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A Guidotti

Publications and source records attributed to A Guidotti.

At least 91 records · Page 5Linked to original sources
PubMed1994

CSF levels of diazepam-binding inhibitor correlate with REM latency in schizophrenia, a pilot study.

CSF diazepam-binding inhibitor-like immunoreactivity (DBI-LI) and polysomnography were studied in 28 drug-free male schizophrenic (DSM-III-R) patients. They underwent a three-night polysomnography evaluation and a lumbar puncture. CSF DBI-LI correlated positively with REM latency, the REM latency/2d nonREM period ratio and stage-4% sleep, and negatively with stage-1% sleep. CSF DBI-LI did not correlate significantly with duration of sleep or sleep latency. CSF DBI-LI during haloperidol treatment did not correlate significantly with sleep EEG measures. The results of this first study of the relationship between endogenous DBI and sleep in humans suggest that physiological effects of DBI other than interactions with the BZD/GABAA receptor complex may explain its positive effects on sleep. However, the absence of similar sleep data in normal subjects precludes us from establishing a specific relationship between DBI and sleep in schizophrenia.

Adult↗
PubMed1994

Brain content of glycosphingolipids after oral administration of monosialogangliosides GM1 and LIGA20 to rats.

Natural (GM1) and semisynthetic [113-Neu-5-AcGgOse4-2-D-erythro-1,3- dihydroxy-2-dichloroacetylamide-4-trans-octadecene (LIGA20)] glycosphingolipids, given parenterally, protect neurones against glutamate-induced death without producing the side effects typical of glutamate receptor antagonists. Chronic glutamate-related neurotoxicity (e.g., in recurring strokes in elderly hypertensive patients, and in Parkinson disease) could be prevented also by glycosphingolipids treatment, but this therapeutic intervention will require a protracted administration of orally active glycosphingolipids. Here we demonstrate that 3-6 h after oral administration of 68 mumol/kg of LIGA20 and GM1 to rats, the brain content of LIGA20 is 50-fold higher than that of GM1. The brain concentration of LIGA20 remains elevated for at least 12-24 h. Because the LIGA20 that reaches the brain is slowly metabolized, repeated oral administrations of this glycosphingolipid can yield to its accumulation in brain, and can yield various brain levels depending on the dose and frequency of drug administration. In contrast this is not possible with GM1, which given orally for 7 d, cannot accumulate in brain in pharmacologically significant concentrations.

Administration, Oral↗
PubMed1994

Pituitary adenylate cyclase activating polypeptide (PACAP) potently enhances tyrosine hydroxylase (TH) expression in adrenal chromaffin cells.

In primary cultured bovine adrenal chromaffin cells (BACC), pituitary adenylate cyclase activating polypeptide 1-38 (PACAP) produced a dose related increase in tyrosine hydroxylase (TH) Vmax when measured 48 hours after the beginning of the treatment; a significant increase was observed with 0.5 nM and the maximal induction of close to 2.5-fold was found with 0.1 microM PACAP. The potency of PACAP was nearly 3 orders of magnitude greater than forskolin and VIP in inducing TH activity. These effects were preceded by an increase in TH mRNA levels, that started 2 hours after treatment and peaked 12 hours later. The presence of the phosphodiesterase inhibitor HL 725 further increased the stimulation of TH activity by PACAP, indicating that this activation was mediated via a cascade of events initiated by cAMP. Nicotine (1 microM) failed to increase TH activity significantly, however, when added in association with PACAP, a statistically significant increase of TH was elicited with peptide concentrations 5 times lower (0.1 nM) than the threshold dose of the peptide. The stimulation of nicotinic receptors facilitates the TH induction elicited by PACAP.

Adrenal Medulla↗
PubMed1994

The pharmacology of neurosteroidogenesis.

