Antidepressants and changes in neuronal structure
Another possible mechanism whereby antidepressants may change the physical relationship between neurons in the brain is by inhibiting neurite outgrowth from nerve cells. In support of this view, it has been shown that the tricyclic antidepressant amitriptyline, at therapeutically relevant concentrations, inhibited neurite outgrowth from chick embryonic cerebral explants in vivo. While the relevance of such findings to the therapeutic effects of amitriptyline in man is unclear, they do suggest that a common mode of action of all antidepressants could be to modify the actual structure of nerve cells and possibly eliminate inappropriate synaptic contacts that are responsible for behavioural and psychological changes associated with depression. There are several mechanisms whereby antidepressants can modify intracellular events that occur proximal to the postsynaptic receptor sites. Most attention has been paid to the actions of antidepressants on those pathways that are controlled by receptor-coupled second messengers (such as cyclic AMP, inositol triphosphate, nitric oxide and calcium binding). However, it is also possible that chronic antidepressant treatment may affect those pathways that involve receptor interactions with protein tyrosine kinases, by increasing specific growth factor synthesis or by regulating the activity of proinflammatory cytokines. These pathways are particularly important because they control many aspects of neuronal function that ultimately underlie the ability of the brain to adapt and respond to pharmacological and environmental stimuli. One mechanism whereby antidepressants could increase the synthesis of trophic factors is by the activation of cyclic AMP-dependent protein kinase which indirectly increases the formation of the transcription factors. There is experimental evidence to show that the infusion of one of these transcription factors (brain derived neutrophic factor) into the midbrain of rats results in antidepressant-like activity, an action associated with an increase in the synthesis of tryptophan hydroxylase, the rate-limiting enzyme in the synthesis of serotonin.
Changes in neuronal structure in depression
1. There is evidence that inadequately treated, or untreated, major depression is associated with a decrease in the hippocampal volume. This could be a consequence of the increase in proinflammatory cytokines and hypercortisolaemia.
2. Experimental evidence suggests that chronic antidepressant treatments increase the formation of transcription factors within the brain which increases neuronal plasticity and leads to recovery.
Another possible mechanism whereby antidepressants may change the physical relationship between neurons in the brain is by inhibiting neurite outgrowth from nerve cells. In support of this view, it has been shown that the tricyclic antidepressant amitriptyline, at therapeutically relevant concentrations, inhibited neurite outgrowth from chick embryonic cerebral explants in vivo. While the relevance of such findings to the therapeutic effects of amitriptyline in man is unclear, they do suggest that a common mode of action of all antidepressants could be to modify the actual structure of nerve cells and possibly eliminate inappropriate synaptic contacts that are responsible for behavioural and psychological changes associated with depression. There are several mechanisms whereby antidepressants can modify intracellular events that occur proximal to the postsynaptic receptor sites. Most attention has been paid to the actions of antidepressants on those pathways that are controlled by receptor-coupled second messengers (such as cyclic AMP, inositol triphosphate, nitric oxide and calcium binding). However, it is also possible that chronic antidepressant treatment may affect those pathways that involve receptor interactions with protein tyrosine kinases, by increasing specific growth factor synthesis or by regulating the activity of proinflammatory cytokines. These pathways are particularly important because they control many aspects of neuronal function that ultimately underlie the ability of the brain to adapt and respond to pharmacological and environmental stimuli. One mechanism whereby antidepressants could increase the synthesis of trophic factors is by the activation of cyclic AMP-dependent protein kinase which indirectly increases the formation of the transcription factors. There is experimental evidence to show that the infusion of one of these transcription factors (brain derived neutrophic factor) into the midbrain of rats results in antidepressant-like activity, an action associated with an increase in the synthesis of tryptophan hydroxylase, the rate-limiting enzyme in the synthesis of serotonin.
Changes in neuronal structure in depression
1. There is evidence that inadequately treated, or untreated, major depression is associated with a decrease in the hippocampal volume. This could be a consequence of the increase in proinflammatory cytokines and hypercortisolaemia.
2. Experimental evidence suggests that chronic antidepressant treatments increase the formation of transcription factors within the brain which increases neuronal plasticity and leads to recovery.
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