Finasteride/propecia's ill effects on GABA
kofi
prescribed drug for hair loss, propecia, inhibits 5ar which in turn can
interfere with the proper functioning of GABA in the body.
1: J Neurosci 2003 May 1;23(9):3572-3576 Related Articles, Links
Click here to read
sigma 1 Receptor-Related Neuroactive Steroids Modulate
Cocaine-Induced Reward.
Romieu P, Martin-Fardon R, Bowen WD, Maurice T.
Centre National de la Recherche Scientifique Unite Mixte de
Recherche 5102, University of Montpellier II, 34095 Montpellier cedex 5,
France, Department of Neuropharmacology, The Scripps Research Institute,
La Jolla, California 92307, and Unit on Receptor Biochemistry and
Pharmacology, Laboratory of Medicinal Chemistry, National Institute of
Diabetes and Digestive and Kidney Diseases, National Institutes of
Health, Bethesda, Maryland 20892.
The varsigma(1) receptor is critically involved in the rewarding
effect of cocaine, as measured using the conditioned place preference
(CPP) procedure in mice. Neuroactive steroids exert rapid
neuromodulatory effects in the brain by interacting with GABA(A), NMDA,
and varsigma(1) receptors. At the varsigma(1) receptor level,
3beta-hydroxy-5-androsten-17-one [dehydroepiandrosterone (DHEA)] and
3beta-hydroxy-5-pregnen-20-one (pregnenolone) act as agonists, whereas
4-pregnene-3,20-dione (progesterone) is an efficient antagonist. The
present study sought to investigate the action of neuroactive steroids
in acquisition of cocaine-induced CPP in C57BL/6 mice. None of these
steroids induced CPP alone. However, pretreatment with DHEA or
pregnenolone (5-20 mg/kg, s.c.) during conditioning with cocaine (10
mg/kg, i.p.) increased the conditioned score. On the contrary,
pretreatment with either progesterone (10 or 20 mg/kg, s.c.) or
finasteride (25 mg/kg, twice a day), a 5alpha-reductase inhibitor,
blocked acquisition of cocaine (20 mg/kg)-induced CPP. A crossed
pharmacology was observed between steroids and varsigma(1) ligands. The
varsigma(1) antagonist
N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine
blocked cocaine-induced CPP and its potentiation by DHEA or
pregnenolone. Progesterone blocked cocaine-induced CPP and its
potentiation by the varsigma(1) agonist igmesine. These results showed
that neuroactive steroids play a role in cocaine-induced appetence,
through their interaction with the varsigma(1) receptor. Therefore,
neuroendocrine control of cocaine addiction may not involve solely
glucocorticoids. The importance of neuroactive steroids as factors of
individual vulnerability to drug addiction should, thus, be considered.
PMID: 12736327 [PubMed - as supplied by publisher]
2: Ann Neurol 2003 Mar;53(3):390-1 Related Articles, Links
Comment in:
* Ann Neurol. 2003 Mar;53(3):288-91.
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Seizure exacerbation associated with inhibition of progesterone
metabolism.
Herzog AG, Frye CA.
Harvard Neuroendocrine Unit, Beth Israel Deaconess Medical Center,
Boston, MA 02215, USA.
The reduced progesterone metabolite tetrahydroprogesterone is a
potent positive modulator of GABA(A) chloride conductance that exerts
powerful neuroinhibitiory and anti-seizure effects in animal models.
Cyclic natural progesterone use may lessen seizure frequency in women
with catamenial seizure exacerbation. We report a case in which efficacy
was eliminated during concomitant treatment with a reductase inhibitor.
The observation suggests that a reduced metabolite, rather than
progesterone itself, was responsible for improved seizure control.
PMID: 12601707 [PubMed - indexed for MEDLINE]
3: Neuropharmacology 2002 Dec;43(8):1339-50 Related Articles, Links
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Behavioral action of ethanol in Porsolt's forced swim test:
modulation by 3 alpha-hydroxy-5 alpha-pregnan-20-one.
Hirani K, Khisti RT, Chopde CT.
Department of Pharmaceutical Sciences, Nagpur University Campus,
Amravati Road, Nagpur 440 010, Maharashtra, India.
Ethanol is known to increase cortical and plasma content of
GABAergic neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one
(3alpha,5alpha-THP) which is responsible for some of its behavioral and
electrophysiological effects. We have previously demonstrated the
antidepressant like effect of 3alpha,5alpha-THP in mice. This study
investigated the role of 3alpha,5alpha-THP in acute, chronic and
withdrawal effects of ethanol using mouse forced swim test (FST)
paradigm. While acute systemic ethanol (2 or 2.5 g/kg) administration
exhibited an antidepressant like effect, its prolonged consumption
produced tolerance to this effect and its withdrawal, on the other hand,
elicited enhanced behavioral despair (depression). The antidepressant
like effect of ethanol was potentiated by GABA(A) receptor agonist,
muscimol (0.5 mg/kg, i.p.), 3alpha,5alpha-THP (0.5, 1 or 2 microg/mouse,
i.c.v.) and by neurosteroidogenic drugs viz. selective serotonin
reuptake inhibitor (SSRI), fluoxetine (5 or 20 mg/kg, i.p.), agonist at
mitochondrial diazepam binding inhibitor receptor, FGIN 1-27 (0.5 or 1
microg/mouse, i.c.v.), or 11beta-hydroxylase inhibitor, metyrapone (0.5
or 1 microg/mouse, i.c.v.) which are known to increase endogenous
3alpha,5alpha-THP content. Furthermore, inhibition of the endogenous
neurosteroid biosynthesis by drugs like 5alpha-reductase inhibitor,
finasteride (50 mg/kg, s.c.), 3beta-hydroxysteroid dehydrogenase
inhibitor, trilostane (30 mg/kg i.p.) or 3alpha-hydroxysteroid
dehydrogenase inhibitor, indomethacin (5 mg/kg, i.p.) and GABA(A)
receptor antagonist, bicuculline (1 mg/kg, i.p.) blocked the
antidepressant like effect of ethanol. Withdrawal of ethanol from mice
consuming it chronically displayed enhanced behavioral despair and
elicited tolerance to antidepressant like action of acute ethanol (2.5,
3 or 3.5 g/kg). Moreover, sub-antidepressant doses (0.25 or 0.5
microg/mouse, i.c.v.) of 3alpha,5alpha-THP and fluoxetine (5 mg/kg,
i.p.) but not imipramine (1 mg/kg, i.p.) reversed the depression
associated with ethanol withdrawal indicating sensitization to their
antidepressant action. Thus, 3alpha,5alpha-THP plays a pivotal role in
the actions of ethanol and in the depression associated with ethanol
withdrawal. These findings may be of potential ramification to
contribute to the depression associated with alcoholism and its
treatment using neurosteroids.