In adrenal cortex and other steroidogenic tissues including glial cells, the conversion of cholesterol into pregnenolone is catalyzed by the cytochrome P450scc located in the inner mitochondrial membrane. A complex mechanism operative in regulating cholesterol access to P450scc limits the rate of pregnenolone biosynthesis. Participating in this mechanism are DBI (diazepam binding inhibitor), an endogenous peptide that is highly expressed in steroidogenic cells and some of the DBI processing products including DBI 17-50 (TTN). DBI and TTN activate steroidogenesis by binding to a specific receptor located in the outer mitochondrial membrane, termed mitochondrial DBI receptor complex (MDRC). MDRC is a hetero-oligomeric protein: only the subunit that includes the DBI and benzodiazepine (BZD) recognition sites has been cloned. Several 2-aryl-3-indoleacetamide derivatives (FGIN-1-X) with highly selective affinity (nM) for MDRC were synthesized which can stimulate steroidogenesis in mitochondrial preparations. These compounds stimulate adrenal cortex steroidogenesis in hypophysectomized rats but not in intact animals. Moreover, this steroidogenesis is inhibited by the isoquinoline carboxamide derivative PK 11195, a specific high affinity ligand for MDRC with a low intrinsic steroidogenic activity. Some of the FGIN-1-X derivatives stimulate brain pregnenolone accumulation in adrenalectomized-castrated rats. The FGIN-1-X derivatives that increase brain pregnenolone content, elicit antineophobic activity and antagonize punished behavior in the Vogel conflict test in rats. These actions of FGIN-1-X are resistant to inhibition by flumazenil, a specific inhibitor of BZD action in GABAA receptors but are antagonized by PK 11195, a specific blocker of the steroidogenesis activation via MDRC stimulation. It is postulated that the pharmacological action of FGIN-1-X depends on a positive modulation of the GABA action on GABAA receptors mediated by the stimulation of brain neurosteroid production.

Animals↗
PubMed1994

Neurochemical correlates of sympathetic activation during severe alcohol withdrawal.

Cerebrospinal fluid (CSF) was obtained from 17 patients during acute alcohol withdrawal. Eight of these 17 patients had a second lumbar puncture a mean of 11.9 +/- 8.1 (SD) days later, when the clinical signs of alcohol withdrawal had subsided. CSF 3-methoxy-4-hydroxyphenylglycol concentrations declined significantly (p < 0.05) during the course of alcohol withdrawal from 52.0 +/- 22.1 (SD) to 39.6 +/- 12.6 pM/ml. In early withdrawal, there was a significant positive correlation between CSF norepinephrine (NE) and corticotropin releasing hormone (CRH) concentrations (r = 0.95, p < 0.001). Both NE and CRH concentrations correlated positively with diastolic blood pressure (r = 0.88, p < 0.001 and r = 0.62, p < 0.05, respectively). In all samples, CSF 5-hydroxyindole acetic acid concentrations correlated positively with CSF-homovanillic acid concentrations (r = 0.83, p < 0.001). These findings indicate significant perturbations of the noradrenergic neuronal system and a change in CRH-NE interactions during acute alcohol withdrawal.

Adult↗
PubMed1994

Imidazenil, a partial positive allosteric modulator of GABAA receptors, exhibits low tolerance and dependence liabilities in the rat.

Long-term treatment of rats with full (triazolam) or selective (diazepam) allosteric modulators of gamma-aminobutyric acid type A (GABAA) receptors rapidly induced tolerance to the protective effect of these drugs against bicuculline-induced convulsion. In contrast, long-term administration of partial allosteric modulators (imidazenil and bretazenil) of GABAA receptors, in doses equipotent to those of diazepam and triazolam that induce anticonvulsant tolerance, failed to elicit such a tolerance. Furthermore, no cross-tolerance was observed between diazepam and imidazenil. Discontinuation of long-term treatment with diazepam or triazolam, but not of long-term treatment with imidazenil or bretazenil, sensitized rats to behavioral inhibition by punishment (electric shock) in a manner that was potentiated by flumazenil. Administration of a single oral dose of [14C]diazepam or [3H] imidazenil to rats treated repeatedly with the corresponding unlabeled drug or vehicle revealed that the brain concentrations of drugs and their metabolites were similar in both groups of animals. This suggests that tolerance to the full or selective allosteric modulators of GABAA receptors may be associated with changes in the efficacy of the allosteric modulation rather than with changes in drug metabolism. Imidazenil has a longer half-life than an equipotent dose of diazepam and protects rats against bicuculline-induced convulsions for a significantly longer time than diazepam or bretazenil.(ABSTRACT TRUNCATED AT 250 WORDS)

Allosteric Regulation↗
PubMed1994

Mitochondrial diazepam-binding inhibitor receptor complex agonists antagonize dizocilpine amnesia: putative role for allopregnanolone.

