The role of the glutamatergic system in the action of antidepressants
Whereas much emphasis has been placed on the monoamine neurotransmitters with respect to the mechanism of action of antidepressants, little attention has been paid to the changes in the glutamate system, the primary excitatory neurotransmitter pathway in the brain. Experimental evidence shows that tricyclic antidepressants inhibit the binding of dizolcipine to the ion channel of the main glutamate receptor, the N-methyl-D-aspartate receptor in the brain. The initial studies have more recently been extended to show that both typical and atypical antidepressants have a qualitatively similar effect by reducing the binding of dizolcipine to the NMDA receptors. Whether this is due to direct action of the antidepressants on the ion channel receptor sites, or an indirect effect possibly involving the modulation of the glycine receptor site, is uncertain, but there is evidence that glycine and drugs modulating the glycine site have antidepressant-like activity in animal models of depression. These results suggest that antidepressants act as functional NMDA receptor antagonists.
Intracellular changes that occur following chronic antidepressant treatment
The recent advances in molecular neurobiology have demonstrated how information is passed from the neurotransmitter receptors on the outer side of the neuronal membrane to the secondary messenger system on the inside. The coupling of this receptor to the secondary messenger is brought about by a member of the G protein family. Beta-adrenoceptors are linked to adenylate cyclase, and, depending on the subtype of receptors, 5-HT is linked to either adenylate cyclase (5-HT1A, 5-HT1B) or phospholipase (5-HT2A, 5-HT2C). Activation of phospholipase results in an intracellular increase in the secondary messengers diacylglycerol and inositol triphosphate (IP3), the IP3 then mobilizing intraneuronal calcium. The net result of the activation of the secondary messenger systems is to increase the activity of the various protein kinases that phosphorylate membrane-bound proteins to produce a physiological response. Some researchers have investigated the effect of chronic antidepressant treatment on the phosphorylation of proteins associated with the cytoskeletal structure of the nerve cell. Their studies suggest that antidepressants could affect the function of the cytoskeleton by changing the component of the associated protein phosphorylation system. In support of their hypothesis, these researchers showed that both typical (e.g. desipramine) and atypical (e.g. (+) oxaprotiline, a specific noradrenaline reuptake inhibitor, and fluoxetine, a selective 5-HT uptake inhibitor) antidepressants increased the synthesis of a microtubule fraction possibly by affecting the regulatory subunit of protein kinase type II. These changes in cytoskeletal protein synthesis occurred only after chronic antidepressant treatments and suggest that antidepressants, besides their well-established effects on pre- and postsynaptic receptors and amine uptake systems, might change neuronal signal transduction processes distal to the receptor. Glucocorticoid receptors: adaptive changes following antidepressant treatment Interest in the possible association of glucocorticoid receptors with central neurotransmitter function arose from the observation that such receptors have been identified in the nuclei of catecholamine and 5-HT-containing cell bodies in the brain. Experimental studies have shown that glucocorticoid receptors activate as DNA binding proteins which can modify the transcription of genes. The link to antidepressant treatments is indicated by the chronic administration of imipramine which increases glucocorticoid receptor immunoreactivity in rat brain, the changes being particularly pronounced in the noradrenergic and serotonergic cell body regions. Preliminary clinical studies have shown that lymphocyte glucocorticoid receptors are subsensitive in depressed patients. The failure of the negative feedback mechanism that regulates the secretion of adrenal glucocorticoids further suggests that the central glucocorticoid receptors are subsensitive.