PMID: 12527484 [PubMed - indexed for MEDLINE]
4: World J Biol Psychiatry 2002 Apr;3(2):87-95 Related Articles, Links
GABAergic neurosteroid modulation of ethanol actions.
Khisti RT, Penland SN, VanDoren MJ, Grobin AC, Morrow AL.
Departments of Psychiatry and Pharmacology, Bowles Center for
Alcohol Studies, CB#7178, 3027 Thurston Bowles Bldg., University of
North Carolina at Chapel Hill, Chapel Hill, NC 27599-7178, USA.
Systemic administration of ethanol elevates plasma and cerebral
cortical GABAergic neuroactive steroids. The increase in neurosteroids
is responsible for specific behavioural and electrophysiological actions
of ethanol in rodents. This article recapitulates the current knowledge
of the novel interaction between ethanol and neurosteroids and addresses
the potential mechanism for ethanol-induced increase in brain
neurosteroid levels. Ethanol-induced increase in the cortical
neurosteroid content is modified by neurosteroid biosynthesis inhibitors
and completely prevented by adrenalectomy in male rats. In line with
this, adrenalectomy prevented the anticonvulsant and hypnotic effects of
acute ethanol administration. It is speculated that acute ethanol
administration might resemble acute stress and increase neuroactive
steroids due to activation of hypothalamic-pituitary adrenal axis.
Ethanol-induced increases in neuroactive steroids might be responsible
for the antidepressant, anxiolytic, spatial learning deficits and drug
discriminatory actions in rodents. Thus ethanol-induced increases in
neuroactive steroids represent a novel mechanism of ethanol's action,
responsible for several pharmacological and behavioural actions of
ethanol. The development of new therapeutic strategies for alcoholism
may arise based on the novel interaction between ethanol and
neurosteroids in the brain.
PMID: 12479081 [PubMed - indexed for MEDLINE]
5: Brain Res Brain Res Protoc 2002 Apr;9(2):130-4 Related Articles, Links
Click here to read
A rapid method for obtaining finasteride, a 5alpha-reductase
inhibitor, from commercial tablets.
Trapani G, Dazzi L, Pisu MG, Reho A, Seu E, Biggio G.
Pharmaco-Chemistry Department, University of Bari, Via Orabona 4,
70125, Bari, Italy. tra...@farmchim.uniba.it
To study the effects of allopregnanolone (AP) depletion on
stress-induced dopamine changes in cortical dopamine, the
5alpha-reductase inhibitor finasteride on a gram-scale is required. Two
procedures for the extraction of finasteride from tablets are outlined
(method A and B). In method A, a suspension of powdered tablets was
preliminary extracted with chloroform and the extracts dried and
evaporated. The resulting residue was then purified on column
chromatography. Method B involves a direct chromatographic separation of
the powdered tablets. In terms of isolated yields, the second procedure
works well, is cheaper, and less time-consuming. The efficiency of the
method was tested by measuring progesterone, AP and THDOC content in
plasma and cerebral cortex of rats. The protocol enables the prompt
availability of sufficient amount of finasteride in experimental grade,
useful in examining the role of endogenous cerebrocortical AP in brain
homeostasis.
PMID: 12034332 [PubMed - indexed for MEDLINE]
6: J Neurosci 2002 May 1;22(9):3795-805 Related Articles, Links
Click here to read
Stress-induced deoxycorticosterone-derived neurosteroids modulate
GABA(A) receptor function and seizure susceptibility.
Reddy DS, Rogawski MA.
Epilepsy Research Section, National Institute of Neurological
Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
20892, USA.
Stress affects seizure susceptibility in animals and humans, but the
underlying mechanisms are obscure. Here, we provide evidence that
GABA(A) receptor-modulating neurosteroids derived from
deoxycorticosterone (DOC) play a role in stress-related changes in
seizure control. DOC, an adrenal steroid whose synthesis is enhanced
during stress, undergoes sequential metabolic reduction by
5alpha-reductase and 3alpha-hydroxysteroid oxidoreductase to form
5alpha-dihydrodeoxycorticosterone (DHDOC) and
allotetrahydrodeoxycorticosterone (THDOC), a GABA(A) receptor-modulating
neurosteroid with anticonvulsant properties. Acute swim stress in rats
significantly elevated plasma THDOC concentrations and raised the
pentylenetetrazol (PTZ) seizure threshold. Small systemic doses of DOC
produced comparable increases in THDOC and PTZ seizure threshold.
