Sports-related head impact and injury has become a very highly contentious public health and medico-legal issue. Neardaily news accounts describe the travails of concussed athletes as they struggle with depression, sleep disorders, mood swings, and cognitive problems. Some of these individuals have developed chronic traumatic encephalopathy, a progressive and debilitating neurodegenerative disorder. Animal models have always been an integral part of the study of traumatic brain injury in humans but, historically, they have concentrated on acute, severe brain injuries. This review will describe a small number of new and emerging animal models of sports-related head injury that have the potential to increase our understanding of how multiple mild head impacts, starting in adolescence, can have serious psychiatric, cognitive and histopathological outcomes much later in life. Keywords: animal models, cognitive dysfunction, neuropathological disorders, psychiatric outcomes, repetitive mild traumatic brain injury, Sports-related head injury. Traumatic brain injury (TBI) results from a blow to the head and the severity of injury can range along a continuum from mild (e.g., headache, dizziness) to severe (e.g., extended coma, amnesia) to fatal. TBI is one of the most common neurological diagnoses in the US (Rutland-Brown et al.
Aims Mephedrone is a stimulant drug of abuse with close structural and mechanistic similarities to methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA). Although mephedrone does not damage dopamine nerve endings it increases the neurotoxicity of amphetamine, methamphetamine and MDMA. The effects of mephedrone on serotonin (5HT) nerve endings are not fully understood, with some investigators reporting damage while others conclude it does not. Presently, we investigate if mephedrone given alone or with methamphetamine or MDMA damages 5HT nerve endings of the hippocampus. Main methods The status of 5HT nerve endings in hippocampus of female C57BL mice was assessed through measures of 5HT by HPLC and by immunoblot analysis of serotonin transporter (SERT) and tryptophan hydroxylase 2 (TPH2), selective markers of 5HT nerve endings. Astrocytosis was assessed through measures of glial fibrillary acidic protein (GFAP) (immunoblotting) and microglial activation was determined by histochemical staining with Isolectin B4. Key findings Mephedrone alone did not cause persistent reductions in the levels of 5HT, SERT or TPH2. Methamphetamine and MDMA alone caused mild reductions in 5HT but did not change SERT and TPH2 levels. Combined treatment with mephedrone and methamphetamine or MDMA did not change the status of 5HT nerve endings to an extent that was different from either drug alone. Significance Mephedrone does not cause toxicity to 5HT nerve endings of the hippocampus. When co-administered with methamphetamine or MDMA, drugs that are often co-abused with mephedrone by humans, toxicity is not increased as is the case for dopamine nerve endings when these drugs are taken together.
Reductions in function within the serotonin (5HT) neuronal system have long been proposed as etiological factors in depression. Serotonin selective reuptake inhibitors (SSRIs) are the most common treatment for depression and their therapeutic effect is generally attributed to their ability to increase the synaptic levels of 5HT. Tryptophan hydroxylase 2 (TPH2) is the initial and ratelimiting enzyme in the biosynthetic pathway of 5HT in the CNS and losses in its catalytic activity lead to reductions in 5HT production and release. The time differential between the onset of 5HT reuptake inhibition by SSRIs (minutes) and onset of their anti-depressant efficacy (weeks to months), when considered with their overall poor therapeutic effectiveness, has cast some doubt on the role of 5HT in depression. Mice lacking the gene for TPH2 are genetically depleted of brain 5HT and were tested for a depression-like behavioral phenotype using a battery of valid tests for affective-like disorders in animals. The behavior of TPH2 −/− mice on the sucrose preference test, tail suspension test and forced swim test and their responses in the unpredictable chronic mild stress and learned helplessness paradigms was the same as wild-type controls. While TPH2−/− mice as a group were not responsive to SSRIs, a subset responded to treatment with SSRIs in the same manner as wild-type controls with significant reductions in immobility time on the tail suspension test, indicative of antidepressant drug effects. The behavioral phenotype of the TPH2 −/− mouse questions the role of 5HT in depression. Furthermore, the TPH2 −/− mouse may Detroit, MI 48201-1916. Phone: 313-476-4457, Fax: 313-576-1112. donald.kuhn@wayne.edu. Author Contributions MAP, MJK, DIB, NHM and CES conducted the in vivo behavioral and pharmacological experiments. DMF and MAP conducted the in vitro synaptosomal 5HT uptake experiments. MAP, MJK and DMK interpreted the data. MAP, MJK and DMK conceived of project and wrote the paper. All authors edited and approved the final version of the manuscript. NotesThe authors declare no competing financial interest. SUPPORTING INFORMATION AVAILABLEThe numbers of TPH2+/+ and TPH2−/− mice classified as responders or non-responders (specified by sex) to the SSRIs fluoxetine, citalopram and paroxetine is included in SI Table 1. The immobility time cutoff values for defining whether a subject was classified as a responder or non-responder to SSRIs is presented in SI Table 2. Information on the specific stressors used in the UCMS is included in SI Table 3. This information is available free of charge via the Internet at http://pubs.acs.org. U.S. Department of Veterans Affairs VA Author ManuscriptVA Author Manuscript VA Author Manuscriptserve as a useful model in the search for new medications that have therapeutic targets for depression that are outside of the 5HT neuronal system. Keywordsserotonin; TPH2; TPH2 knock out; depression-like behavior; SSRIs; SERT The serotonin (5HT) neuronal system innervates nearly the entire neuraxis from...
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