Self-Reported Concussion Symptomology during Deployment: Differences as a Function of Injury Mechanism and Low-Level Blast Exposure.

Traumatic brain injury (TBI), which can result from either direct impact to the head or blast exposure, has been the leading cause of morbidity and mortality in recent military conflicts. However, little research has compared mTBIs by mechanism of injury. The present research addressed two research questions: (1) Are blast-related mTBIs (mbTBIs) associated with significantly more symptoms than impact-related mTBIs (miTBIs), and (2) are mTBIs associated with more self-reported symptoms among service members with higher (vs. lower) risk of low-level blast (LLB) exposure. We obtained data from 181,423 active duty enlisted United States Marines deployed between 2003 and 2012, who completed the Post-Deployment Health Assessment. We examined the self-reported symptoms of Marines who completed an mTBI screen and could be classified as at high or low risk for LLB exposure, using their military occupation as a proxy (n = 12,013). Symptoms were compared as a function of blast exposure (blast vs. impact), probable mTBI (yes vs. no), occupational risk of LLB (high vs. low), and symptom type (neurological vs. musculoskeletal vs. immunological). Overall, musculoskeletal symptoms were reported more frequently than neurological and immunological symptoms. However, Marines with probable mTBIs (regardless of mechanism of injury) and those with probable mbTBIs specifically reported more neurological symptoms, which rose to the level of musculoskeletal symptom reporting. Among Marines with probable mTBI, those with high risk of LLB exposure also reported significantly more neurological symptoms. Our results indicate that mbTBIs and miTBIs may be fundamentally different, and that LLB may increase susceptibility to injury.

Impact of RNA editing on functions of the serotonin 2C receptor in vivo.

Transcripts encoding 5-HT(2C) receptors are modified posttranscriptionally by RNA editing, generating up to 24 protein isoforms. In recombinant cells, the fully edited isoform, 5-HT(2C-VGV), exhibits blunted G-protein coupling and reduced constitutive activity. The present studies examine the signal transduction properties of 5-HT(2C-VGV) receptors in brain to determine the in vivo consequences of altered editing. Using mice solely expressing the 5-HT(2C-VGV) receptor (VGV/Y), we demonstrate reduced G-protein coupling efficiency and high-affinity agonist binding of brain 5-HT(2C-VGV) receptors. However, enhanced behavioral sensitivity to a 5-HT(2C) receptor agonist was also seen in mice expressing 5-HT(2C-VGV) receptors, an unexpected finding given the blunted G-protein coupling. In addition, mice expressing 5-HT(2C-VGV) receptors had greater sensitivity to a 5-HT(2C) inverse agonist/antagonist enhancement of dopamine turnover relative to wild-type mice. These behavioral and biochemical results are most likely explained by increases in 5-HT(2C) receptor binding sites in the brains of mice solely expressing 5-HT(2C-VGV) receptors. We conclude that 5-HT(2C-VGV) receptor signaling in brain is blunted, but this deficiency is masked by a marked increase in 5-HT(2C) receptor binding site density in mice solely expressing the VGV isoform. These findings suggest that RNA editing may regulate the density of 5-HT(2C) receptor binding sites in brain. We further caution that the pattern of 5-HT(2C) receptor RNA isoforms may not reflect the pattern of protein isoforms, and hence the inferred overall function of the receptor.

The serotonin 2C receptor potently modulates the head-twitch response in mice induced by a phenethylamine hallucinogen.

RATIONALE: Hallucinogenic serotonin 2A (5-HT(2A)) receptor partial agonists, such as (+ or -)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), induce a frontal cortex-dependent head-twitch response (HTR) in rodents, a behavioral proxy of a hallucinogenic response that is blocked by 5-HT(2A) receptor antagonists. In addition to 5-HT(2A) receptors, DOI and most other serotonin-like hallucinogens have high affinity and potency as partial agonists at 5-HT(2C) receptors. OBJECTIVES: We tested for involvement of 5-HT(2C) receptors in the HTR induced by DOI. RESULTS: Comparison of 5-HT(2C) receptor knockout and wild-type littermates revealed an approximately 50% reduction in DOI-induced HTR in knockout mice. Also, pretreatment with either the 5-HT(2C) receptor antagonist SB206553 or SB242084 eradicated a twofold difference in DOI-induced HTR between the standard inbred mouse strains C57BL/6J and DBA/2J, and decreased the DOI-induced HTR by at least 50% in both strains. None of several measures of 5-HT(2A) receptors in frontal cortex explained the strain difference, including 5-HT(2A) receptor density, Galpha(q) or Galpha(i/o) protein levels, phospholipase C activity, or DOI-induced expression of Egr1 and Egr2. 5-HT(2C) receptor density in the brains of C57BL/6J and DBA/2J was also equivalent, suggesting that 5-HT(2C) receptor-mediated intracellular signaling or other physiological modulators of the HTR may explain the strain difference in response to DOI. CONCLUSIONS: We conclude that the HTR to DOI in mice is strongly modulated by 5-HT(2C) receptor activity. This novel finding invites reassessment of hallucinogenic mechanisms involving 5-HT(2) receptors.