Pretreatment with finasteride, a 5alpha-reductase inhibitor that blocks
the conversion of DOC to DHDOC, reversed the antiseizure effects of
stress. DOC also elevated plasma THDOC levels and protected mice against
PTZ, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate,
picrotoxin, and amygdala-kindled seizures in mice (ED50 values, 84-97
mg/kg). Finasteride reversed the antiseizure activity of DOC (ED50, 7.2
mg/kg); partial antagonism was also obtained with indomethacin (100
mg/kg), an inhibitor of 3alpha-hydroxysteroid oxidoreductase.
Finasteride had no effect on seizure protection by DHDOC and THDOC,
whereas indomethacin partially reversed DHDOC but not THDOC. DHDOC, like
THDOC, potentiated GABA-activated Cl- currents in cultured hippocampal
neurons (< or =1 microm) and directly activated GABA(A) receptor
currents (> or =1 microm), compatible with a role for DHDOC in the
antiseizure activity of DOC. DOC is a mediator of the physiological
effects of acute stress that could contribute to stress-induced changes
in seizure susceptibility through its conversion to neurosteroids with
modulatory actions on GABA(A) receptors including THDOC and possibly
also DHDOC.
PMID: 11978855 [PubMed - indexed for MEDLINE]
7: Brain Res 2002 Apr 5;932(1-2):135-9 Related Articles, Links
Click here to read
Depletion of cortical allopregnanolone potentiates stress-induced
increase in cortical dopamine output.
Dazzi L, Serra M, Vacca G, Ladu S, Latrofa A, Trapani G, Biggio G.
B. Loddo Department of Experimental Biology, Centre for
Neuropharmacology, University of Cagliari, 09042 Cagliari, Italy.
da...@unica.it
In freely moving rats finasteride markedly reduced the cortical
content of allopregnanolone. This treatment significantly prolonged the
increase in the extracellular concentration of dopamine in the
prefrontal cortex induced by foot shock. Moreover, finasteride enhanced
both maximal increase of dopamine and its duration elicited by a single
injection of the anxiogenic drug FG 7142. These results suggest that
endogenous allopregnanolone may modulate the excitatory response of
cortical dopaminergic neurons to stressful and anxiogenic stimuli.
PMID: 11911871 [PubMed - indexed for MEDLINE]
8: J Neurochem 2001 Oct;79(2):417-25 Related Articles, Links
Click here to read
Increased expression of the neuropeptide Y receptor Y(1) gene in the
medial amygdala of transgenic mice induced by long-term treatment with
progesterone or allopregnanolone.
Ferrara G, Serra M, Zammaretti F, Pisu MG, Panzica GC, Biggio G, Eva
C.
Dipartimento di Anatomia, Farmacologia e Medicina Legale, Sezione di
Farmacologia, Universita di Torino, Torino, Italy.
The neurosteroid allopregnanolone, a reduced metabolite of
progesterone, induces anxiolytic effects by enhancing GABA(A) receptor
function. Neuropeptide Y (NPY) and GABA are thought to interact
functionally in the amygdala, and this interaction may be important in
the regulation of anxiety. By using Y(1)R/LacZ transgenic mice, which
harbour a fusion construct comprising the promoter of the mouse gene for
the Y(1) receptor for NPY linked to the lacZ gene, we previously showed
that long-term treatment with benzodiazepine receptor ligands modulates
Y(1) receptor gene expression in the medial amygdala. We have now
investigated the effects of prolonged treatment with progesterone or
allopregnanolone on Y(1)R/LacZ transgene expression, as determined by
quantitative histochemical analysis of beta-galactosidase activity.
Progesterone increased both the cerebrocortical concentration of
allopregnanolone and beta-galactosidase expression in the medial
amygdala. Finasteride, a 5alpha-reductase inhibitor, prevented both of
these effects. Long-term administration of allopregnanolone also
increased both the cortical concentration of this neurosteroid and
transgene expression in the medial amygdala. Treatment with neither
progesterone nor allopregnanolone affected beta-galactosidase activity
in the medial habenula. These data suggest that allopregnanolone
regulates Y(1) receptor gene expression through modulation of GABA(A)
receptor function, and they provide further support for a functional
interaction between GABA and neuropeptide Y in the amygdala.
PMID: 11677270 [PubMed - indexed for MEDLINE]
9: Life Sci 2001 Sep 21;69(18):2167-77 Related Articles, Links
Anxiolytic effect of Kami-Shoyo-San (TJ-24) in mice: possible
mediation of neurosteroid synthesis.
Mizowaki M, Toriizuka K, Hanawa T.
Oriental Medicine Research Center of the Kitasato Institute, Tokyo,
Japan. mizow...@kitasato.or.jp
We assessed the anxiolytic effect of Kami-Shoyo-San
(Jia-wei-xiao-yao-san; TJ-24), one of a traditional Chinese herbal
medicine used for the treatment of menopausal anxiety, by the social
interaction (SI) test in male mice. Acute administration of TJ-24
(25-100 mg/kg, p.o.), as well as the gamma-amino-butyric
acidA/benzodiazepine (GABA(A)/BZP) receptor agonist diazepam (1-3 mg/kg,
i.p.), dose dependently increased the SI time, respectively. The GABA(A)
receptor antagonist picrotoxin blocked the effects of TJ-24 and
diazepam. TJ-24-induced SI behavior was significantly blocked by the
GABA(A)/BZP receptor inverse agonist Ro 15-4513 and the GABA(A)/BZP
receptor antagonist flumazenil. In addition, 5alpha-reductase inhibitor
finasteride potently blocked the effect of TJ-24 without attenuating the
basal level by itself. These findings suggest that TJ-24 shows the
anxiolytic effect through the neurosteroid synthesis followed by
GABA(A)/BDZ receptor stimulations.
