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NEUROGENESIS AND ANTIDEPRESSIVE DRUGS

One of the dogmas of neurobiology has it that when nerve cells in the vertebrate brain die, they are not replaced by new ones. However it is already for long time known that when the adult canary needs to learn new songs, it does grow some new neurons (Nottebohm F. Sci Am. 1989 ; 260:74-9). That neurogenesis occurs in human brain is noted almost 20 years ago (Berry M. Food Chem Toxicol. 1986 ; 24:79-89, but major attention was attracted by observation of Eriksson at all. (Nat Med. 1998 ; 4:1313-7) who first using more sophisticated methods (bromodeoxyuridine and one of the neuronal markers, NeuN, calbindin or neuron specific enolase) demonstrated neurogenesis in adult human hippocampus. In adult mammalian brain, significant rates of adult neurogenesis are restricted to two brain regions, the olfactory bulb and the hippocampus. In the hippocampus, progenitor cells are located in the subgranular zone where they divide and give rise to new neurons. A recent detailed analysis of neurogenesis reports that there are approximately 9, 000 new cells per day or in adult rodent hippocampus. Approximately 50% of these cells differentiate and express cellular markers characteristic of neurons. These findings indicate that the number of new neurons, presumably with distinct characteristics, would be sufficient to contribute in a significant manner to the function of hippocampus. Exact determinations of the number of new neurons in primate brain have not been conducted, but estimates are that there may be 10 to 20% of the number of newborn cells observed in rodent brain. This amount of new neurons would be sufficient to influence the function of hippocampus in primates. (Cameron and McKay J Comparative Neurology 2001 ; 435, 406– 417). Adult neurogenesis is an extremely dynamic process that is regulated in both a positive and negative manner by neuronal activity and environmental factors. It has been suggested that neurogenesis plas a role in several important neuronal functions, including learning, memory, and response to novelty. In addition, exposure to psychotropic drugs or stress regulates the rate of neurogenesis in adult brain, suggesting a possible role for neurogenesis in the pathophysiology and treatment of neurobiological illnesses such as depression, post-traumatic stress disorder, and drug abuse (Duman RS, at all J Pharmacol Exp Ther. 2001 ; 299:401-7). In the field of depression research the major findings are the observationas that treatment with antidepressant drugs increases hippocampal neurogenesis. Most promising in that respect are SSRI as well as serotonergic system seem to be one of the most important neurotransmitter potentially regulating neurogenesis in the brain. Additionally the clinical effects of antidepressants take several weeks to manifest, suggesting that these drugs induce adaptive changes in brain structures affected by anxiety and depression. In this respect neurogenesis perfectly fits expectation of clinical science. Although hippocampus, where neurogenesis is most intensive, does not directly influence mood, connections with other brain regions such as the amygdala and prefrontal cortex could result in regulation of emotional state and news about neurogenesis have been accompanied with increasing enthusiasm. There are now (Sept.25 2005) 105 abstracts in Public Medline (EntrezPubMed) matching descriptors: neurogenesis AND depression. However, any of these publications are reviews. In fact under the same descriptors 51 reviews were found. Apparently the number of reviews and research papers is similar. This observation clearly suggests a great clinical interest in the phenomenon but relatively limited research results. Furthermore practically all of the research results were obtained on experimental animals (usually healthy) or even tissue culture of brain steam cells. However not all authors share enthusiasm about neurogenesis and depression. Data from the animal models tested to date show that decreasing the rate of neurogenesis does not lead to depressive behavior. Furthermore, evidence shows that an effective treatment for depression, transcranial magnetic stimulation, does not alter rates of neurogenesis. On the basis of these findings, Henn FA, Vollmayr B. (Biol Psychiatry. 2004 ; 56:146-50) suggested that neurogenesis might play a subtle role in depression but that it is not the primary factor in the final common pathway leading to depression. Indeed arguments pro and contra should be carefully reviewed and balanced since practically all observations associating neurogenesis and psychiatric disorders are done on experimental animals (usually healthy) or even on tissue culture.

Neurotransmitter; Mitogen; Neurogenesis

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