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

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.

Myricetin Inhibited Fear and Anxiety-Like Behaviors by HPA Axis Regulation and Activation of the BDNF-ERK Signaling Pathway in Posttraumatic Stress Disorder Rats

“…To evaluate anxiety-like behavior using the apparatus detailed in a previous study (EPM test) [ 32 ], rats were placed in the center of a maze and tested for 5 min. The apparatus consisted of two open arms (50 cm × 10 cm) and two closed arms with dark walls (50 cm × 10 cm × 50 cm).…”

Nutraceutical Interventions for Post-Traumatic Stress Disorder in Animal Models: A Focus on the Hypothalamic–Pituitary–Adrenal Axis

“…SPS and inescapable shock-induced models are well-known animal models for PTSD [ 21 , 22 , 23 ]. In SPS-induced PTSD animal models, increased plasma levels of CORT, CRH, and ACTH are associated with memory impairment due to dysregulation of the HPA axis [ 24 , 25 ]. Furthermore, animal studies have strongly implicated the role of CRH in fear-related behaviors; CRH regulates the activation of the noradrenergic and dopaminergic systems [ 25 , 26 ].…”

“…In SPS-induced PTSD animal models, increased plasma levels of CORT, CRH, and ACTH are associated with memory impairment due to dysregulation of the HPA axis [ 24 , 25 ]. Furthermore, animal studies have strongly implicated the role of CRH in fear-related behaviors; CRH regulates the activation of the noradrenergic and dopaminergic systems [ 25 , 26 ]. Moreover, the 5-HT concentration is reduced and the monoamine oxidase A (MAO-A) activity and the 5-hydroxyindoleacetic acid (5-HIAA)/5-HT ratio increased in the hippocampi of SPS-induced PTSD animal models [ 27 ].…”

“…Furthermore, it decreased the serum CORT and ACTH levels. Finally, it increased the 5-HT level in the mPFC and hippocampus, and also increased tryptophan and 5-HIAA mRNA expression in the hippocampus [ 25 ].…”

Could Cannabidiol Be a Treatment for Coronavirus Disease-19-Related Anxiety Disorders?

“…The Artelo CBD cocrystal uses the coformer tetramethylpyrazine (TMP), which itself has evidence of activity in anxiety-related disorders or PTSD. 75,76 Funding Information Funding was provided by Artelo Biosciences.…”