PMID: 11669460 [PubMed - indexed for MEDLINE]
10: J Neurophysiol 2001 Aug;86(2):1052-6 Related Articles, Links
Click here to read
Neurosteroids mediate habituation and tonic inhibition in the
auditory midbrain.
Disney A, Calford MB.
Psychobiology Laboratory, Division of Psychology, The Australian
National University, Canberra.
Habituation of the behavioral response to a repetitive stimulus is a
well-established observation in perceptual studies and is considered a
basic form of nonassociative learning. There is also a long history of
physiological studies suggesting that central nervous system habituation
is mediated by inhibition. At higher levels of the sensory pathways,
such inhibition is mainly contributed by GABAa receptor mechanisms.
Concepts of modification of synaptic efficacy that apply to excitatory
amino acid synaptic transmission do not have direct parallels with these
inhibitory synapses: quantal release of GABA rapidly saturates available
receptors at a synapse, placing an upper limit on responsiveness to
increased transmitter release. However, pharmacological modulation of
GABAa-receptor efficacy with exogenous agents (e.g., benzodiazepines and
beta-carbolines) is known to occur through allosteric mechanisms that
modulate the effectiveness (positive and negative) of GABA at this
receptor. The most potent endogenous modulators are 5alpha-reduced
steroids. Production of these steroids was attenuated in adult rats with
systemic injection of Finasteride, a competitive substrate for
5alpha-reductase. This treatment was sufficient to block habituation of
the evoked midbrain response to repetitive presentation of an acoustic
click. This result confirms that simple habituation is due to an
increase in active inhibition, the increase being mediated by steroid
modulation of the GABAa-receptor. Finasteride treatment also brought
about a 23% increase in the evoked response to a click stimulus,
suggesting that 5alpha-reduced steroids normally contribute to tonic
inhibition in the rat inferior colliculus.
PMID: 11495974 [PubMed - indexed for MEDLINE]
11: Epilepsia 2001 Mar;42(3):337-44 Related Articles, Links
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Enhanced anticonvulsant activity of neuroactive steroids in a rat
model of catamenial epilepsy.
Reddy DS, Rogawski MA.
Epilepsy Research Branch, National Institute of Neurological
Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
20892-1408, USA.
PURPOSE: Perimenstrual catamenial epilepsy may in part be due to
withdrawal of the endogenous progesterone-derived neurosteroid
allopregnanolone that potentiates gamma-aminobutyric acidA (GABA(A))
receptor-mediated inhibition. Here we sought to determine whether the
anticonvulsant potencies of neuroactive steroids, benzodiazepines,
phenobarbital (PB), and valproate (VPA) are altered during the
heightened seizure susceptibility accompanying neurosteroid withdrawal
in a rat model of perimenstrual catamenial epilepsy. METHODS: Test drugs
were evaluated for their ability to alter the convulsant activity of
pentylenetetrazol (PTZ) in young adult female rats, in pseudopregnant
rats with prolonged exposure to high levels of progesterone (and its
neurosteroid metabolites), and in pseudopregnant rats 24 h after acute
withdrawal of neurosteroids by treatment with the 5alpha-reductase
inhibitor finasteride. Test drugs were administered at doses equivalent
to twice their ED50 values for protection against PTZ-induced clonic
seizures in naive young adult female rats. RESULTS: The anticonvulsant
activity of allopregnanolone (5 mg/kg, s.c.), pregnanolone (5 mg/kg,
s.c.), allotetrahydrodeoxycorticosterone (15 mg/kg, s.c.), and
tetrahydrodeoxycorticosterone (10 mg/kg, s.c.) were enhanced by 34-127%
after neurosteroid withdrawal. The anticonvulsant activity of PB (65
mg/kg, i.p.) was also enhanced by 24% in neurosteroid-withdrawn animals.
In contrast, the anticonvulsant activity of diazepam (4 mg/kg, i.p.),
bretazenil (0.106 mg/kg, i.p.), and VPA (560 mg/kg, i.p.) were reduced
or unchanged in neurosteroid-withdrawn animals. CONCLUSIONS: The
anticonvulsant activity of neuroactive steroids is potentiated after
neurosteroid withdrawal, supporting the use of such agents in the
treatment of perimenstrual catamenial epilepsy.
PMID: 11442150 [PubMed - indexed for MEDLINE]
12: Epilepsia 2001 Mar;42(3):328-36 Related Articles, Links
Click here to read
Neurosteroid withdrawal model of perimenstrual catamenial epilepsy.
Reddy DS, Kim HY, Rogawski MA.
Epilepsy Research Branch, National Institute of Neurological
Disorders and Stroke, National Institutes of Health, Rockville, Maryland
20892-1408, USA.
