Behavioural brain research
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DBS of the medial forebrain bundle (MFB) has been investigated clinically in major depressive disorder patients with rapid and long-term reduction of symptoms. In the context of chronic bilateral high frequency deep brain stimulation (DBS) of the MFB, the current study looked at the impact of lesioning the ascending dopaminergic pathway at the level of the ventral tegmental area (VTA). Sprague-Dawley female rats were given bilateral injection of 6-OHDA into the VTA (VTA-lx group) or were left unlesioned (control group). ⋯ Our results confirm a potential role for dopamine in symptom relief observed in clinical MFB-DBS. Although mechanisms are not fully understood, the data suggests that the rescue of depressive phenotype in rodents can work via both dopamine-dependent and independent mechanisms. Further investigations concerning the network of depression using neuromodulation platforms in animal models might give insight into genesis and treatment of major depression disorder.
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Tetrabenazine (TBZ) is prescribed for the treatment of chorea associated with Huntington's disease. Via inhibition of the vesicular monoamine transporter (VMAT-2), TBZ blocks dopamine (DA) storage and depletes striatal DA; this drug also has been shown to induce Parkinsonian motor side effects in patients. Recently, TBZ was shown to induce tremulous jaw movements (TJMs) in rats and mice. ⋯ Consistent with the behavioral data, TBZ alone produced a biphasic effect on extracellular DA, with an initial increases followed by a prolonged decrease during the period in which TJMs are displayed. Co-administration of deprenyl with TBZ increased DA levels compared to rats treated with TBZ alone. These results provide support for use of TBZ as a rodent model of Parkinsonism, and future studies should utilize this model to evaluate putative anti-Parkinsonian agents.
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Opioids produce antinociception by activation of G protein signaling linked to the mu-opioid receptor (MOPr). However, opioid binding to the MOPr also activates β-arrestin signaling. Opioids such as DAMGO and fentanyl differ in their relative efficacy for activation of these signaling cascades, but the behavioral consequences of this differential signaling are not known. ⋯ Microinjection of DAMGO, but not fentanyl, into the vlPAG induced phosphorylation of ERK1/2, which was blocked by inhibiting receptor internalization with administration of dyn-DN, but not by inhibition of Gαi/o proteins. ERK1/2 inhibition also prevented the development and expression of tolerance to repeated DAMGO microinjections, but had no effect on fentanyl tolerance. These data reveal that ERK1/2 activation following MOPr internalization contributes to the antinociceptive effect of some (e.g., DAMGO), but not all opioids (e.g., fentanyl) despite the known similarities for these agonists to induce β-arrestin recruitment and internalization.
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Comparative Study
Greater neurobehavioral deficits occur in adult mice after repeated, as compared to single, mild traumatic brain injury (mTBI).
Mild traumatic brain injury (mTBI) accounts for the majority of all brain injuries and affected individuals typically experience some extent of cognitive and/or neuropsychiatric deficits. Given that repeated mTBIs often result in worsened prognosis, the cumulative effect of repeated mTBIs is an area of clinical concern and on-going pre-clinical research. Animal models are critical in elucidating the underlying mechanisms of single and repeated mTBI-associated deficits, but the neurobehavioral sequelae produced by these models have not been well characterized. ⋯ We found that the repeated mTBI mice demonstrated deficits in MWM testing and poorer performance on species-typical behaviors. While neither single nor repeated mTBI affected behavior in the EPM or FST, sleep disturbances were observed after both single and repeated mTBI. Here, we conclude that behavioral alterations shown after repeated mTBI resemble several of the deficits or disturbances reported by patients, thus demonstrating the relevance of this murine model to study repeated mTBIs.
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Trauma induced neuroinflammation plays a key role in the development of postoperative cognitive dysfunction (POCD). The blood-brain barrier (BBB), a highly specialized endothelial layer, is exquisitely sensitive to inflammatory insults, which can result in numerous neurocognitive syndromes. While brain mast cells are the "first responder" in the injury, the functional interactions between mast cells and the BBB remain poorly understood. ⋯ Disodium cromoglycate (cromolyn)--which acts as a mast cell stabilizer--inhibited this effect. Specifically, cromolyn resulted in ameliorated cognitive ability, decrease of inflammatory cytokines and increase of BBB stability. Taken together, these results suggest that activated mast cells contributed to central nervous system inflammation and cognitive dysfunction by promoting BBB disruption, and interactions between mast cells and the BBB could constitute a new and unique therapeutic target for POCD.