Abstract: BACKGROUND: Post traumatic stress disorder (PTSD) can be considered the result of a failure to recover after a traumatic experience. Here we studied possible protective and therapeutic aspects of environmental enrichment (with and without a running wheel) in Sprague Dawley rats exposed to an inescapable foot shock procedure (IFS). METHODOLOGY/PRINCIPAL FINDINGS: IFS induced long-lasting contextual and non-contextual anxiety, modeling some aspects of PTSD. Even 10 weeks after IFS the rats showed reduced locomotion in an open field. The antidepressants imipramine and escitalopram did not improve anxiogenic behavior following IFS. Also the histone deacetylase (HDAC) inhibitor sodium butyrate did not alleviate the IFS induced immobility. While environmental enrichment (EE) starting two weeks before IFS did not protect the animals from the behavioral effects of the shocks, exposure to EE either immediately after the shock or one week later induced complete recovery three weeks after IFS. In the next set of experiments a running wheel was added to the EE to enable voluntary exercise (EE/VE). This also led to reduced anxiety. Importantly, this behavioral recovery was not due to a loss of memory for the traumatic experience. The behavioral recovery correlated with an increase in cell proliferation in hippocampus, a decrease in the tissue levels of noradrenalin and increased turnover of 5-HT in prefrontal cortex and hippocampus. CONCLUSIONS/SIGNIFICANCE: This animal study shows the importance of (physical) exercise in the treatment of psychiatric diseases, including post-traumatic stress disorder and points out the possible role of EE in studying the mechanism of recovery from anxiety disorders.
Abstract: Recombinant adeno-associated viral vectors (AAVs) are very promising gene transfer tools for the nervous system. We have compared the efficiency of gene expression of seven AAV serotypes in young adult rats following a single injection in a major nucleus of the mid brain, the red nucleus, which is the origin of the rubrospinal tract. AAV serotypes 1-6 and 8 and a lentiviral vector (LV) were used, all encoding green fluorescent protein (GFP) under control of the cytomegalovirus (CMV) promoter. AAV vectors were titer matched at 5x10(11) genomic copies (GC)/ml and 1mul was injected into the red nucleus. The proportion of transduced neurons in the red nucleus was determined at 1 and 4 weeks post-injection. AAV1 would be the vector of choice if the aim would be to overexpress a transgene at high level for a longer period of time. AAV5 and AAV8 would be the preferred serotype if onset of expression is should be somewhat delayed. The use of lentiviral vectors should be considered when transduction of both glial cells and neurons is required. Serotypes 3 and 4 did not transduce red nucleus neurons. AAV1, AAV6 and LV would be the vectors of choice if the aim of the experiment would be to rapidly express a transgene. The current data are important for the design of experiments that aim to study the effects of transgene products on the regenerative capacity of injured red nucleus neurons.
Abstract: Triple reuptake inhibitors (TRIs) that block the dopamine (DAT), norepinephrine (NET), and serotonin (SERT) transporters, are being developed as a new class of antidepressant that may have better efficacy and fewer side effects compared to traditional antidepressants. We describe a novel TRI, JZAD-IV-22 (2-[4-(4-chlorophenyl)-1-methylpiperidin-3-ylmethylsulfanyl]-1-(3-methylpiperidin-1-yl)-ethanone), that inhibits all three monoamine transporters with approximately equal potency in vitro. DOV 216,303, a TRI shown to be an effective antidepressant in a clinical trial, shows similar reuptake inhibition as JZAD-IV-22 in vitro. Furthermore, both JZAD-IV-22 and DOV 216,303 increase levels of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in the mouse prefrontal cortex (PFC) when administered by peripheral injection. JZAD-IV-22 and DOV 216,303 exhibited antidepressant-like efficacy in the mouse forced swim and tail suspension tests at doses that increased neurotransmitter levels. Because development of DAT inhibitors could be hindered by abuse liability, both JZAD-IV-22 and DOV 216,303 were compared in two assays that are markers of abuse potential. Both JZAD-IV-22 and DOV 216,303 partially substituted for cocaine in a drug discrimination assay in rats, and high doses of DOV 216,303 produced locomotor sensitization in mice. JZAD-IV-22 showed no evidence of sensitization at any dose tested. These results demonstrate that JZAD-IV-22 is a TRI with antidepressant-like activity similar to DOV 216,303. The striking feature that distinguishes the two TRIs is that locomotor sensitization, a common underlying feature of drugs of abuse, is seen with DOV 216,303 but is completely lacking in JZAD-IV-22. These findings may have implications for the potential for abuse liability in humans.