PURPOSE: Perimenstrual catamenial epilepsy, the increase in seizure
frequency that some women with epilepsy experience near the time of
menstruation, may in part be related to withdrawal of the progesterone
metabolite allopregnanolone, an endogenous anticonvulsant neurosteroid
that is a potent positive allosteric gamma-aminobutyric acidA (GABA(A))
receptor modulator. The objective of this study was to develop an animal
model of perimenstrual catamenial epilepsy for use in evaluating
drug-treatment strategies. METHODS: A state of prolonged high serum
progesterone (pseudopregnancy) was induced in 26-day-old female rats by
sequential injection of pregnant mares' serum gonadotropin and human
chorionic gonadotropin. Neurosteroid withdrawal was induced by treatment
with finasteride (100 mg/kg, i.p.), a 5alpha-reductase inhibitor that
blocks the conversion of progesterone to allopregnanolone. Plasma
progesterone and allopregnanolone levels were measured by gas
chromatography/electron capture negative chemical ionization mass
spectrometry. Seizure susceptibility was evaluated with the convulsant
pentylenetetrazol (PTZ). RESULTS: Plasma allopregnanolone levels were
markedly increased during pseudopregnancy (peak level, 55.1 vs. control
diestrous level, 9.3 ng/mL) and were reduced by 86% 24 h after
finasteride treatment (6.4 ng/mL). Progesterone levels were unaffected
by finasteride. After finasteride-induced withdrawal, rats showed
increased susceptibility to PTZ seizures. There was a significant
increase in the number of animals exhibiting clonic seizures when
challenged with subcutaneous PTZ (60 mg/kg) compared with control
pseudopregnant animals not undergoing withdrawal and nonpseudopregnant
diestrous females. The CD50 (50% convulsant dose) was 46 mg/kg, compared
with 73 mg/kg in nonwithdrawn pseudopregnant animals and 60 mg/kg in
diestrous controls. The threshold doses for induction of various seizure
signs, measured by constant intravenous infusion of PTZ, were reduced by
30-35% in neurosteroid-withdrawing animals compared with control
diestrous females. No change in threshold was observed in pseudopregnant
rats treated from days 7 to 11 with finasteride, demonstrating that high
levels of progesterone alone do not alter seizure reactivity.
CONCLUSIONS: Neurosteroid withdrawal in pseudopregnant rats results in
enhanced seizure susceptibility, providing an animal model of
perimenstrual catamenial epilepsy that can be used for the evaluation of
new therapeutic approaches.
PMID: 11442149 [PubMed - indexed for MEDLINE]
13: J Endocrinol Invest 2001 Jun;24(6):399-407 Related Articles, Links
Inhibition of 5alpha-reductase enzyme or GABA(A) receptors in the
VMH and the VTA attenuates progesterone-induced sexual behavior in rats
and hamsters.
Frye CA.
Department of Psychology, Biological Sciences, and Center for
Neurobiology, University at Albany, SUNY, NY, USA.
caf...@cnsunix.albany.edu
Progesterone (P) to the ventromedial hypothalamus (VMH) and the
ventral tegmental area (VTA) of ovariectomized (OVX), estradiol benzoate
(EB)-primed rats and hamsters produces female sexual behavior similar to
that seen in proestrous, receptive rodents. Because P's 5alpha-reduced
metabolites can have facilitative effects on female sexual receptivity
through actions at GABA(A)/benzodiazepine receptor complexes (GBRs), the
role of 5alpha-reductase and GBRs in the VMH and the VTA was
investigated. In Experiment 1, 5alpha-reductase immunoreactivity
(5alpha-red-IR) and GBR immunoreactivity (GBR-IR) in the VMH and the VTA
of OVX, EB (10 microg) and P (500 microg)-primed rats and hamsters was
examined. More 5alpha-red-IR and GBR-IR was seen in the VMH and the VTA
of receptive (EB and P-primed) compared to non-receptive (sesame oil
vehicle) rodents. In Experiment 2, OVX, EB and P-primed rats and
hamsters received implants of finasteride, a 5alpha-reductase inhibitor,
or no implants to the VMH and the VTA and were tested for sexual
receptivity with a male. Ovariectomized EB and P-primed rats and
hamsters receiving finasteride to the VMH and the VTA had decreased
lordosis compared to rodents receiving control implants to the VMH and
the VTA. In Experiment 3, OVX, EB and P-primed rats and hamsters
received infusions of picrotoxin, a GBR antagonist, or vehicle infusion
to the VMH and the VTA and were tested for sexual receptivity with a
male. Ovariectomized EB and P-primed rats and hamsters receiving
picrotoxin to the VMH and the VTA had decreased lordosis compared to
rodents receiving vehicle infusions to the VMH and the VTA. These data
suggest that 5alpha-reductase and GBRs are present in the VMH and VTA,
and that inhibiting 5alpha-reductase activity or blocking GBRs in the
VMH and the VTA attenuates EB+P-primed sexual receptivity of OVX rats
and hamsters.
PMID: 11434663 [PubMed - indexed for MEDLINE]
14: Neurosci Lett 2001 Jun 22;306(1-2):13-6 Related Articles, Links
Click here to read
Effect of finasteride on behavioural arousal and somatosensory
evoked potentials in fetal sheep.
Nicol MB, Hirst JJ, Walker DW.
Department of Physiology, Monash University, Victoria 3168, Clayton,
Australia.
