99 In animal experiments, BDNF ameliorated learned helplessness, an effect that is normally observed with antidepressant treatment.100 Further studies underlined these interrelations and it was shown that treatment with antidepressants, including specific inhibitors of 5-HT or NE uptake as well as MAOIs, elevates BDNF mRNA levels in the rat hippocampus via the 5-HT2A and the β-adrenoceptor subtypes, and prevents the stress-induced decreases in BDNF mRNA.101 Interestingly, this effect became evident after 3 weeks of Inhibitors,research,lifescience,medical treatment, but not after a single dose, thus being reminiscent of the delay in treatment

response. The results of these animal experiments were confirmed by a recent postmortem finding of increased BDNF expression in patients being treated with antidepressants.102 Understanding the mechanism of how these drugs elevate BDNF mRNA could be Inhibitors,research,lifescience,medical particularly important, since BDNF concentration cannot be increased by exogenous neurotrophins, which Inhibitors,research,lifescience,medical are relatively

large lipophobic proteins that do not cross the blood-brain barrier. However, small molecules that pass through the blood-brain barrier and subsequently boost endogenous neurotrophin levels could represent a new generation of antidepressants.103 Interaction between monoamines and other neurotransmitters and neuropeptides Inhibitors,research,lifescience,medical Three decades after its formulation, the monoamine hypothesis of depression underwent various adaptations. Although it has contributed to our understanding of the regulation of neuronal function in general, there is no doubt that a LDK378 dysfunction in one of the monoaminergic systems alone does not provide an adequate explanation for the pathophysiology

of depression or the mechanism of drug action. One of the intriguing problems of therapy is the fact that it takes several days to weeks before the antidepressant effect becomes apparent, although the neurotransmitter concentrations are increased within hours of a single dose of reuptake inhibitor. The results Inhibitors,research,lifescience,medical of depletion studies further support the hypothesis that a simple change in the level of one of the monoamines or their receptor affinity is sufficient to induce or alleviate depression.104 It is now well established that there are considerable interactions of monoaminergic neurones with each other and with other systems in the brain, and Selleck FLT3 inhibitor there are many behavioral overlaps that reflect interactions among these neurotransmitters. Although NE.controls vigilance, like 5-HT, it also influences anxiety and irritability. In addition, impulsive behavior appears to be controlled by 5-HT, and yet it shares with DA an influence on appetite, sex, and aggression. Moreover, DA and NE. appear to affect euphoria and pleasure, thus influencing motivation and energy.