In rats trained to retain a passive avoidance response or to retrieve a learned task in the radial and water maze tests, a pretreatment with 2-hexyl-3-indoleacetamide (FGIN-1-27) (IC50 57 mumol/kg p.o.) or 4' chlorodiazepam (4'CD) (15 mumol/kg i.p.), two steroidogenic ligands at the mitochondria diazepam-binding inhibitor receptor complex (MDRC), antagonized the performance deficit elicited by dizocilpine (0.3 mumol/kg i.p.), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. The 1-(2-chlorophenyl)-N-methyl-N-(-1-methyl-propyl)-3-isoquinoline carboxamide (PK-11195), an antagonist at MDRC in vivo, failed to modify the disruptive effect of dizocilpine in the passive avoidance response but reversed the FGIN-1-27- or 4' CD-induced antagonism of dizocilpine behavioral actions. Pretreatment with pregnenolone sulfate (48 mumol/kg i.p.), 3 alpha, 21-dihydroxy-5 alpha-pregnan-20-one (THDOC) (15 mumol/kg i.v.) and 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone) (15 mumol/kg i.v.) also reduced the passive avoidance retention deficit elicited by dizocilpine. The (17-beta)-17-[[bis(1-methylethyl)amino[carbonyl]androstane-3,5-diene-3- carboxylic acid (SKF-105111), a 5 alpha-reductase inhibitor, blocked the antagonism of dizocilpine behavioral actions by pregnenolone sulfate or by FGIN-1-27 but not those caused by THDOC or allopregnanolone either in normal or adrenalectomized-castrated rats. Thus, it is inferred that the amnesic effect of dizocilpine is counteracted by FGIN-1-27, 4'CD and pregnenolone sulfate because of their ability to increase brain accumulation of allopregnanolone.

Amnesia↗
PubMed1994

[Reproducibility of Doppler ultrasonography in the study of hepatic blood flow].

The reproducibility of hepatic blood flow measurement with pulsed Doppler US was assessed in 6 healthy volunteers. All subjects underwent two different study sessions and were examined by three different operators after overnight fasting. Each operator was blind to his measurements. Hepatic arterial and portal venous blood flow and hepatic arterial maximum velocity were measured; resistive index (RI), pulsatility index (PI) and hepatic perfusion index (HPI) were calculated. Each measurement was repeated three times per session. The data from repeated measurements were analyzed with the analysis of variance (ANOVA) method to assess the intra- and intersubject variations for each variable. The Scheffe test was used to evaluate intra- and interobserver variations. Significant differences among the 6 examined subjects were found for all the variables measured, except for hepatic arterial maximum velocity. The same subject exhibited significant differences in mean velocity of the main portal vein trunk and of its right branch, in maximum hepatic arterial velocity, RI, portal vein section area and blood flow. No significant interobserver variation was observed in the same session and no intraobserver variation detected for all the measurements performed in different sessions. Thus, we conclude that pulsed Doppler US is a repeatable method for measuring hepatic blood flow and may therefore be useful to detect changes in hepatic perfusion.

Analysis of Variance↗
PubMed1994

[Color Doppler ultrasonography in the identification and characterization of secondary focal lesions of the liver].

This study was aimed at assessing the potentials of color Doppler US in the detection of hepatic metastases by measuring changes in hepatic perfusion. Color-Doppler US was performed on 40 patients with multiple metastatic lesions (mean theta: 3 cm). In each patient both smaller and bigger lesions were studied--80 lesions on the whole. Differences in flow distribution (peritumoral or intratumoral) and the highest systolic peak flow velocity were investigated on color Doppler US scans. Hepatic arterial and portal venous blood flow measured in 40 patients with hepatic metastases were compared with those in 40 healthy controls. The two groups were homogeneous relative to age, sex, height and weight. The ratio of hepatic arterial to total liver blood flow (Doppler perfusion index, DPI) and the ratio of hepatic arterial to portal venous blood flow (Doppler flow ratio, DFR) were calculated. Color flow US scans were obtained in 56 of 80 metastatic lesions. We observed peritumoral flow in 76% of the lesions, intratumoral flow in 6% and mixed peritumoral and intratumoral flow in 18% of cases. The DPI and DFR values were significantly higher in the patients with liver metastases than in the control group. The changes in DPI and DFR resulted from an increase in hepatic arterial flow; no changes in portal venous blood flow were observed. These results suggest that Doppler measurements of hemodynamic hepatic changes may be of great value for the earlier detection of hepatic metastases.