This study examines the effect of inhibiting the synthesis of
gamma-aminobutyric acid(A) (GABA(A)) agonist steroids on behavioural
activity and somatosensory evoked potentials (SEP) in late gestation
fetuses. Pregnane steroid production was suppressed by infusion of the
5alpha-reductase inhibitor, finasteride in chronically catheterised
fetal sheep, 130-135 days gestation. Finasteride treatment (160 mg in 10
ml of vehicle over 2 h) significantly increased the incidence of fetal
arousal during the period 4-10 h after commencing the infusion (P<0.05,
n=6), whereas other behavioural parameters were not effected. In three
of four animals, finasteride produced an increase in the amplitude of
the N22 peak of the SEP during high voltage electrocortical activity. We
conclude that suppression of pregnane steroid synthesis, by inhibition
of the 5alpha-reductase enzyme, increases arousal activity in the fetus
which is consistent with a reduction in GABA(A) receptor mediated
inhibition.
PMID: 11403946 [PubMed - indexed for MEDLINE]
15: Pharmacol Biochem Behav 2000 Aug;66(4):879-86 Related Articles, Links
Click here to read
Anticonvulsive effect of swim stress in mice.
Pericic D, Svob D, Jazvinscak M, Mirkovic K.
Laboratory for Molecular Neuropharmacology, Ruder Boskovic
Institute,Bijenicka c. 54, P.O.B. 1016, 10000 Zagreb, Croatia.
To explore the possible involvement of glucocorticoids in the
previously observed anticonvulsive effect of swim stress, mice were,
prior to administration of convulsants, subjected to treatments that
diminish or enhance plasma corticosterone levels. Aminoglutethimide, the
inhibitor of steroid synthesis, failed to modify convulsant doses of
picrotoxin, but enhanced threshold doses of pentylenetetrazole producing
myoclonus and death, both in unstressed and stressed animals. The same
drug prevented the effect of stress on pentylenetetrazole-induced
running bouncing clonus (RB clonus) and abolished the appearance of
tonic hindlimb extension (THE). Doses of kainic acid producing
convulsions and death were not affected by stress, but they were
enhanced by aminoglutethimide. Corticosterone administration could not
imitate the effect of swim stress. Finasteride, a 5 alpha-reductase
inhibitor, did not interfere with the effect of stress on
picrotoxin-induced convulsions. Swim stress failed to modify the binding
of the convulsant t[3H]-butylbicycloorthobenzoate [3H]TBOB, to washed
mouse forebrain membranes. The results confirmed an anticonvulsant
effect of swim stress against convulsions produced by GABA-related
convulsants, but they do not support the hypothesis suggesting the
involvement of glucocorticoids or neurosteroids in this effect.
PMID: 10973529 [PubMed - indexed for MEDLINE]
16: Mol Pharmacol 2000 Jun;57(6):1262-70 Related Articles, Links
Click here to read
Allopregnanolone synthesis in cerebellar granule cells: roles in
regulation of GABA(A) receptor expression and function during
progesterone treatment and withdrawal.
Follesa P, Serra M, Cagetti E, Pisu MG, Porta S, Floris S, Massa F,
Sanna E, Biggio G.
Department of Experimental Biology "Bernardo Loddo," University of
Cagliari, Italy. fol...@vaxca1.unica.it
Rat cerebellar granule cells were cultured for 5 days with
progesterone, resulting in the conversion of progesterone to
allopregnanolone, a potent and efficacious modulator of
gamma-aminobutyric acid (GABA) type-A receptors, as well as in decreases
in the abundance of GABA(A) receptor alpha(1), alpha(3), alpha(5), and
gamma(2) subunit mRNAs. These effects were accompanied by decreases in
the efficacies of diazepam and the beta-carboline DMCM with regard to
modulation of GABA-evoked Cl(-) currents. Withdrawal from such
progesterone treatment resulted in a rapid and selective increase in the
abundance of the GABA(A) alpha(4) subunit mRNA that was associated with
a restoration of receptor sensitivity to the negative modulatory action
of DMCM, a positive receptor response to flumazenil, and continued
reduced responsiveness of receptors to diazepam. Prevention of
allopregnanolone synthesis by the 5alpha-reductase inhibitor finasteride
also prevented the changes in both GABA(A) receptor gene expression and
receptor function elicited by progesterone treatment and withdrawal.
PMID: 10825399 [PubMed - indexed for MEDLINE]
17: J Neurosci 2000 Mar 1;20(5):1982-9 Related Articles, Links
Click here to read
Neuroactive steroid 3alpha-hydroxy-5alpha-pregnan-20-one modulates
electrophysiological and behavioral actions of ethanol.
VanDoren MJ, Matthews DB, Janis GC, Grobin AC, Devaud LL, Morrow AL.
Department of Psychiatry, University of North Carolina at Chapel
Hill, Chapel Hill, North Carolina 27599-7178, USA.
Neuroactive steroids are synthesized de novo in brain, yet their
physiological significance remains elusive. We provide biochemical,
electrophysiological, and behavioral evidence that several specific
actions of alcohol (ethanol) are mediated by the neurosteroid
3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP;
allopregnanolone). Systemic alcohol administration elevates 3alpha,
5alpha-THP levels in the cerebral cortex to pharmacologically relevant
concentrations. The elevation of 3alpha,5alpha-THP is dose- and
time-dependent. Furthermore, there is a significant correlation between
3alpha,5alpha-THP levels in cerebral cortex and the hypnotic effect of
ethanol. Blockade of de novo biosynthesis of 5alpha-reduced steroids
using the 5alpha-reductase inhibitor finasteride prevents several
effects of ethanol. Pretreatment with finasteride causes no changes in
baseline bicuculline-induced seizure threshold but reverses the
anticonvulsant effect of ethanol. Finasteride pretreatment also reverses
ethanol inhibition of spontaneous neural activity in medial
septal/diagonal band of Broca neurons while having no direct effect on
spontaneous firing rates. Thus, elevation of 3alpha,5alpha-THP levels by
acute ethanol administration represents a novel mechanism of ethanol
action as well as an important modulatory role for neurosteroids in the
CNS.
