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Neurotrophins and depression

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Abstract

Exogenous delivery of the neurotrophic factors, brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3), promotes the function, sprouting and regrowth of 5-HT-containing neurones in the brains of adult rats. Similar infusions of BDNF into the dorsal raphe nucleus produce an antidepressant effect, as evaluated by several ‘learned helplessness’ paradigms. Environmental stressors such as immobilization induce depression and decrease BDNF mRNA. Antidepressants increase BDNF mRNA in the brain, via 5-HT2A and β-adrenoceptor subtypes and prevent the stress-induced decreases in BDNF mRNA. In this article, Tony Altar discusses how existing treatments of depression might work by increasing endogenous brain levels of BDNF or NT-3, which in turn could promote monoamine-containing neurone growth and function. Drugs that selectively stimulate the production of neurotrophins could represent a new generation of antidepressants.

Section snippets

Neurotrophins: growth factors for 5-HT-containing neurones

Before the link between neurotrophins and depression was suspected, this family of growth factors had been studied for its role in the adult nervous system. Among these endogenous proteins, BDNF and NT-3 were shown to promote the function and growth of 5-HT-containing neurones in the adult brain. Unlike chronic infusions of nerve growth factor (NGF), chronic infusions of BDNF or NT-3 into the rat midbrain increased the turnover of 5-HT and levels of noradrenaline in many forebrain areas

BDNF ameliorates learned helplessness

To evaluate the potential link between neurotrophins and depression, Suiciak studied the behavioural effects of the same midbrain infusions of BDNF that had elevated 5-HT turnover in the earlier studies. Chronic infusions of BDNF or its saline vehicle were made near the dorsal raphe nucleus, a cluster of 5-HT cell bodies that innervate the forebrain9. When tested one week later, the vehicle-infused rats that had been pre-exposed to inescapable shock showed the typical ‘learned helplessness’

Small molecules boost neurotrophin message

Although infusions of exogenous BDNF could produce antidepressant-like effects, it remained unknown whether there was a link between endogenous neurotrophins and treatments for depression. Duman and colleagues have shown that treatment with antidepressants, including specific inhibitors of 5-HT or noradrenaline reuptake, or inhibitors of monoamine oxidase, elevate BDNF messenger RNA levels in the rat hippocampus10, 11. Reminiscent of the delay in treating depression in humans, these compounds

Stress, neurotrophins and antidepressants

Further evidence linking BDNF and depression comes from studies in which stress, often a precipitating factor in depression, has been shown to decrease BDNF mRNA. The stress of being immobilized10, 11, 13, 14, 15 (which induces learned helplessness) or systemic injections of glucocorticoids16, 17 lower BDNF but not NT-3 mRNA levels in the hippocampus and other brain areas. Glucocorticoids can also depress the activity-dependent expression of BDNF mRNA within cultured hippocampal neurones18.

Areas for future research

An important issue in this area is whether antidepressants or chronic ECT can actually increase brain levels of BDNF or TrkB protein, and where such increases might occur. Although other examples with more sensitive methods will undoubtedly follow, to date only the study by Smith and colleagues20 has shown that BDNF protein was elevated in the ECT-treated brain. Such increases occurred in the mossy-fibre terminals of hippocampal dentate granule neurones. It will also be important to determine

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