This leads to the hypersecretion of cortisol, a characteristic feature of many patients with major depression. Such findings lend support to the hypothesis that the changes in central neurotransmission occurring in depression are a reflection of the effects of chronic glucocorticoids on the transcription of proteins that play a crucial role in neuronal structure and function. If the pituitary–adrenal axis plays such an important role in central neurotransmission, it may be speculated that glucocorticoid synthesis inhibitors (e.g. metyrapone) could reduce the abnormality in neurotransmitter function by decreasing the cortisol concentration. Recent in vitro hybridization studies in the rat have demonstrated that typical antidepressants increase the density of glucocorticoid receptors. Such an effect could increase the negative feedback mechanism and thereby reduce the synthesis and release of cortisol. In support of this hypothesis, there is preliminary clinical evidence that metyrapone (and the steroid synthes is inhibitor ketoconazole) may have antidepressant effects. Recently several lipophilic antagonists of corticotrophin releasing factor (CRF) type 1 receptor, which appears to be hyperactive in the brain of depressed patients, have been shown to be active in animal models of depression. Clearly this is a potentially important area for antidepressant development. Glucocorticoid receptors are present in a high density in the amygdala and neuroimaging studies have shown that the amygdala is the only structure in which the regional blood flow and glucose metabolism consistently correlate positively with the severity of depression. This hypermetabolism appears to reflect an underlying pathological process as it also occurs in asymptomatic patients and in the close relatives of the patients.
Possible role of excitatory amino acids and intracellular second messengers in the action of antidepressants
1. In experimental studies, chronic antidepressant treatments have been shown to reduce the behavioural effects of the NMDA-glutamate receptor antagonist dizolcipine. This suggests that antidepressants may act as functional NMDA receptor antagonists and thereby reduce excitatory glutamate transmission which is mediated by NMDA receptors.
2. Intracellular protein phosphorylation is enhanced by chronic antidepressant treatment. This leads to the increased synthesis of microtubules that form an important feature of the cellular cytoskeleton. Thus antidepressants might change signal transduction with the neurone.
3. Enhanced synthesis and transport of neurotransmitter synthesizing enzymes (e.g. tyrosine and tryptophan hydroxylase).
Role of glucocorticoids in modulating brain amines in depression
1. Glucocorticoid receptors occur on catecholamine and 5-HT cell bodies in the brain.
2. There is evidence that the glucocorticoid receptors are hyposensitive in the depressed patients.
3. Chronic antidepressant treatment sensitizes these receptors, thereby normalizing the noradrenergic and serotonergic function that is reduced by the hypercortisolaemia which occurs in major depression.
Whereas much emphasis has been placed on the monoamine neurotransmitters with respect to the mechanism of action of antidepressants, little attention has been paid to the changes in the glutamate system, the primary excitatory neurotransmitter pathway in the brain. Experimental evidence shows that tricyclic antidepressants inhibit the binding of dizolcipine to the ion channel of the main glutamate receptor, the N-methyl-D-aspartate receptor in the brain. The initial studies have more recently been extended to show that both typical and atypical antidepressants have a qualitatively similar effect by reducing the binding of dizolcipine to the NMDA receptors. Whether this is due to direct action of the antidepressants on the ion channel receptor sites, or an indirect effect possibly involving the modulation of the glycine receptor site, is uncertain, but there is evidence that glycine and drugs modulating the glycine site have antidepressant-like activity in animal models of depression. These results suggest that antidepressants act as functional NMDA receptor antagonists.
