Large scale hippocampal cellular distress may explain the behavioral consequences of repetitive traumatic experiences--a proteomic approach.

Early life traumatic experiences are associated with psychopathology in adulthood. This may be due in part to the effects of trauma on hippocampal development and protein expression. The purpose of the study was to investigate the effects of early life trauma and adult re-stress on ventral hippocampal protein expression. Adolescent rats (n = 19) were subjected to a triple stressor on post-natal day 28 followed 7 days later by the first re-stress session and 25 days later (post-natal day 60 = adulthood) by the second re-stress session. Ventral hippocampi were collected on post-natal day 68 for protein expression determinations using protein arrays and 2D-gel electrophoresis with liquid chromatography tandem mass spectrometry. Compared to controls, traumatized animals showed an increase in Ca(2+) homeostatic proteins, dysregulated signaling pathways and energy metabolism enzymes, cytoskeletal protein changes, a decrease in neuroplasticity regulators, energy metabolism enzymes and an increase in apoptotic initiator proteins. These results indicate the extensive impact of trauma on adult brain development and behavior.

Early maternal separation alters the response to traumatization: resulting in increased levels of hippocampal neurotrophic factors.

Early life adversity predisposes individuals to the development of psychopathology in later life, especially depression and anxiety disorders. Prior history of stressors may also be a vulnerability factor for developing posttraumatic stress disorder (PTSD) in response to trauma. We examined the mechanisms underlying this phenomenon by employing two animal stress models, early maternal separation followed by later time-dependent sensitization (TDS). In animals exposed to adult TDS, those with prior early adversity did not differ from controls on tests of anxiety (elevated plus maze, open field), or HPA function (ACTH and corticosterone levels). However, those with prior early adversity had increased levels of neurotrophic factors (BDNF, NGF and NT-3) in both the dorsal and ventral hippocampus. Although early adversity is known to be associated with negative effects on neuronal function, it may also be associated with an increased ability to respond to subsequent stressors with compensatory mechanisms such as increased neurotrophic factor release.

Neuroproteomics: relevance to anxiety disorders.

Despite advances in the treatment of anxiety disorders, there is a need for medications with greater efficacy and fewer side effects. Advances in techniques to facilitate high throughput, mass analysis of proteins potentially allows for new drug targets, with a shift in focus from membrane receptor proteins and enzymes of neurotransmitter metabolism to molecules in intracellular signal transduction and other pathways. A computerized literature search was done to collect studies on recently developed proteomic techniques and their application in psychiatric research. Particular techniques, such as two-dimensional electrophoresis, two-dimensional differential gel electrophoresis, isotope-coded affinity tags, and isotope tags for relative and absolute quantification, are reviewed. In addition, a combination of these techniques with MALDI-TOF/TOF and ESI-Q-TOF mass spectrometry analysis is discussed in relation to possible novel signaling pathways relevant to anxiety disorders, and to the development of biomarkers for the evaluation of these conditions.

Developmental trauma is associated with behavioral hyperarousal, altered HPA axis activity, and decreased hippocampal neurotrophin expression in the adult rat.

Effects of early-life trauma on adult behavioral responses, corticosterone (CORT) concentration, and levels of nerve growth factor (NGF), brain-derived neutrophic factor (BDNF), and neurotrophin-3 (NT-3) in hippocampus and frontal cortex were investigated. Traumatized animals showed an increase in rearing in both the elevated plus maze and open field after adult restress, higher basal levels of CORT, lower levels of BDNF in dorsal hippocampus, and lower levels of NT-3 in dorsal and ventral hippocampus. Trauma-related behavioral hyperarousal and altered hypothalamic-pituitary-adrenal (HPA) axis activity may be mediated by decreases in hippocampal neurotrophin expression.

Early maternal separation followed by later stressors leads to dysregulation of the HPA-axis and increases in hippocampal NGF and NT-3 levels in a rat model.

Early adverse life events, followed by subsequent stressors, appear to increase susceptibility for subsequent onset of psychiatric disorders in humans. The molecular mechanisms that underlie this phenomenon remain unclear, but dysregulation of the HPA axis and alterations in neurotrophic factors have been implicated. The present study investigated the effects in rodents of early maternal separation, followed by stress in adolescence and adulthood on later HPA-axis activity and hippocampal neurotrophin levels (brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3). Animals subjected to repeated stressors showed a significant decrease in basal ACTH (p < 0.05) and CORT (p < 0.05) levels when compared to controls, as well as significantly increased levels of NGF in the dorsal (p < 0.001) and ventral hippocampus (p < 0.01), and of NT-3 in the dorsal hippocampus (p < 0.01). Dysregulation of the HPA axis after multiple stressors is consistent with previous preclinical and clinical work. Given that neurotrophins are important in neuronal survival and plasticity, it is possible to speculate that their elevation reflects a compensatory mechanism.

Pharmacological aspects of the combined use of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and gamma-hydroxybutyric acid (GHB): a review of the literature.

Epidemiological studies show that the use of club drugs is on the rise. Furthermore, the last few decades have seen a rise in patterns of polydrug use. One of the combinations frequently used is ecstasy (MDMA) with gammahydroxybutyrate (GHB). For effective prevention it is important to be aware of this phenomenon and of the pharmacology of these drugs. The effects of the combination extend to different neurotransmitter systems, including serotonin, dopamine and noradrenaline. Studies investigating the effects of combinations of psychoactive substances are limited. In this review we describe the subjective effects of the MDMA/GHB combination. Furthermore, we review the individual actions of MDMA on serotonin, dopamine and noradrenaline systems. In addition, actions of GHB on these systems are discussed as a possible pharmacological basis for the interaction of both drugs. It is postulated that GHB attenuates the unpleasant or dysphoric effects of MDMA by its effect on the central dopaminergic system.

Animal models of anxiety disorders.

Animal models may be useful in investigating the fundamental mechanisms underlying psychiatric disorders, and may contribute to the development of new medications. A computerized literature search was used to collect studies on recently developed animal models for anxiety disorders. Particular cognitive-affective processes (eg, fear conditioning, control of stereotypic movements, social submissiveness, and trauma sensitization) may be particularly relevant to understanding specific anxiety disorders. Delineation of the phenomenology and psychobiology of these processes in animals leads to a range of useful models of these conditions. These models demonstrate varying degrees of face, construct, and predictive validity.