PMID: 10684899 [PubMed - indexed for MEDLINE]
18: Eur J Pharmacol 1999 Jun 30;375(1-3):225-35 Related Articles, Links
Physiological modulation of GABA(A) receptor plasticity by
progesterone metabolites.
Concas A, Follesa P, Barbaccia ML, Purdy RH, Biggio G.
Department of Experimental Biology, University of Cagliari, Italy.
aco...@unica.it
The possible functional relation between changes in brain and plasma
concentrations of neurosteroids and the plasticity of gamma-aminobutyric
acid type A (GABA(A)) receptors in the brain during pregnancy and after
delivery was investigated in rats. The concentrations in the cerebral
cortex and plasma of pregnenolone as well as of progesterone and its
neuroactive derivatives allopregnanolone
(3alpha-hydroxy-5alpha-pregnan-20-one) and
allotetrahydrodeoxycorticosterone (5alpha-hydroxy-3alpha,21-diol-20-one)
increased during pregnancy, peaking around day 19, before returning to
control (estrus) values immediately before delivery (day 21). In the
postpartum period, steroid concentrations in plasma and brain did not
differ from control values. The densities of [3H]GABA,
[3H]flunitrazepam, and t-[35S]butylbicyclophosphorotionate (TBPS)
binding sites in the cerebral cortex also increased during pregnancy,
again peaking on day 19 and returning to control values on day 21;
receptor density was decreased further 2 days after delivery and again
returned to control values within 7 days. These changes were accompanied
by a decrease in the apparent affinity of the binding sites for the
corresponding ligand on day 19 of pregnancy. The amount of the gamma2L
subunit mRNA decreased progressively during pregnancy, in the cerebral
cortex and hippocampus, returned to control value around the time of
delivery and did not change in the postpartum period. On the contrary,
the amount of alpha4 subunit mRNA was not modified during pregnancy both
in the cerebral cortex and hippocampus whereas significantly increased 7
days after delivery only in the hippocampus. No significant changes were
apparent for alpha1, alpha2, alpha3, beta1, beta2, beta3 and gamma2S
subunit mRNAs. Administration of finasteride, a specific
5alpha-reductase inhibitor, to pregnant rats from days 12 to 18 markedly
reduced the increases in the plasma and brain concentrations of
allopregnanolone and allotetrahydrodeoxycorticosterone as well as
prevented both the increase in the densities of [3H]flunitrazepam and
[35S]TBPS binding sites and the decrease of gamma2L mRNA normally
observed during pregnancy. The results demonstrate that the changes in
the plasticity of GABA(A) receptors that occur in rat brain during
pregnancy and after delivery are related to the physiological changes in
plasma and brain concentrations of neurosteroids.
PMID: 10443579 [PubMed - indexed for MEDLINE]
19: Pharmacol Biochem Behav 1999 Jul;63(3):441-8 Related Articles, Links
Click here to read
Reduced progesterone metabolites are not critical for plus-maze
performance of lactating female rats.
Kellogg CK, Barrett KA.
Department of Brain and Cognitive Sciences, University of Rochester,
NY 14627, USA.
Lactation has been associated with anxiolysis in several tests of
anxiety. These observations, considered together with observations that
progesterone and its 5alpha-reduced metabolites are anxiolytic in
cycling, nonlactating females, raised the question of whether the
changes in anxiety-related behaviors that accompany lactation are driven
by reduced progesterone metabolites. Lactating female rats were tested
on the plus-maze on postpartum days 2 or 7, and demonstrated enhanced
open-arm performance relative to cycling, nonlactating females. Hormonal
analysis indicated that while serum levels of both progesterone and its
3alpha,5alpha-reduced metabolite were increased in lactating females,
the turnover of progesterone to the metabolite was markedly reduced
during lactation. Furthermore, treatment with a 5alpha-reductase
inhibitor for 3 days prior to testing potentiated the open-arm
performance in lactating females, implying that enhanced open-arm
performance was not mediated by the reduction of progesterone or other
steroids. Additionally, analysis of GABA(A) receptor function indicated
that parturition and lactation did not alter the sensitivity of the
receptor to GABA or to modulation by reduced steroids. The mechanisms
driving enhanced plus-maze behavior in lactating females appear to
differ from mechanisms identified in nonlactating females.
PMID: 10418786 [PubMed - indexed for MEDLINE]
20: Proc Natl Acad Sci U S A 1998 Oct 27;95(22):13284-9 Related
Articles, Links
Click here to read
Role of brain allopregnanolone in the plasticity of
gamma-aminobutyric acid type A receptor in rat brain during pregnancy
and after delivery.
Concas A, Mostallino MC, Porcu P, Follesa P, Barbaccia ML, Trabucchi
M, Purdy RH, Grisenti P, Biggio G.
Department of Experimental Biology, University of Cagliari, 09123
Cagliari, Italy. aco...@vaxc1.unica.it
The relation between changes in brain and plasma concentrations of
neurosteroids and the function and structure of gamma-aminobutyric acid
type A (GABAA) receptors in the brain during pregnancy and after
delivery was investigated in rats. In contrast with plasma, where all
steroids increased in parallel, the kinetics of changes in the
cerebrocortical concentrations of progesterone, allopregnanolone (AP),
and allotetrahydrodeoxycorticosterone (THDOC) diverged during pregnancy.