Intracellular changes that occur following chronic antidepressant treatment
The recent advances in molecular neurobiology have demonstrated how information is passed from the neurotransmitter receptors on the outer side of the neuronal membrane to the secondary messenger system on the inside. The coupling of this receptor to the secondary messenger is brought about by a member of the G protein family. Beta-adrenoceptors are linked to adenylate cyclase, and, depending on the subtype of receptors, 5-HT is linked to either adenylate cyclase (5-HT1A, 5-HT1B) or phospholipase (5-HT2A, 5-HT2C). Activation of phospholipase results in an intracellular increase in the secondary messengers diacylglycerol and inositol triphosphate (IP3), the IP3 then mobilizing intraneuronal calcium. The net result of the activation of the secondary messenger systems is to increase the activity of the various protein kinases that phosphorylate membrane-bound proteins to produce a physiological response. Some researchers have investigated the effect of chronic antidepressant treatment on the phosphorylation of proteins associated with the cytoskeletal structure of the nerve cell. Their studies suggest that antidepressants could affect the function of the cytoskeleton by changing the component of the associated protein phosphorylation system. In support of their hypothesis, these researchers showed that both typical (e.g. desipramine) and atypical (e.g. (+) oxaprotiline, a specific noradrenaline reuptake inhibitor, and fluoxetine, a selective 5-HT uptake inhibitor) antidepressants increased the synthesis of a microtubule fraction possibly by affecting the regulatory subunit of protein kinase type II. These changes in cytoskeletal protein synthesis occurred only after chronic antidepressant treatments and suggest that antidepressants, besides their well-established effects on pre- and postsynaptic receptors and amine uptake systems, might change neuronal signal transduction processes distal to the receptor. Glucocorticoid receptors: adaptive changes following antidepressant treatment Interest in the possible association of glucocorticoid receptors with central neurotransmitter function arose from the observation that such receptors have been identified in the nuclei of catecholamine and 5-HT-containing cell bodies in the brain. Experimental studies have shown that glucocorticoid receptors activate as DNA binding proteins which can modify the transcription of genes. The link to antidepressant treatments is indicated by the chronic administration of imipramine which increases glucocorticoid receptor immunoreactivity in rat brain, the changes being particularly pronounced in the noradrenergic and serotonergic cell body regions. Preliminary clinical studies have shown that lymphocyte glucocorticoid receptors are subsensitive in depressed patients. The failure of the negative feedback mechanism that regulates the secretion of adrenal glucocorticoids further suggests that the central glucocorticoid receptors are subsensitive.
This leads to the hypersecretion of cortisol, a characteristic feature of many patients with major depression. Such findings lend support to the hypothesis that the changes in central neurotransmission occurring in depression are a reflection of the effects of chronic glucocorticoids on the transcription of proteins that play a crucial role in neuronal structure and function. If the pituitary–adrenal axis plays such an important role in central neurotransmission, it may be speculated that glucocorticoid synthesis inhibitors (e.g. metyrapone) could reduce the abnormality in neurotransmitter function by decreasing the cortisol concentration. Recent in vitro hybridization studies in the rat have demonstrated that typical antidepressants increase the density of glucocorticoid receptors. Such an effect could increase the negative feedback mechanism and thereby reduce the synthesis and release of cortisol. In support of this hypothesis, there is preliminary clinical evidence that metyrapone (and the steroid synthes is inhibitor ketoconazole) may have antidepressant effects. Recently several lipophilic antagonists of corticotrophin releasing factor (CRF) type 1 receptor, which appears to be hyperactive in the brain of depressed patients, have been shown to be active in animal models of depression. Clearly this is a potentially important area for antidepressant development. Glucocorticoid receptors are present in a high density in the amygdala and neuroimaging studies have shown that the amygdala is the only structure in which the regional blood flow and glucose metabolism consistently correlate positively with the severity of depression. This hypermetabolism appears to reflect an underlying pathological process as it also occurs in asymptomatic patients and in the close relatives of the patients.
Possible role of excitatory amino acids and intracellular second messengers in the action of antidepressants
1. In experimental studies, chronic antidepressant treatments have been shown to reduce the behavioural effects of the NMDA-glutamate receptor antagonist dizolcipine. This suggests that antidepressants may act as functional NMDA receptor antagonists and thereby reduce excitatory glutamate transmission which is mediated by NMDA receptors.
2. Intracellular protein phosphorylation is enhanced by chronic antidepressant treatment. This leads to the increased synthesis of microtubules that form an important feature of the cellular cytoskeleton. Thus antidepressants might change signal transduction with the neurone.
3. Enhanced synthesis and transport of neurotransmitter synthesizing enzymes (e.g. tyrosine and tryptophan hydroxylase).
Role of glucocorticoids in modulating brain amines in depression
1. Glucocorticoid receptors occur on catecholamine and 5-HT cell bodies in the brain.
2. There is evidence that the glucocorticoid receptors are hyposensitive in the depressed patients.
3. Chronic antidepressant treatment sensitizes these receptors, thereby normalizing the noradrenergic and serotonergic function that is reduced by the hypercortisolaemia which occurs in major depression.
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