Aged↗
PubMed1993

CSF diazepam binding inhibitor and schizophrenia: clinical and biochemical relationships.

Diazepam-binding inhibitor (DBI) is a 9-kD neuropeptide that interacts with the benzodiazepine (BZD) binding sites of the neuronal gamma-aminobutyric acid type A (GABAA) receptor and with the glial mitochondrial BZD receptor (MBR). We explored the involvement of CSF DBI-LI in schizophrenia, based on the potential role of GABA in the negative symptoms associated with schizophrenia, the relationship of its receptors with dopamine and norepinephrine release, and the proposed therapeutic efficacy of BZDs in schizophrenia. Clinical data, CSF DBI-LI and CSF monoamine measures were obtained in 65 drug-free male chronic (DSM-IIIR) schizophrenic patients, 53 of whom were also tested prior to haloperidol withdrawal. Following haloperidol withdrawal, CSF DBI-LI increased significantly. Drug-free CSF DBI-LI did not correlate with CSF monoamines. CSF DBI-LI was significantly higher in paranoid compared to chronic undifferentiated schizophrenic patients. The data suggest that DBI may have a symptom modulatory rather than an etiological role in schizophrenia.

Adult↗
PubMed1993

Chemistry, binding affinities, and behavioral properties of a new class of "antineophobic" mitochondrial DBI receptor complex (mDRC) ligands.

The mitochondrial DBI receptor complex (mDRC; previously called the peripheral benzodiazepine receptors) is linked to the production of neurosteroids such as pregnenolone sulfate, dehydroepiandrosterone sulfate, and others. In order to gain further information as to the function of the mDRC in the brain, we have constructed and tested both in vitro and in vivo a novel series of ligands, 2-arylindole-3-acetamides. The SAR studies detailed herein delineate some of the structural features required for high affinity binding to the mDRCs. In most cases the new ligands were prepared by use of the Fischer indole synthesis. Variations in the length and number of the alkyl groups on the amide nitrogen were probed together with the effects of halogen substituents on one or both of the aryl rings. Some ligands were also synthesized for study which represent conformationally constrained versions of the parent structure. Broad screening studies revealed these indoleacetamides to be highly selective for the mDRC, since they failed to bind with any significant affinity to other receptor systems. Some of the ligands were found to exhibit Ki values in the low nanomolar range for the mDRC as measured by the displacement of [3H]4'-chlorodiazepam. A subset of these ligands was also shown to stimulate pregnenolone formation from the mitochondria of C6-2B glioma cells with an EC50 of about 3 nM. In animal experiments ligands selected for further study were found to exhibit antineophobic effects, in spite of the fact that they exhibit no direct action on GABAA receptors. Consequently, it is postulated that these ligands owe their action to an indirect modulation of GABAA receptor function, presumably by stimulation of neurosteroid production and release from glial cells, followed by neurosteroid modulation of GABA's action on the chloride ion channel conductance of GABAA receptors.

Acetamides↗
PubMed1993

Molecular parameters of semisynthetic derivatives of gangliosides and sphingosine in monolayers at the air-water interface.

The molecular parameters (molecular area, surface potential, collapse pressure, dipole moment contributions) of semisynthetic derivatives of ganglioside GM1 and of sphingosine were studied in lipid monolayers at the air-NaCl (145 mM, pH 5.6) interface at 22 +/- 0.3 degrees C. The chemical modifications included alterations of the fatty acyl chain moiety linked to the 2-amino position of the sphingosine (Sph) base. The compounds studied were PKS-1 (N-acetyl Sph), PKS-2 (N-chloroacetyl Sph), PKS-3 (N-dichloroacetyl Sph), PKS-4 (N-trichloroacetyl Sph), Lyso-GM1 (ganglioside GM1 lacking the N-linked fatty acyl chain and the N-acetyl group on the sialic acid), Liga-4 (N-acetyl, lyso[NeuAc]GM1) and Liga-20 (N-dichloroacetyl, lyso[NeuAc]GM1). Relatively small modifications of the chemical structure of sphingolipids introduce dramatic consequences on their surface molecular properties. The absence of the long chain fatty acyl moiety and of the N-acetyl group on the neuraminic acid in Lyso-GM1 leads to a more condensed behavior and to an increase of the collapse pressure compared with GM1. The acetylation or chloroacetylation at the 2-amino position in Liga-4 and Liga-20 induce an expansion of the surface pressure-area isotherm and a decrease of the collapse pressure. The limiting molecular areas of GM1 derivatives, taken at the collapse pressure point, are consistent with the oligosaccharide chain being oriented approximately perpendicularly to the interface. Sphingosine shows a liquid expanded isotherm. The acetylation and successive chlorination of the acetyl residue at the 2-amino position of Sph cause a progressive increase in the limiting molecular area. The variation of the resultant dipole moment under compression, calculated from the surface potential values, suggests the reorientation of selective groups within these molecules that depend on the degree of intermolecular packing. Thermodynamic-geometric correlations on the basis of the molecular parameters of these derivatives suggest that small alterations of the substituent group at the 2-amino position of Sph could have large and amplified consequences on the type, curvature and stability of the possible self-aggregated structure that these lipids may form in aqueous medium.