Abstract: The first line of antidepressant treatment nowadays are selective serotonin reuptake inhibitors. Although they are relatively safe to use, selective serotonin reuptake inhibitors (SSRIs) can induce severe side effects. New promising antidepressants may be the triple monoamine reuptake inhibitors, which not only enhance serotonin and norepinephrine neurotransmission, but also increase brain dopamine levels. Recently it has been shown that one of the triple reuptake inhibitors, DOV 216,303 has antidepressant-like effects in the olfactory bulbectomy (OBX) model of depression, but the alterations in monoaminergic neurotransmission in these animals are still unknown. In the present study we investigated not only the effect of acute, but also chronic treatment of DOV 216,303 in OBX rats on monoamine and metabolite levels. The main results are decreased baseline dopamine levels in the prefrontal cortex one day after OBX, while 38days after OBX no difference could be observed in monoamine levels after vehicle treatment. Treatment with DOV 216,303 leads to increased extracellular levels of serotonin and norepinephrine neurotransmission, but also increased dopamine levels in OBX animals as well as their controls. This increase could be observed after one single administration, but also after chronic treatment. However, a DOV 216,303 challenge in chronically treated animals resulted in lower monoamine concentrations than the same challenge in untreated animals. More research is needed to investigate this seemingly hyporesponsivity to chronic DOV 216,303 treatment.
Abstract: DOV 216,303 belongs to a new class of antidepressants, the triple reuptake inhibitors (TRIs), that blocks serotonin, norepinephrine and dopamine transporters and thereby increases extracellular brain monoamine concentrations. The aim of the present study was to measure extracellular monoamine concentrations both in the prefrontal cortex (PFC) and dorsal hippocampus (DH) after chronic administration of DOV 216,303 in the OBX animal model of depression and to compare the effects with acute drug treatment. OBX animals showed lower dopamine levels in PFC upon acute administration of DOV 216,303 than sham animals for up to five weeks after surgery. No such changes were observed in the DH. Unexpectedly, a DOV 216,303 challenge in chronic DOV 216,303 treated sham animals resulted in a blunted dopamine response in the PFC compared to the same challenge in vehicle treated animals. This blunted response probably reflects pharmacokinetic adaptations and/or pharmacodynamic changes, since brain and plasma concentrations of DOV 216,303 were significantly lower after chronic administration compared to acute administration. Surprisingly, and in contrast what we have reported earlier, chronic DOV 216,303 treatment was unable to normalize the hyperactivity of the OBX animals. Interestingly, by measuring the drug plasma and brain levels, it was demonstrated that at the time of behavioral testing (24h after last drug treatment) DOV 216,303 was not present anymore in either plasma or brain. This seems to indicate that this putative antidepressant drug has no lasting antidepressant-like behavioral effects in the absence of the drug in the brain.
Abstract: Darwin's largest contribution to science is without doubt the mechanism of natural selection, an evolutionary game with players, strategies, and pay-offs. Game theory, which attempts to mathematically capture behaviour in situations where an organism's success in making choices depends on the choices of others, is not only important for economists, but also for biologists, veterinarians and other scientists, as it increases understanding of why individual differences exist. John Maynard Smith showed that the success of an individual's behaviour often depends on others and his Hawk-Dove model is one of the best known examples of game theory: the 'hawk' initiates aggressive behaviour (not stopping until injured or until the opponent backs down); the 'dove' retreats immediately if the opponent initiates aggressive behaviour and will not fight under any circumstances. Simultaneous hawkish behaviour has the worst pay-off for both players, whereas hawkish behaviour with a dove opponent has the best pay-off. Maynard Smith showed that natural selection will work towards an evolutionarily stable strategy that, when used by an entire population, is resistant to invasion by new mutant strategies. Thus, natural selection actually favours a particular ratio of aggressive hawkish and non-aggressive dovish behaviours in order to maintain a balance of different characteristics in the population. Natural selection has sculpted physiology and behaviour differently in hawks and doves, each in their own way so as to maintain stability of the internal environment through change--a process which is defined as allostasis. In the short term, allostasis has benefits, but in the long run it produces costs. Farm animals have been genetically selected by man for increased product quantity and quality, such as increased muscle volume, lean meat and egg shell quality, accompanied by altered steroid balance (such as more testosterone and less corticosteroids) and lower brain monoamine concentrations (serotonin and dopamine). It is hypothesised that such genetic selection results in the production of farm animals that prefer the hawk behavioural strategy. There is a growing body of evidence that hawk-like animals (such as laying hens and pigs) are more vulnerable to the development of increased impulsivity and compulsivity (stereotypies) as well as violent behaviour.
