Olanzapine and fluoxetine administration and coadministration increase rat hippocampal pregnenolone, allopregnanolone and peripheral deoxycorticosterone: Implications for therapeutic actions

Marx, Christine E.; Shampine, Lawrence J.; Khisti, Rahul T.; Trost, William T.; Bradford, Daniel W.; Grobin, A. Chistina; Massing, Mark W.; Madison, Roger D.; Butterfield, Marian I.; Lieberman, Jeffrey A.; Morrow, A. Leslie

doi:10.1016/j.pbb.2006.07.032

Cited by 74 publications

(41 citation statements)

References 44 publications

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“…In this study it was demonstrated that fluoxetine and/or olanzepine are beneficial in depression by correcting the decreased pregnanolone levels, which have been linked to depression [15]. Marx et al also used fluoxetine at doses (5, 10, 20 mg/kg) similar to ours [15]. Fluoxetine human dose ranges between 20-60 mg/day [16].…”

Section: Discussionmentioning

confidence: 61%

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Fluoxetine Partly Exerts its Actions Through GABA: A Neurochemical Evidence

et al. 2007

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Fluoxetine, as a serotonin re-uptake inhibitor augments serotonin concentration within the synapse by inhibiting the serotonin transporter. The contribution of amino acids has also been shown in depression. We hypothesized that fluoxetine exerts its actions at least in part by intervening brain signaling operated by amino acid transmitters. Therefore the aim of this study is to supply neurochemical evidence that fluoxetine produces changes in amino acids in cerebrospinal fluid of rats. Sprague-Dawley rats were anesthetized and concentric microdialysis probes were implanted stereotaxically into the right lateral ventricle. Intraperitoneal fluoxetine (2.5 or 5 mg/kg) or physiological saline was administered and the probes were perfused with artificial cerebrospinal fluid at a rate of 1 mul/min. In the chronic fluoxetine group, the rats were treated daily with oral fluoxetine solution or inert syrup for 3 weeks. The microdialysis probes were placed on the 21st day and perfused the next day. Fluoxetine was ineffective in changing the cerebrospinal fluid GABA levels at the dose of 2.5 mg/kg but produced a significant increase in the perfusates following injection of 5 mg/kg of fluoxetine (P < 0.05). Oral fluoxetine administration (5 mg/kg) for 21 days also elevated the CSF GABA levels by approximately 2-fold (P < 0.05). L: -glutamic acid levels were not affected in all groups. These neurochemical findings show that fluoxetine, a selective serotonin re-uptake inhibitor affects brain GABA levels indirectly, and our results suggest that acute or chronic effects may be involved in beneficial and/or adverse effects of the drug.

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Section: Discussionmentioning

confidence: 61%

“…Marx et al studied the effects of olanzepine and fluoxetine on GABAergic neuroactive steroid allopregnanolone [15]. In this study it was demonstrated that fluoxetine and/or olanzepine are beneficial in depression by correcting the decreased pregnanolone levels, which have been linked to depression [15].…”

Section: Discussionmentioning

confidence: 84%

Fluoxetine Partly Exerts its Actions Through GABA: A Neurochemical Evidence

et al. 2007

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“…Olanzapine also increases ALLO levels in rodent hippocampus (Marx et al, 2006a). It has been hypothesized that olanzapine- and clozapine-induced elevations in ALLO may represent a potential mechanism contributing to the therapeutic efficacy of these agents (Marx et al, 2003, 2005).…”

Section: Comparison Of Antipsychotic Drugs In Animal Models Of Amentioning

confidence: 99%

“…For example, ALLO administration in vitro increases myelin basic protein expression (Ghoumari et al, 2003), and the ALLO precursor progesterone, a steroid that can be synthesized in the brain and in the periphery, also affects myelination (Schumacher et al, 2000; Ibanez et al, 2003). Both clozapine and olanzapine dose dependently increase progesterone in rodents (Barbaccia et al, 2001; Marx et al, 2003, 2006a). If alterations in ALLO and progesterone also occur in patients with schizophrenia after antipsychotic drug administration, these changes could be relevant to myelin regulation, a process that seems to be dysregulated in subjects with schizophrenia (Hakak et al, 2001; Tkachev et al, 2003).…”

Section: Comparison Of Antipsychotic Drugs In Animal Models Of Amentioning

confidence: 99%

Antipsychotic Drugs: Comparison in Animal Models of Efficacy, Neurotransmitter Regulation, and Neuroprotection

et al. 2008

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Various lines of evidence indicate the presence of progressive pathophysiological processes occurring within the brains of patients with schizophrenia. By modulating chemical neurotransmission, anti-psychotic drugs may influence a variety of functions regulating neuronal resilience and viability and have the potential for neuroprotection. This article reviews the current literature describing preclinical and clinical studies that evaluate the efficacy of antipsychotic drugs, their mechanism of action and the potential of first- and second-generation antipsychotic drugs to exert effects on cellular processes that may be neuroprotective in schizophrenia. The evidence to date suggests that although all antipsychotic drugs have the ability to reduce psychotic symptoms via D2 receptor antagonism, some antipsychotics may differ in other pharmacological properties and their capacities to mitigate and possibly reverse cellular processes that may underlie the pathophysiology of schizophrenia.

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“…In contrast, pregnenolone levels in postmortem brain tissue samples (posterior cingulate and parietal cortex) were higher in schizophrenia (Marx et al 2006c), potentially reflecting medication-induced pregnenolone elevations. Specifically, clozapine (Barbaccia et al 2001;Marx et al 2006a) and olanzapine (Marx et al 2006b) significantly elevate pregnenolone levels in multiple rodent brain regions, as do antidepressants such as fluoxetine (Barbaccia et al 2001;Marx et al 2006b;Uzunov et al 1996). Clozapine also increases translocator protein (TSPO) binding in rodent brain (Danovich et al 2008), a protein that is integrally involved in the synthesis of pregnenolone from cholesterol.…”

Section: Translational and Clinical Overview-pregnenolone And Pregnenmentioning

confidence: 99%