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Neurobiological Mechanisms Involved

Posted by Shawn. T. on August 2, 2003, at 11:50:00

In reply to Other brain questions, posted by Zenclearer on August 2, 2003, at 10:13:26

Zenclearer: Amphetamine has been shown to increase BDNF in the rat amygdala, piriform cortex and hypothalamus (see http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12213320&dopt=Abstract ); I'm not sure about how it affects the hippocampus with regards to BDNF expression. I don't know how Wellbutrin affects BDNF; however, I would *assume* that it increases BDNF levels. Most antidepressants have been shown to increase BDNF expression.

Switching gears, I believe that cortisol plays a key role in the hippocampal neurodegenerative effects of depression. Cortisol probably augments the neurotoxic effects of glutamate released in the hippocampus during stress; cortisol may also play a role in increasing extracellular hippocampal glutamate levels. In addition, cortisol is likely to decrease BDNF levels in the hippocampus. This is significant because BDNF is probably responsible for basal neurogenesis in the hippocampus. CREB is also an important factor in neurogenesis; however, I'm not aware of how cortisol might affect CREB. Some evidence suggests that CREB is essential for BDNF upregulation, but I'd like to see more research to support that conclusion.

So antidepressants influence the hippocampus in two key ways: counteracting neurotoxicity and increasing neurogenesis via key factors such as BDNF and CREB. SSRI's probably affect the size of the hippocampus by reducing the effect of cortisol and possibly by desensitizing/downregulating 5-HT2A receptors; 5-HT2A receptor activation has been associated with decreased BDNF expression in the hippocampus. I believe that it is possible that norepinephrine reuptake inhibitors could increase BDNF expression by downregulating beta-adrenoceptors; however, I lack the evidence to state that with any assuredness. Furthermore, the normalizing effects of SNRI's on the HPA axis suggests that these drugs may influence the damaging effects of cortisol. I believe that the effects of antidepressants on BDNF and cortisol definitely provides evidence that suggests that they can increase the size of the hippocampus after successful treatment; the degree to which this occurs would probably depend on the individual, the antidepressant, and environmental stressors.

For anyone really interested in learning more about this topic, here's a bibliography:

Cortisol, glutamate, and the hippocampus:

Corticosterone peak is responsible for stress-induced elevation of glutamate in the hippocampus.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9787265&dopt=Abstract

The exacerbation of hippocampal excitotoxicity by glucocorticoids is not mediated by apoptosis.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12624538&dopt=Abstract

Stress and depression: possible links to neuron death in the hippocampus.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12071509&dopt=Abstract

3D MRI studies of neuroanatomic changes in unipolar major depression: the role of stress and medical comorbidity.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11063975&dopt=Abstract

Protective and Damaging Effects of Stress Mediators
http://content.nejm.org/cgi/content/full/338/3/171?ijkey=2ayL2HP0PzdXQ

Detrimental effects of chronic hypothalamic-pituitary-adrenal axis activation. From obesity to memory deficits.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9824846&dopt=Abstract

BDNF:

How antidepressants work
New perspectives on the pathophysiology of depressive disorder
http://bjp.rcpsych.org/cgi/content/full/178/4/299

Stress, metaplasticity, and antidepressants.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12420802&dopt=Abstract

Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12420802&dopt=Abstract

Corticosterone effects on BDNF expression in the hippocampus. Implications for memory formation.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10938581&dopt=Abstract

Corticosterone inhibits generation of long-term potentiation in rat hippocampal slice: involvement of brain-derived neurotrophic factor.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11102572&dopt=Abstract

Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11522260&dopt=Abstract

Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12842310&dopt=Abstract

Decreased serum brain-derived neurotrophic factor levels in major depressed patients.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11927139&dopt=Abstract

Antidepressants and neuroplasticity.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12180273&dopt=Abstract

5-HT2A Receptor-Mediated Regulation of Brain-Derived Neurotrophic Factor mRNA in the Hippocampus and the Neocortex
http://www.jneurosci.org/cgi/content/full/17/8/2785

Role of 5-HT2A receptors in the stress-induced down-regulation of brain-derived neurotrophic factor expression in rat hippocampus.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10076858&dopt=Abstract

Differential regulation of hippocampal BDNF mRNA by typical and atypical antipsychotic administration.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12393228&dopt=Abstract

CREB:

Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8601816&dopt=Abstract

Abnormal expression and functional characteristics of cyclic adenosine monophosphate response element binding protein in postmortem brain of suicide subjects.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12622660&dopt=Abstract

Changes in CREB-phosphorylation during recovery from major depression.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12393305&dopt=Abstract

Abnormalities in the cAMP signaling pathway in post-mortem brain tissue from the Stanley Neuropathology Consortium.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11576759&dopt=Abstract

cAMP response element-binding protein is essential for the upregulation of brain-derived neurotrophic factor transcription, but not the behavioral or endocrine responses to antidepressant drugs.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11943827&dopt=Abstract

Shawn


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Psycho-Babble Medication | Framed

poster:Shawn. T. thread:247363
URL: http://www.dr-bob.org/babble/20030802/msgs/247586.html