Comparison of time-dependent effects of (+)-methamphetamine or forced swim on monoamines, corticosterone, glucose, creatine, and creatinine in rats

Division of Neurology, Cincinnati Children's Research Foundation and University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
BMC Neuroscience (Impact Factor: 2.67). 02/2008; 9(1):49. DOI: 10.1186/1471-2202-9-49
Source: PubMed


Methamphetamine (MA) use is a worldwide problem. Abusers can have cognitive deficits, monoamine reductions, and altered magnetic resonance spectroscopy findings. Animal models have been used to investigate some of these effects, however many of these experiments have not examined the impact of MA on the stress response. For example, numerous studies have demonstrated (+)-MA-induced neurotoxicity and monoamine reductions, however the effects of MA on other markers that may play a role in neurotoxicity or cell energetics such as glucose, corticosterone, and/or creatine have received less attention. In this experiment, the effects of a neurotoxic regimen of (+)-MA (4 doses at 2 h intervals) on brain monoamines, neostriatal GFAP, plasma corticosterone, creatinine, and glucose, and brain and muscle creatine were evaluated 1, 7, 24, and 72 h after the first dose. In order to compare MA's effects with stress, animals were subjected to a forced swim test in a temporal pattern similar to MA administration [i.e., (30 min/session) 4 times at 2 h intervals].
MA increased corticosterone from 1-72 h with a peak 1 h after the first treatment, whereas glucose was only increased 1 h post-treatment. Neostriatal and hippocampal monoamines were decreased at 7, 24, and 72 h, with a concurrent increase in GFAP at 72 h. There was no effect of MA on regional brain creatine, however plasma creatinine was increased during the first 24 h and decreased by 72 h. As with MA treatment, forced swim increased corticosterone more than MA initially. Unlike MA, forced swim reduced creatine in the cerebellum with no change in other brain regions while plasma creatinine was decreased at 1 and 7 h. Glucose in plasma was decreased at 7 h.
Both MA and forced swim increase demand on energy substrates but in different ways, and MA has persistent effects on corticosterone that are not attributable to stress alone.

