Search

Nearly half of Operation Enduring Freedom/Operation Iraqi Freedom veterans experience continued pain post-deployment. Several investigations report analgesic effects of allopregnanolone and other neurosteroids in animal models, but few data are currently available focusing on neurosteroids in clinical populations. Allopregnanolone positively modulates GABA receptors and demonstrates pronounced analgesic and anxiolytic effects in rodents, yet studies examining the relationship between pain and allopregnanolone in humans are limited. We thus hypothesized that endogenous allopregnanolone and other neurosteroid levels may be negatively correlated with self-reported pain symptoms in humans. We determined serum neurosteroid levels by gas chromatography/mass spectrometry (allopregnanolone, pregnenolone) or radioimmunoassay (dehydroepiandrosterone [DHEA], progesterone, DHEA sulfate [DHEAS]) in 90 male veterans who served in the U.S. military after September 11, 2001. Self-reported pain symptoms were assessed in four areas (low back pain, chest pain, muscle soreness, headache). Stepwise linear regression analyses were conducted to investigate the relationship between pain assessments and neurosteroids, with the inclusion of smoking, alcohol use, age, and history of traumatic brain injury as covariates. Durham VA Medical Center. Allopregnanolone levels were inversely associated with low back pain ( P = 0.044) and chest pain ( P = 0.013), and DHEA levels were inversely associated with muscle soreness ( P = 0.024). DHEAS levels were positively associated with chest pain ( P = 0.001). Additionally, there was a positive association between traumatic brain injury and muscle soreness ( P = 0.002). Neurosteroids may be relevant to the pathophysiology of self-reported pain symptoms in this veteran cohort, and could represent future pharmacological targets for pain disorders. [ABSTRACT FROM AUTHOR]

Evidence suggests that neuroactive steroids may be candidate modulators of schizophrenia pathophysiology and therapeutics. We therefore investigated neuroactive steroid levels in post-mortem brain tissue from subjects with schizophrenia, bipolar disorder, nonpsychotic depression, and control subjects to determine if neuroactive steroids are altered in these disorders. Posterior cingulate and parietal cortex tissue from the Stanley Foundation Neuropathology Consortium collection was analyzed for neuroactive steroids by negative ion chemical ionization gas chromatography/mass spectrometry preceded by high-performance liquid chromatography. Subjects with schizophrenia, bipolar disorder, nonpsychotic depression, and control subjects were group matched for age, sex, ethnicity, brain pH, and post-mortem interval (n=14–15 per group, 59–60 subjects total). Statistical analyses were performed by ANOVA with post-hoc Dunnett tests on log transformed neuroactive steroid levels. Pregnenolone and allopregnanolone were present in human post-mortem brain tissue at considerably higher concentrations than typically observed in serum or plasma. Pregnenolone and dehydroepiandrosterone levels were higher in subjects with schizophrenia and bipolar disorder compared to control subjects in both posterior cingulate and parietal cortex. Allopregnanolone levels tended to be decreased in parietal cortex in subjects with schizophrenia compared to control subjects. Neuroactive steroids are present in human post-mortem brain tissue at physiologically relevant concentrations and altered in subjects with schizophrenia and bipolar disorder. A number of neuroactive steroids act at inhibitory GABAA and excitatory NMDA receptors and demonstrate neuroprotective and neurotrophic effects. Neuroactive steroids may therefore be candidate modulators of the pathophysiology of schizophrenia and bipolar disorder, and relevant to the treatment of these disorders.Neuropsychopharmacology (2006) 31, 1249–1263. doi:10.1038/sj.npp.1300952; published online 23 November 2005 [ABSTRACT FROM AUTHOR]

Abstract: Olanzapine and fluoxetine elevate the GABAergic neuroactive steroid allopregnanolone to physiologically relevant concentrations in rodent cerebral cortex. It is unknown if these agents also alter pregnenolone or deoxycorticosterone. Since olanzapine and fluoxetine in combination have clinical utility and may demonstrate synergistic effects, we investigated neuroactive steroid alterations following olanzapine, fluoxetine or coadministration. Male rats received IP vehicle, olanzapine, fluoxetine or the combination of both agents in higher-dose (0, 10, 20 or 10/20 mg/kg, respectively) and lower-dose (0, 5, 10 or 5/10 mg/kg, respectively) experiments. Pregnenolone and allopregnanolone levels in hippocampus were determined by gas chromatography/mass spectrometry. Peripheral deoxycorticosterone and other steroid levels were determined by radioimmunoassay. Olanzapine, fluoxetine or the combination increased hippocampal pregnenolone and serum deoxycorticosterone in both higher- and lower-dose experiments, and elevated hippocampal allopregnanolone in higher-dose conditions. No synergistic effects on pregnenolone or allopregnanolone were observed following olanzapine and fluoxetine coadministration compared to either compound alone. Pregnenolone and its sulfate enhance learning and memory in rodent models, and therefore pregnenolone elevations may be relevant to cognitive changes in psychotic and affective disorders. Since pregnenolone decreases have been linked to depression, it is possible that olanzapine- and fluoxetine-induced pregnenolone elevations may contribute to the antidepressant actions of these agents. [Copyright &y& Elsevier]

Abstract: Clozapine demonstrates superior efficacy in patients with schizophrenia, but the precise mechanisms contributing to this clinical advantage are not clear. Clozapine and olanzapine increase the GABAergic neuroactive steroid (NS) allopregnanolone, and it has been hypothesized that NS induction may contribute to the therapeutic actions of these agents. Pregnenolone administration improves learning and memory in rodent models, and decreases in this NS have been associated with depressive symptoms in humans. These pregnenolone characteristics may be relevant to the actions of antipsychotics. We therefore investigated potential pregnenolone alterations in rat hippocampus and cerebral cortex following clozapine, olanzapine, and other second generation agents as a candidate NS mechanism contributing to antipsychotic efficacy. In the first set of experiments, intact, adrenalectomized, and sham-operated male rats received vehicle or clozapine (20 mg/kg) IP. In the second set, male rats received vehicle, olanzapine (5 mg/kg), quetiapine (20 mg/kg), ziprasidone (10 mg/kg) or aripiprazole (5 mg/kg) IP. Pregnenolone levels were determined by gas chromatography/mass spectrometry. Clozapine markedly elevates pregnenolone in rat hippocampus, cerebral cortex, and serum; hippocampal levels were strongly correlated with serum levels (r =0.987). Olanzapine also elevates pregnenolone levels, but to a lesser degree than clozapine. Pregnenolone induction may contribute to the clinical actions of clozapine and olanzapine. [Copyright &y& Elsevier]