Air↗
PubMed1993

ACTH-induced mitochondrial DBI receptor (MDR) and diazepam binding inhibitor (DBI) expression in adrenals of hypophysectomized rats is not cause-effect related to its immediate steroidogenic action.

Diazepam binding inhibitor (DBI) is a 10-kDa polypeptide that is enriched in steroidogenic cells such as adrenocortical, Leydig, and glial cells. In these cells, DBI and some of its processing products bind to the mitochondrial DBI receptor (MDR), located on the outer mitochondrial membrane, and stimulate pregnenolone formation by facilitating cholesterol access to the inner mitochondrial membrane where the cytochrome P-450 side chain cleavage enzyme is located. To determine whether the ACTH-induced increase in adrenal steroidogenesis occurs via changes in DBI and MDR expression the adrenal content of DBI-like immunoreactivity (DBI-LI), the MDR density, and the expression of mRNAs encoding for DBI and MDR were studied in hypophysectomized rats treated with vehicle or ACTH. After 9 days from the hypophysectomy, the levels of DBI-like immunoreactivity (DBI-LI) and DBI-mRNA declined to approximately 20% of their normal value; in contrast MDR-density and MDR-mRNA levels were reduced by 50-60% and were associated to a similar decrease in the activity of type A monoamine oxidase, a marker for mitochondrial proteins. Prolonged administration of ACTH-R (ACTH in saline containing 16% gelatin, 15 U/kg/day, from day 7 after surgery) to hypophysectomized rats, completely restored DBI and MDR adrenal expression to values similar to those of sham-operated rats. Our results indicate that ACTH, probably acting at the transcriptional level, is required for the normal expression of DBI and MDR in adrenal cortex. Changes in DBI and MDR expression after ACTH administration were not temporally related to the immediate steroidogenesis induced by ACTH, and may reflect its long-term trophic action on adrenocortical cells.

Adrenal Glands↗
PubMed1993

Induction of ornithine decarboxylase by N-methyl-D-aspartate receptor activation is unrelated to potentiation of glutamate excitotoxicity by polyamines in cerebellar granule neurons.

Polyamines positively modulate the activity of the N-methyl-D-aspartate (NMDA)-sensitive glutamate receptors. The concentration of polyamines in the brain increases in certain pathological conditions, such as ischemia and brain trauma, and these compounds have been postulated to play a role in excitotoxic neuronal death. In primary cultures of rat cerebellar granule neurons, exogenous application of the polyamines spermidine and spermine (but not putrescine) potentiated the delayed neurotoxicity elicited by NMDA receptor stimulation with glutamate. Furthermore, both toxic and nontoxic concentrations of glutamate stimulated the activity of ornithine decarboxylase (ODC)--the key regulatory enzyme in polyamine synthesis--and increased the concentration of ODC mRNA in cerebellar granule neurons but not in glial cells. Glutamate-induced ODC activation but not neurotoxicity was blocked by the ODC inhibitor difluoromethylornithine. Thus, high extracellular polyamine concentrations potentiate glutamate-triggered neuronal death, but the glutamate-induced increase in neuronal ODC activity may not play a determinant role in the cascade of intracellular events responsible for delayed excitotoxicity.

Animals↗
PubMed1993

Regional and interspecies differences in brain progesterone metabolism.

