Creatine transporter expression after antidepressant therapy in rats bred for learned helplessness

Lugenbiel, Patrick; Sartorius, Alexander; Vollmayr, Barbara; Schloss, Patrick D.

doi:10.3109/15622970903131597

Cited by 9 publications

(1 citation statement)

References 28 publications

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“…The 5-HT system has been shown to play an important role in the acquisition of LH (Maier & Seligman 2016). Additionally, Lugenbiel et al (2010) found that rats bred for a congenital LH response (cLH) without induction have decreased Slc6a8 expression in Lack of creatine alters serotonin and affect 1 0 the hippocampus, but not the prefrontal cortex (Lugenbiel et al 2010). Both escitalopram and electroconvulsive shock administration are antidepressant treatments that attenuate LH-responses (Reed et al 2009;Sartorius et al 2003).…”

Section: Discussionmentioning

confidence: 99%

Creatine transporter knockout mice (Slc6a8) show increases in serotonin-related proteins and are resilient to learned helplessness

Abdulla

Pennington

Gutierrez

et al. 2019

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Scale; LH: learned helplessness; MAO: monoamine oxidase; PCA: parachloroamphetamine; PCr: phosphocreatine; Slc6a8 -/y : male Slc6a8 knockout mice; Slc6a8 +/y : male wild type mice; Slc6a8 +/-: female mice heterozygous for Slc6a8; Slc6a8 +/+ : female wild type mice; SSRI: selective serotonin reuptake inhibitor; TPH-2: tryptophan hydroxylase-2; TST: tail-suspension test; cLH: rats bred for a congenital LH response Lack of creatine alters serotonin and affect 2 AbstractApproximately 20% of adults in the U.S. will experience an affective disorder during their life. While it is well established that serotonin (5-HT) is a crucial factor in mood, impaired cellular bioenergetics are also implicated. Creatine (Cr), through the Cr/Phospho-Cr (PCr) shuttle, maintains high ATP concentrations in the neuron. This system may be implicated in the etiology of affective disorders, as reduced Cr, PCr, and ATP are often seen in the brains of affected patients. To address this issue, Cr transporter (Crt) deficient male mice (Slc6a8 -/y ) and female mice heterozygous for Crt expression (Slc6a8 +/-) were used to evaluate how a Cr deficient system would alter affective-like behaviors. Slc6a8 -/y and Slc6a8 +/mice had more escapes and faster escape latencies in learned helplessness, indicating a potential resilience to behavioral despair. Elevated zero maze and tail-suspension test performance matched that of wildtype mice, however. Slc6a8 -/y mice have increased 5-hydroxyindoleacetic acid content in the hippocampus and striatum and increased monoamine oxidase protein and tryptophan hydroxylase-2 protein content in the hippocampus, while serotonin levels are unchanged. This indicates an increase in 5-HT turnover. Our results indicate that Cr plays a complex role in affective disorders and 5-HT neurotransmission, warranting further investigation. Lack of creatine alters serotonin and affect 3

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Section: Discussionmentioning

confidence: 99%

Creatine transporter knockout mice (Slc6a8) show increases in serotonin-related proteins and are resilient to learned helplessness

Abdulla

Pennington

Gutierrez

et al. 2019

Preprint

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Serotonergic treatment normalizes midbrain dopaminergic neuron increase after periaqueductal gray stimulation

et al. 2020

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Background: Electrical stimulation of the dorsolateral periaqueductal gray (dlPAG) in rats has been shown to elicit panic-like behaviour and can be a useful tool for modelling anticipatory fear and agoraphobia. Methods: In this study, we further analysed our previous data on the effects of escitalopram (a selective serotonin reuptake inhibitor, SSRI) and buspirone (a 5-HT1A receptor partial agonist) on dlPAG-induced anticipatory fear behaviour in a rat model using freezing as a measure. We then used tyrosine hydroxylase (TH) immunohistochemistry to probe the effects on dopaminergic neurons. Results: Although acute treatment of escitalopram, but not buspirone, was effective in reducing anticipatory freezing behaviour, chronic administrations of both drugs were comparably effective. We found that the number of dopaminergic neurons in the ventral tegmental area (VTA) was lowered in both chronic buspirone and escitalopram groups. We showed a strong correlation between the number of dopaminergic neurons and freezing in the VTA. We further showed positive correlations between dopaminergic neurons in the VTA and substantia nigra pars compacta in escitalopram and buspirone groups, respectively. Limitations: Although our data strongly hint to a role of dopaminergic mechanisms in the dlPAG induced fear response, more in-depth studies with larger sample sizes are needed to understand the neuronal mechanisms underlying the interactions between serotonergic drugs and dopaminergic cell number and fear behavior. Conclusion: Chronic treatment with an SSRI and a 5-HT1A agonist decrease the number of dopaminergic neurons in the VTA. These effects seem to be associated with reduced dlPAG-induced anticipatory freezing behaviour.

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The modulation of NMDA receptors and l-arginine/nitric oxide pathway is implicated in the anti-immobility effect of creatine in the tail suspension test

et al. 2015

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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 NO x 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.

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Creatine transporter expression after antidepressant therapy in rats bred for learned helplessness

Cited by 9 publications

References 28 publications

Creatine transporter knockout mice (Slc6a8) show increases in serotonin-related proteins and are resilient to learned helplessness

Creatine transporter knockout mice (Slc6a8) show increases in serotonin-related proteins and are resilient to learned helplessness

Serotonergic treatment normalizes midbrain dopaminergic neuron increase after periaqueductal gray stimulation

The modulation of NMDA receptors and l-arginine/nitric oxide pathway is implicated in the anti-immobility effect of creatine in the tail suspension test

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