Progesterone was already maximally increased between days 10 and 15,
whereas AP and allotetrahydrodeoxycorticosterone peaked around day 19.
The stimulatory effect of muscimol on 36Cl- uptake by cerebrocortical
membrane vesicles was decreased on days 15 and 19 of pregnancy and
increased 2 days after delivery. Moreover, the expression in cerebral
cortex and hippocampus of the mRNA encoding for gamma2L GABAA receptor
subunit decreased during pregnancy and had returned to control values 2
days after delivery. Also alpha1, alpha2, alpha3, alpha4, beta1, beta2,
beta3, and gamma2S mRNAs were measured and failed to change during
pregnancy. Subchronic administration of finasteride, a 5alpha-reductase
inhibitor, to pregnant rats reduced the concentrations of AP more in
brain than in plasma as well as prevented the decreases in both the
stimulatory effect of muscimol on 36Cl- uptake and the decrease of
gamma2L mRNA observed during pregnancy. These results indicate that the
plasticity of GABAA receptors during pregnancy and after delivery is
functionally related to fluctuations in endogenous brain concentrations
of AP whose rate of synthesis/metabolism appears to differ in the brain,
compared with plasma, in pregnant rats.
PMID: 9789080 [PubMed - indexed for MEDLINE]
21: J Neuroendocrinol 1998 Apr;10(4):291-6 Related Articles, Links
Click here to read
Finasteride blocks the reduction in ictal activity produced by
exogenous estrous cyclicity.
Frye CA, Scalise TJ, Bayon LE.
Department of Psychology, Connecticut College, New London 06320, USA.
The purpose of the present study was to examine seizure activity
during reduced 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP)
production. Ovariectomized Long-Evans rats were stereotaxically
implanted with bipolar electrodes above the perforant pathway; silastic
implants filled with estradiol-17-benzoate (EB) and progesterone were
inserted subcutaneously to mimic diestrus. Estrus was then induced in
half of these animals by injection of EB (30 microg) and progesterone
(2.5 mg), 48 and 4 h, respectively, prior to perforant pathway
stimulation. Half of the estrous and diestrous rats also received a
5alpha-reductase inhibitor, finasteride (50 mg/kg), 6 h prior to
perforant pathway stimulation. The estrous condition was associated with
reduced number and duration of partial seizures, improved performance on
a Morris water maze recovery of function test, reduced neuronal loss in
the hilar region of the hippocampus, and elevated central and plasma
3alpha,5alpha-THP, compared to estrus+finasteride, diestrus+vehicle and
diestrus+finasteride conditions, which did not differ from each another.
These data suggest antiseizure effects of estrus may be caused, in part,
by the action of 3alpha,5alpha-THP and that the precipitous decline in
3alpha,5alpha-THP may restore seizure threshold to control levels.
PMID: 9630399 [PubMed - indexed for MEDLINE]
22: Brain Res 1997 Mar 7;750(1-2):277-84 Related Articles, Links
Regulation of proopiomelanocortin gene expression by endogenous
ligands of the GABAA receptor complex as evaluated by in situ
hybridization in the rat pars intermedia.
Garcia de Yebenes E, Li S, Pelletier G.
MRC Group in Molecular Endocrinology, CHUL Research Center, Quebec,
Canada.
The neurotransmitter gamma-aminobutyric acid (GABA) exerts a tonic
inhibitory influence on proopiomelanocortin (POMC) neurons in the
hypothalamus as well as on the melanotrope cells of the intermediate
lobe (IL) of the pituitary gland. Moreover, the activation of the GABAA
receptor complex by different ligands has been shown to exert a negative
influence on the POMC gene expression at the hypothalamic level. In
order to elucidate the in vivo regulation of the POMC mRNA levels in the
intermediate lobe of the pituitary by endogenous ligands of the GABAA
receptor complex, we have studied the effect of intravenous (i.v.) and
intracerebroventricular (i.c.v) injections of octadecaneuropeptide
(ODN), a peptide derived from diazepam-binding inhibitor (DBI). The
possible involvement of neurosteroids in the action of ODN on
melanotropic cells was evaluated following inhibition of two enzymes
involved in the biosynthesis of neurosteroids known as activators of
G3BAA receptor complex: trilostane, an inhibitor of 3
beta-hydroxysteroid dehydrogenase (3 beta-HSD), and MK-906, an inhibitor
of 5 alpha-reductase. The i.v. injection of ODN produced a
dose-dependent inhibition of POMC gene expression in the IL. The i.c.v.
injection of ODN also depressed POMC mRNA. These effects were completely
reversed by the concomitant administration of the GABAA antagonist
picrotoxin. Similar results were obtained in POMC neurons in the arcuate
nucleus (AN) of the hypothalamus. Trilostane administration induced an
increase in POMC mRNA and also prevented the inhibitory influence of
ODN. The neurosteroid pregnenolone-sulfate, a negative modulator of the
GABAA receptor, also stimulated POMC gene expression. On the other hand,
MK-906 produced a decrease in mRNA levels and could not reverse the
effect of ODN. The results indicate that activation of the GABAA
receptor complex by the endogenous benzodiazepine receptor ligand ODN
can induce a negative regulation of POMC gene expression in the IL of
the pituitary and neurons in the AN. The present results do not provide
clear evidence that neurosteroids are involved in the action of ODN on
POMC gene expression in the IL.
PMID: 9098553 [PubMed - indexed for MEDLINE]