Metabolites of [3H]progesterone were studied in slices prepared from different brain regions of male rat, mouse, and monkey. The major metabolites were 5 alpha-dihydroprogesterone (5 alpha-DHP) and 3 alpha,5 alpha-tetrahydroprogesterone (3 alpha,5 alpha-THP) in rat brain slices, 5 alpha-DHP and 20 alpha-dihydroprogesterone (20 alpha-DHP) in mouse brain slices, and 20 alpha-DHP in monkey brain slices. In rat olfactory bulb slices, 5 alpha-DHP represented 25.2 +/- 3.3% of total radioactivity and 3 alpha,5 alpha-THP 17.5 +/- 2.8%, whereas in rat medulla oblongata slices, 5 alpha-DHP was 31.3 +/- 3.5% and 3 alpha,5 alpha-THP 5.4 +/- 1.5% of total radioactivity. In slices from other rat brain regions, both metabolites represented 12-20% of total radioactivity. The highest metabolite content in mouse brain was also detected in olfactory bulb slices, where 5 alpha-DHP represented 16.6 +/- 4.6% and 20 alpha-DHP 9.5 +/- 2.3% of total radioactivity. In cortical and corpus callosum slices of monkey brain, 26.8 +/- 4.4% and 2.4 +/- 0.5% of total radioactivity, respectively, were converted to 20 alpha-DHP, and less than 3% of total radioactivity could be attributed to any of the other metabolites detected. The 3 alpha, 5 alpha-THP content in both rat and monkey brain was below 1 nM, but increased in rat brain to 6.7 +/- 2.5 nM after electroshock. Endogenous 3 alpha,5 alpha-THP might play an important role in the regulation of rat behavior through the modulation of GABA action on the GABAA receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Stimulation of brain pregnenolone synthesis by mitochondrial diazepam binding inhibitor receptor ligands in vivo.

Evidence that neurosteroids are potent modulators of the action of GABA at GABAA receptors has prompted the investigation of the mechanism that controls brain neurosteroid synthesis by glial cell mitochondria in vivo. In vitro studies suggest that the interaction of the diazepam binding inhibitor (DBI)--a polypeptide that is abundant in steroidogenic cells--with glial mitochondrial DBI receptors (MDRs) is a crucial step in the physiological regulation of neurosteroid biosynthesis. MDRs bind 4'-chlorodiazepam (4'-CD), N,N-di-n-hexyl-2-(4-fluorophenyl)-indol-3-acetamide (FGIN-1-27), and the isoquinoline carboxamide PK 11195 with high affinity, and these ligands have been used to investigate whether the stimulation of glial MDRs increases brain pregnenolone production in vivo. Adrenalectomized and castrated (A-C) male rats (to eliminate peripheral sources of pregnenolone) were pretreated with trilostane (to prevent pregnenolone metabolism to progesterone), and the pregnenolone content in brain regions dissected after fixation with a 0.8-s exposure to microwave irradiation focused to the head was determined by HPLC followed by specific radioimmunoassay. The forebrain and cerebellum of A-C rats contained 4-7 ng of pregnenolone/g of tissue, and the olfactory bulb contained 10-14 ng/g. These concentrations of brain pregnenolone are only 30-40% lower than those of sham-operated rats. In contrast, the plasma pregnenolone content of sham-operated rats was 2-3 ng/ml, but it was only 0.15-0.20 ng/ml in the plasma of A-C rats. In A-C rats, treatment with the MDR ligands 4'-CD and FGIN-1-27 increased the pregnenolone content in the brain but failed to change the plasma or peripheral tissue content of this steroid. The effect of 4'-CD on brain pregnenolone content was maximal (70-100% increase) at the dose of 18 mumol/kg, 5-10 min after intravenous injection. The effect of oral administration of FGIN-1-27 on brain pregnenolone content was maximal (80-150% increase) at doses of 400-800 mumol/kg and peaked at approximately 1 h. That this effect of FGIN-1-27 was mediated by the MDR was documented by pretreatment with the MDR partial agonist PK 11195 (100 mumol/kg, i.p.). PK 11195 did not affect basal brain pregnenolone content but prevented the accumulation of brain pregnenolone induced by FGIN-1-27. FGIN-1-27 and 4'-CD failed to increase the brain concentration of dehydroepiandrosterone in A-C rats. These data suggest that glial cell MDRs play a role in neurosteroid biosynthesis in vivo.

Adrenalectomy↗