamine reduced proliferating cells in the dentate gyrus and mPFC. a–c Photomicrographs of DAB stained 2-h BrdU cells (a), AC-3 cells (b) and Ki-67 cells (c). Scale bar in c applies a–c = 20 um. d–f Quantitative analysis of immunoreactive cells stained for BrdU (d), AC-3 (e) and Ki-67 (f). Data are expressed as mean ± SEM; n = 9 sedentary group; n = 9 WRw; n = 6 WRc. *p < 0.05 vs. drug naïve rats; #p < 0.05 vs. sedentary methamphetamine rats

Fig. 5

Methamphetamine self-administration increases the number of nNOS expressing neurons; wheel running prior to methamphetamine exposure prevents methamphetamine-induced increase in nNOS neurons. a Schematic of a coronal brain section 2.70 from bregma, a region analyzed for nNOS quantification. b–d Low magnification image of nNOS neurons in the nucleus accumbens shell region [indicated as a square box in a] showing nNOS stained neurons from drug naïve (b) and sedentary methamphetamine (c) rat. d High magnification of nNOS neurons in the nucleus accumbens shell region. Scale bar in d is 200 μm in b, c and 20 μm in d. e Quantitative analysis of nNOS expressing neurons in the nucleus accumbens shell and core regions. Data are expressed as mean ± SEM. n = 9 sedentary group; n = 9 WRw; n = 6 WRc. *p < 0.05 vs. drug naïve; #p < 0.05 vs. sedentary methamphetamine; $p < 0.05 vs. WRw methamphetamine rats

Fig. 6

Methamphetamine self-administration increases the number of AC-3 expressing cells; wheel running prior to methamphetamine exposure prevents methamphetamine-induced increase in the number of AC-3 cells. Quantitative analysis of AC-3 expressing cells in the nucleus accumbens shell region. Data are expressed as mean ± SEM. n = 9 sedentary group; n = 9 WRw; n = 6 WRc. #p <0.05 vs. sedentary methamphetamine by unpaired t test

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Chronic wheel running reduces maladaptive patterns of methamphetamine intake: regulation by attenuation of methamphetamine-induced neuronal nitric oxide synthase - PubMed (original) (raw)