Imipramine and phenelzine decrease glutamate overflow in the prefrontal cortex—a possible mechanism of neuroprotection in major depression?

Michael‐Titus, Adina T.; Bains, Satinder; Jeetle, J.K.; Whelpton, Robin

doi:10.1016/s0306-4522(00)00390-0

Cited by 102 publications

(41 citation statements)

References 19 publications

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“…In the first (Wang et al, 2003), the effect of in vitro application of fluoxetine was studied (see below). In the second, two different drugs (imipramine and phenelzine) were found to reduce depolarization-evoked glutamate overflow from slices of prefrontal cortex after both acute and chronic treatment (Michael-Titus et al, 2000). In our hands, only chronic drug treatments reduced glutamate release from synaptic terminals, whereas acute treatments were devoid of any effect.…”

Section: Discussionmentioning

confidence: 47%

Chronic Antidepressants Reduce Depolarization-Evoked Glutamate Release and Protein Interactions Favoring Formation of SNARE Complex in Hippocampus

Bonanno¹,

Giambelli²,

Raiteri³

et al. 2005

J. Neurosci.

212

141

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Glutamate neurotransmission was recently implicated in the action of stress and in antidepressant mechanisms. We report that chronic (not acute) treatment with three antidepressants with different primary mechanisms (fluoxetine, reboxetine, and desipramine) markedly reduced depolarization-evoked release of glutamate, stimulated by 15 or 25 mM KCl, but not release of GABA. Endogenous glutamate and GABA release was measured in superfused synaptosomes, freshly prepared from hippocampus of drug-treated rats. Interestingly, treatment with the three drugs only barely changed the release of glutamate (and of GABA) induced by ionomycin. In synaptic membranes of chronically treated rats we found a marked reduction in the protein-protein interaction between syntaxin 1 and Thr 286-phosphorylated ␣CaM kinase II (␣-calcium/calmodulin-dependent protein kinase II) (an interaction previously proposed to promote neurotransmitter release) and a marked increase in the interaction between syntaxin 1 and Munc-18 (an interaction proposed to reduce neurotransmitter release). Furthermore, we found a selective reduction in the expression level of the three proteins forming the core SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex. These findings suggest that antidepressants work by stabilizing glutamate neurotransmission in the hippocampus and that they may represent a useful tool for the study of relationship between functional and molecular processes in nerve terminals.

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Section: Discussionmentioning

confidence: 47%

Chronic Antidepressants Reduce Depolarization-Evoked Glutamate Release and Protein Interactions Favoring Formation of SNARE Complex in Hippocampus

Bonanno¹,

Giambelli²,

Raiteri³

et al. 2005

J. Neurosci.

212

141

View full text Add to dashboard Cite

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“…Administration of antidepressant agents decreases glutamate levels in the prefrontal cortex 40 and there are long lasting reductions of glutamatergic activity after chronic, but not acute antidepressant treatments. 41,42 Antagonists at the N-methyl-D-aspartate (NMDA) glutamate receptor have been shown to improve depressive symptoms in subjects diagnosed with major depression 43 and NMDA antagonists are effective in animal models of depression.…”

Section: Discussionmentioning

confidence: 99%

Subjects with major depression or bipolar disorder show reduction of prodynorphin mRNA expression in discrete nuclei of the amygdaloid complex

Hurd

2002

Mol Psychiatry

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The dynorphin system has been associated with the regulation of mood. The expression of the prodynorphin mRNA was currently studied in the amygdaloid complex, a brain region critical for emotional processing, in subjects (14-15 per group) diagnosed with major depression, bipolar disorder, or schizophrenia and compared to normal controls. In situ hybridization histochemistry was used to characterize the anatomical distribution and expression levels of the prodynorphin mRNA within the amygdaloid complex. High prodynorphin mRNA levels were expressed in the parvicellular division of the accessory basal, posterior cortical, periamygdaloid cortex, and amygdalohippocampal area in normal subjects. Individuals with major depression had significantly reduced (41-68%) expression of the prodynorphin mRNA in the accessory basal (both parvicellular and magnocellular divisions; P Ͻ 0.01) and amygdalohippocampal area (P Ͻ 0.001) as compared to controls. The bipolar disorder group also showed a significant reduction (37-38%, P Ͻ 0.01) of the mRNA expression levels in the amygdalohippocampal area and in the parvicellular division of the accessory basal. No other amygdala nuclei studied showed any significant differences for the prodynorphin mRNA levels measured in the major depression and bipolar disorder subjects. Additionally, the prodynorphin mRNA expression levels did not differ significantly between the schizophrenic and normal control subjects in any of the amygdala areas examined. These findings indicate specific prodynorphin amygdala impairment in association with mood disorder. Molecular Psychiatry (2002) 7, 75-81.

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“…49 Chronic and acute treatment with the imipramine and the monoamine oxidase inhibitor phenelzine was also found to reduce the potassium-induced overflow of glutamate in slices from the prefrontal cortex, but not the striatum. 50 The authors suggested that this effect may be neuroprotective against the kind of glutamate excitotoxicity that could be induced by stress and could lead to neuronal loss and atrophy.…”

Section: Molecular Mechanisms Underlying the Antidepressant Drug Effectmentioning

confidence: 99%

Antidepressant mechanisms: functional and molecular correlates of excitatory amino acid neurotransmission

Stewart

Reid

2002

Mol Psychiatry

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Specific targeting of the serotonergic and noradrenergic systems for the development of antidepressant compounds has resulted in drugs with more favourable side-effect profiles but essentially no greater efficacy than those compounds discovered more than 40 years ago. Alternative targets are now being considered in the hope that they will have a faster onset of action and be useful for those patients currently unresponsive to conventional treatments. Excitatory amino acid neurotransmission has been attributed various roles in both normal and abnormal brain function. The N-methyl-D-aspartate receptor in particular has long been postulated to play a role in the formation of memories. Major depressive disorder is characterised by alterations in cognitive function, as well as affect. Although there is evidence that early adverse events and stress can have a causal influence on depression, the underlying neurobiology of the disorder is poorly understood. This review will document current evidence for the involvement of excitatory amino acid neurotransmission in the pathophysiology of the affective disorders. The preclinical literature suggests that both electroconvulsive stimulation and antidepressant drugs can affect hippocampal long-term potentiation and the expression of excitatory amino acid receptor subtypes. Exposing animals to stress, including the kind that produces learned helplessness, can also affect synaptic plasticity in the hippocampus. There is clinical evidence that patients with chronic depression have structural brain abnormalities, including hippocampal atrophy, and a preliminary study has shown that an N-methyl-D-aspartate receptor antagonist may have antidepressant efficacy. Molecular Psychiatry (2002) 7, S15-S22.

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Imipramine and phenelzine decrease glutamate overflow in the prefrontal cortex—a possible mechanism of neuroprotection in major depression?

Cited by 102 publications

References 19 publications

Chronic Antidepressants Reduce Depolarization-Evoked Glutamate Release and Protein Interactions Favoring Formation of SNARE Complex in Hippocampus

Chronic Antidepressants Reduce Depolarization-Evoked Glutamate Release and Protein Interactions Favoring Formation of SNARE Complex in Hippocampus

Subjects with major depression or bipolar disorder show reduction of prodynorphin mRNA expression in discrete nuclei of the amygdaloid complex

Antidepressant mechanisms: functional and molecular correlates of excitatory amino acid neurotransmission

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