Influence of Chronic Creatine Supplementation on Neurogenesis, Synaptic Plasticity and Affective Behavior: Implications for Sex-Specific Differences.
Allen, Patricia.
2013
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Abstract: Rationale: Impairments in creatine metabolism are strongly
implicated in the pathophysiology of psychiatric illness. Growing evidence supports the
potential for creatine, an antioxidant, neuromodulator and key regulator of energy
metabolism, to improve depressive symptoms in humans and animals, especially in females.
Objective: The aim of this dissertation was to examine two highly ... read moreplausible neurobiological
mechanisms that may underlie observed antidepressant effects of creatine. Specifically, it
was hypothesized that creatine would oppose the negative effects of stress on neurotrophic-
and neurogenesis-related activity in hippocampus (HPC) and prefrontal cortex (PFC), akin to
conventional antidepressant drugs, and that these positive effects would depend upon the
presence of sex steroids. Materials and Methods: Four experiments examined whether creatine
supplementation influences gene expression linked to neural growth and survival,
particularly brain-derived neurotrophic factor (BDNF), Tyrosine kinase B (TrkB),
doublecortin (DCX), calretinin (CALR), and calbindin (CALB) in HPC and PFC following the
forced swim test (FST). In the first two experiments, male (Exp. 1) and female (Exp. 2)
rats were maintained on chow alone or chow blended with 4% w/w creatine monohydrate for
five weeks before random assignment to acute swim stress or no stress conditions. In the
last two experiments, male rats (Exp. 3) underwent castration or sham surgery and were
assigned to receive either an empty or a testosterone-filled (T) Silastic implant (10-mm
releasing surface), and female rats (Exp. 4) were ovariectomized (OVX) or underwent sham
surgery and were assigned to receive single weekly injections of estradiol benzoate (EB,
2.5 µg), progesterone (P, 250 µg), EB + P, or sesame oil vehicle. After recovery, rats
received either chow alone or chow blended with 2% or 4% w/w creatine monohydrate for five
weeks before FST, open field and wire suspension tests, equating to a total of seven weeks
of creatine supplementation. For all experiments, plasma and brain tissue were analyzed for
creatine levels and mRNA expression using calorimetric and molecular techniques. Results:
Creatine was highly bioavailable in the HPC of both males and females, and PFC levels of
creatine were consistently higher in females. Contrary to hypothesis, acute swim stress
significantly upregulated HPC BDNF, TrkB, DCX, CALR, and CALB mRNA in males (Exp. 1) and
HPC TrkB, and CALB mRNA and PFC TrkB in females (Exp. 2). Moreover, creatine downregulated
BDNF mRNA in females and marginally reduced HPC TrkB in males and females following acute
swim stress (Exp. 1-2). Creatine's molecular effects were more prevalent after 7 weeks
(Exp. 3-4), whereby HPC BDNF, TrkB, DCX, CALR, and CALB mRNA were downregulated in
sham-operated males fed 4% creatine, and HPC BDNF, DCX, and CALB mRNA were downregulated in
sham-operated females given 4% creatine compared to nonsupplemented controls. In contrast,
4% creatine combined with castration + T or OVX + EB + P was associated with a protective
effect on HPC BDNF, DCX, and CALR mRNA in males and HPC BDNF and CALB mRNA in females.
Corresponding behavioral changes showed that creatine-fed castrates + T displayed
marginally significant antidepressant-like trends and creatine-fed OVX + EB + P rats showed
significantly greater antidepressant- and anxiolytic-like behaviors. Conclusions: Creatine
supplementation produced differential effects on neurobiology and behavior in "healthy"
versus "metabolically challenged" rats in a sex-, stress-, and time-dependent manner.
Dietary creatine combined with hormone replacement had a neuroprotective effect in
castrated and OVX rats. In contrast, creatine downregulated neurotrophic- and
neurogenesis-related gene expression in HPC of otherwise healthy, intact rats after 5 and 7
weeks of supplementation, suggesting a U-shape curve for creatine's effects. Nevertheless,
it is unclear if downregulated gene expression here is necessarily negative as creatine
influences both excitatory glutamate and inhibitory GABA-A receptor activity, which have
opposing effects on neurotrophin signaling. However, tissue oversaturation with creatine
may cause compensatory changes in energy metabolism that downregulate ATP. All together,
these data are consistent with the prediction that sex hormones are necessary, but not
sufficient, for creatine's antidepressant properties, and stress signals mediate creatine's
molecular effects. Careful dose ranging and efficacy studies in humans and rodents are
required to clarify the effects of creatine on neurobiology and behavior and to verify the
safety and usefulness of creatine as an adjunctive treatment for depressive
disorders.
Thesis (Ph.D.)--Tufts University, 2013.
Submitted to the Dept. of Psychology.
Advisor: Robin Kanarek.
Committee: Kristen D'Anci, Joseph DeBold, Perry Renshaw, Maribel Rios, and Lisa Shin.
Keywords: Psychobiology, Nutrition, and Neurosciences.read less - ID:
- 7m01bz08b
- Component ID:
- tufts:21864
- To Cite:
- TARC Citation Guide EndNote