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    • "A growing number of reports have provided evidence for the importance of the creatine kinase/phosphocreatine system in the pathophysiology of depression: (1) brain phosphocreatine , detected by phosphorus-31 magnetic resonance spectroscopy, was shown to be decreased in severely depressed patients (Kato et al. 1992); (2) an inverse correlation between Hamilton Depression Rating Scale scores and white matter creatine levels was shown (Dager et al. 2004); (3) single prolonged stress and forced swimming stress decreased creatine concentrations in the rat prefrontal cortex (Herring et al. 2008; Kim et al. 2010; Knox et al. 2010); (4) learned helplessness, a well-validated animal model of depression, decreased the expression of hippocampal creatine transporter (Lugenbiel et al. 2010); (5) the acute administration of the fast-acting antidepressant ketamine increased creatine kinase activity in rats (Assis et al. 2009); (6) clinical trials show that creatine augmentation in antidepressant treatment-resistant patients may be a promising therapeutic approach that exhibits more rapid and efficacious responses (Kondo et al. 2011; Lyoo et al. 2012); (7) creatine administration in mice produced an anti-immobility effect in the tail suspension test (TST) and forced swimming test (FST), two widely used tests for screening antidepressants (Allen et al. 2010, Cunha et al. 2012, 2013a, b). The mechanisms underlying the neuroprotective and antidepressant actions may be different, although antidepressant agents commonly exhibit neuroprotective properties . "
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    ABSTRACT: The modulation of N-methyl-D-aspartate receptor (NMDAR) and l-arginine/nitric oxide (NO) pathway is a therapeutic strategy for treating depression and neurologic disorders that involves excitotoxicity. Literature data have reported that creatine exhibits antidepressant and neuroprotective effects, but the implication of NMDAR and l-arginine/nitric oxide (NO) pathway in these effects is not established. This study evaluated the influence of pharmacological agents that modulate NMDAR/l-arginine-NO pathway in the anti-immobility effect of creatine in the tail suspension test (TST) in mice. The NOx levels and cellular viability in hippocampal and cerebrocortical slices of creatine-treated mice were also evaluated. The anti-immobility effect of creatine (10 mg/kg, po) in the TST was abolished by NMDA (0.1 pmol/mouse, icv), d-serine (30 µg/mouse, icv, glycine-site NMDAR agonist), arcaine (1 mg/kg, ip, polyamine site NMDAR antagonist), l-arginine (750 mg/kg, ip, NO precursor), SNAP (25 μg/mouse, icv, NO donor), L-NAME (175 mg/kg, ip, non-selective NOS inhibitor) or 7-nitroindazole (50 mg/kg, ip, neuronal NOS inhibitor), but not by DNQX (2.5 µg/mouse, icv, AMPA receptor antagonist). The combined administration of sub-effective doses of creatine (0.01 mg/kg, po) and NMDAR antagonists MK-801 (0.001 mg/kg, po) or ketamine (0.1 mg/kg, ip) reduced immobility time in the TST. Creatine (10 mg/kg, po) increased cellular viability in hippocampal and cerebrocortical slices and enhanced hippocampal and cerebrocortical NOx levels, an effect potentiated by l-arginine or SNAP and abolished by 7-nitroindazole or L-NAME. In conclusion, the anti-immobility effect of creatine in the TST involves NMDAR inhibition and enhancement of NO levels accompanied by an increase in neural viability.
    Amino Acids 01/2015; 47(4). DOI:10.1007/s00726-014-1910-0 · 3.29 Impact Factor
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    • "(A.L.S. Rodrigues). stress and forced swimming stress decreased creatine concentrations in the rat prefrontal cortex (Herring et al., 2008; Kim et al., 2010; Knox et al., 2010); (iv) learned helplessness, a well validated animal model of depression, decreased the hippocampal creatine transporter expression as compared to wild type animals and the selective serotonin reuptake inhibitor escitalopram blocked this effect (Lugenbiel et al., 2010); (v) some antidepressants such as paroxetine and imipramine increase creatine kinase activity (Assis et al., 2009; Reus et al., 2012a,b; Santos et al., 2009); (vi) agents that exert antidepressant action cause changes in brain levels of creatine-containing compounds, such as S-adenosyl-l-methionine that, in turn, increases phosphocreatine brain levels (Papakostas, 2009; Papakostas et al., 2003; Silveri et al., 2003). "
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    ABSTRACT: Creatine was previously shown to produce an antidepressant-like effect in the tail suspension test through a modulation of the dopaminergic system. In this study, the mechanisms underlying its antidepressant-like effect were further evaluated by investigating the involvement of the serotonergic system in its effect. The anti-immobility effect of creatine (1mg/kg) was prevented by the pretreatment of mice with p-chlorophenylalanine methyl ester (PCPA; 100mg/kg, i.p., for 4 consecutive days, an inhibitor of serotonin (5-HT) synthesis). Creatine (0.01mg/kg, sub-effective dose) in combination with sub-effective doses of WAY100635 (0.1mg/kg, s.c., a 5-HT(1A) receptor antagonist), 8-OH-DPAT (0.1mg/kg, i.p., a 5-HT(1A) receptor agonist) or selective serotonin reuptake inhibitors fluoxetine (5mg/kg, p.o.), paroxetine (0.1mg/kg, p.o.), citalopram (0.1mg/kg, p.o.) and sertraline (3mg/kg, p.o.) reduced the immobility time in the tail suspension test as compared with either drug alone. These results indicate that the antidepressant-like effect of creatine is likely mediated by an interaction with 5-HT(1A) receptors. Of note, the present results also indicate that creatine improves the effectiveness of the selective serotonin reuptake inhibitors, a finding that may have therapeutic implications for the treatment of depressive disorders.
    Brain research bulletin 06/2013; DOI:10.1016/j.brainresbull.2013.01.005 · 2.72 Impact Factor
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    • "45 min after intravenous infusion of 0.5 mg/kg METH in experienced users (Harris, Reus, Wolkowitz, Mendelson, & Jones, 2003). This is in agreement with results from studies showing elevated CORT following METH administration to nonhuman primates (Madden et al., 2005) and rats (Herring et al., 2008; Schaefer, Grace, Gudelsky, Vorhees, & Williams, 2010). Further determining the role that CORT plays in substance abuse and its interaction with OT and AVP functioning may advance our understanding of the pathophysiology and treatment of such conditions. "
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    ABSTRACT: The effects of chronic methamphetamine use on neuroendocrine functioning in humans are largely undocumented. Here we assessed basal plasma oxytocin, arginine vasopressin, and cortisol levels in a naturalistic sample of methamphetamine polydrug users (n = 12) compared with controls matched for age, gender, education, occupation status, and marital status (n = 17). All of the methamphetamine users tested positive for blood methamphetamine and/or its main metabolite, amphetamine. Other drugs of abuse were detected in a small number of methamphetamine users (MDMA [3,4-methylenedioxy-N-methylamphetamine; n = 2], THC [delta-9-tetrahydrocannabinol; n = 2]). Almost half of the methamphetamine users reported using methamphetamine intravenously, and others smoked or ingested the drug. Methamphetamine users had significantly lower basal plasma cortisol (p = .025), but similar basal plasma oxytocin and arginine vasopressin levels compared with controls. Basal plasma oxytocin was positively correlated (p = .011), with basal plasma arginine vasopressin in controls, but not in methamphetamine users. Methamphetamine users reported higher rates of psychiatric symptoms including substance use disorders, impulsivity, and positive, negative, manic, and disorientation symptoms compared with controls. Psychiatric symptoms were not related to neuroendocrine functioning in either group. These results provide preliminary evidence for lowered basal cortisol levels in methamphetamine polydrug users and encourage further research in to the effects of methamphetamine on neuroendocrine functioning in humans using more highly controlled experimental research designs. (PsycINFO Database Record (c) 2012 APA, all rights reserved).
    Experimental and Clinical Psychopharmacology 10/2012; 20(6). DOI:10.1037/a0029976 · 2.71 Impact Factor
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