Korean J Physiol Pharmacol.  2018 Sep;22(5):525-538. 10.4196/kjpp.2018.22.5.525.

Tetramethylpyrazine reverses anxiety-like behaviors in a rat model of post-traumatic stress disorder

• Lee B
• Shim I
• Lee H
• Hahm DH

• KMID: 2419002
• DOI: http://doi.org/10.4196/kjpp.2018.22.5.525

Abstract

Post-traumatic stress disorder (PTSD) is a trauma-induced psychiatric disorder characterized by impaired fear extermination, hyperarousal, and anxiety that may involve the release of monoamines in the fear circuit. The reported pharmacological properties of tetramethylpyrazine (TMP) include anti-cancer, anti-diabetic, anti-atherosclerotic, and neuropsychiatric activities. However, the anxiolytic-like effects of TMP and its mechanism of action in PTSD are unclear. This study measured several anxiety-related behavioral responses to examine the effects of TMP on symptoms of anxiety in rats after single prolonged stress (SPS) exposure by reversing the serotonin (5-HT) and hypothalamic-pituitary-adrenal (HPA) axis dysfunction. Rats were given TMP (10, 20, or 40 mg/kg, i.p.) for 14 days after SPS exposure. Administration of TMP significantly reduced grooming behavior, increased the time spent and number of visits to the open arm in the elevated plus maze test, and significantly increased the number of central zone crossings in the open field test. TMP administration significantly reduced the freezing response to contextual fear conditioning and significantly restored the neurochemical abnormalities and the SPS-induced decrease in 5-HT tissue levels in the prefrontal cortex and hippocampus. The increased 5-HT concentration during TMP treatment might be partially attribute to the tryptophan and 5-hydroxyindoleacetic acid mRNA level expression in the hippocampus of rats with PTSD. These findings support a role for reducing the altered serotonergic transmission in rats with PTSD. TMP simultaneously attenuated the HPA axis dysfunction. Therefore, TMP may be useful for developing an agent for treating psychiatric disorders, such those observed in patients with PTSD.

Keyword

Anxiety; Post-traumatic stress disorder; Serotonin; Single prolonged stress; Tetramethylpyrazine

MeSH Terms

Animals
Anxiety
Arm
Freezing
Grooming
Hippocampus
Humans
Models, Animal*
Prefrontal Cortex
Rats*
RNA, Messenger
Serotonin
Stress Disorders, Post-Traumatic*
Thymidine Monophosphate
Tryptophan
RNA, Messenger
Serotonin
Thymidine Monophosphate
Tryptophan

Figure

• 

  Fig. 1 Experiments used to develop single prolonged stress (SPS)-induced anxiety-like behaviors, and tetramethylpyrazine (TMP) treatment in rats. Different groups of rats (n=6 or 7 animals per group) were used for all experiments.

• 

  Fig. 2 Effects of TMP administration on the percentage of time spent in the open and closed arms, numbers of entries into the open and closed arms, anxiety index, number of unprotected head dips, and grooming behavior in the elevated plus maze (EPM) test of rats exposed to SPS. *p<0.05, **p<0.01 vs. SAL group; #p<0.05, ##p<0.01 vs. PTSD group. ***p<0.001.

• 

  Fig. 3 Effects of TMP administration on locomotion and exploratory behavior in the open filed test (OFT) of rats exposed to SPS. Changes in the time spent in the central and peripheral zones, numbers of crossing in the central and peripheral zones, locomotor activity, and number of rearing events in the open field test of rats exposed to SPS. *p<0.05, **p<0.01 vs. SAL group; #p<0.05, ##p<0.01 vs. PTSD group.

• 

  Fig. 4 Effects of TMP on freezing behavior from contextual fear conditioning testing after exposure to SPS in rats. The percentage of time spent freezing was determined on acquisition, day 1, and day 2. **p<0.01 vs. SAL group; #p<0.05, ##p<0.01 vs. SPS group.

• 

  Fig. 5 Effects of TMP on the serotonin (5-HT) concentration in the brains of rats exposed to SPS. *p<0.05, **p<0.01 vs. SAL group; #p<0.05, ##p<0.01 vs. PTSD group.

• 

  Fig. 6 Effects of TMP administration on the expression of tryptophan (TRP), 5-hydroxyindoleacetic acid (5-HIAA), and vesicular monoamine transporter-2 (VMAT-2) mRNA in rats during SPS-induced anxiety symptoms. The polymerase chain reaction bands on an agarose gel and their relative intensities are indicated. The expression levels of TRH, 5-HIAA, and VMAT-2 mRNA were normalized to that of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA as an internal control. *p<0.05, **p<0.01 vs. the SAL group, #p<0.05 vs. the PTSD group.

• 

  Fig. 7 Effects of TMP administration on the plasma corticosterone (CORT), corticotropin-releasing hormone (CRH), and adrenocorticotroic hormone (ACTH) levels in rats with SPS-induced anxiety-like symptoms analyzed by enzyme-linked immunosorbent assay. **p<0.01 vs. the SAL group, #p<0.05 vs. the PTSD group.

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