Biomedical subjects

J N Reynolds

Publications and source records attributed to J N Reynolds.

At least 19 recordsLinked to original sources

PubMed2006

Effects of chronic prenatal ethanol exposure on mitochondrial glutathione and 8-iso-prostaglandin F2alpha concentrations in the hippocampus of the perinatal guinea pig.

It is hypothesised that oxidative stress is a key mechanism of ethanol neurobehavioural teratogenicity, resulting in altered endogenous antioxidant status and increased membrane lipid peroxidation in the hippocampus of chronic prenatal ethanol exposure (CPEE) offspring. To test this hypothesis, timed pregnant guinea-pigs (term, approximately gestational day (GD) 68) received chronic daily oral administration of (i) 4 g ethanol kg(-1) maternal bodyweight, (ii) isocaloric sucrose with pair feeding, or (iii) water. At GD 65 (term fetus) and postnatal day (PD) 0 (neonate), individual offspring were killed, the brain was excised and the hippocampi were dissected. Glutathione (GSH) concentration was measured in the cytosolic and mitochondrial fractions of hippocampal homogenate. The occurrence of lipid peroxidation was determined by measuring the concentration of 8-iso-prostaglandin F2+/- (8-iso-PGF2+/-). There was CPEE-induced decreased brain weight and hippocampal weight at GD 65 and PD 0, decreased mitochondrial GSH concentration in the hippocampus at PD 0, with no change in mitochondrial GSH concentration at GD 65 or cytosolic GSH concentration at GD 65 or PD 0, and no change in mitochondrial or whole-homogenate 8-iso-PGF2+/- concentration in the hippocampus at GD 65 or PD 0. The data demonstrate that CPEE produces selective mitochondrial dysfunction in the hippocampus of the neonatal guinea-pig, involving GSH depletion.

Animals↗

PubMed2006

Chronic prenatal ethanol exposure increases glucocorticoid-induced glutamate release in the hippocampus of the near-term foetal guinea pig.

Exposure to high cortisol concentration can injure the developing brain, possibly via an excitotoxic mechanism involving glutamate (Glu). The present study tested the hypothesis that chronic prenatal ethanol exposure (CPEE) activates the foetal hypothalamic-pituitary-adrenal axis to produce high cortisol exposure in the foetal compartment and alters sensitivity to glucocorticoid-induced Glu release in the foetal hippocampus. Pregnant guinea pigs received daily oral administration of ethanol (4 g/kg maternal body weight/day) or isocaloric-sucrose/pair-feeding from gestational day (GD) 2 until GD 63 (term, approximately GD 68) at which time they were euthanised, 1 h after their final treatment. Adrenocorticotrophic hormone (ACTH) and cortisol concentrations were determined in foetal plasma. Basal and electrically stimulated Glu and gamma-aminobutyric acid (GABA) efflux in the presence or absence of dexamethasone (DEX), a selective glucocorticoid-receptor agonist, were determined ex vivo in foetal hippocampal slices. Glucocorticoid receptor (GR), mineralocorticoid receptor (MR) and N-methyl-D-aspartate (NMDA) receptor NR1 subunit mRNA expression were determined in situ in the hippocampus and dentate gyrus. In the near-term foetus, CPEE increased foetal plasma ACTH and cortisol concentrations. Electrically stimulated glutamate, but not GABA, release was increased in CPEE foetal hippocampal slices. Low DEX concentration (0.3 microM) decreased stimulated glutamate, but not GABA, release in both CPEE and control foetal hippocampal slices. High DEX concentration (3.0 microM) increased basal release of Glu, but not GABA, in CPEE foetal hippocampal slices. GR, but not MR, mRNA expression was elevated in the hippocampus and dentate gyrus, whereas NR1 mRNA expression was increased in the CA1 and CA3 fields of the foetal hippocampus. These data demonstrate that CPEE increases high glucocorticoid concentration-induced Glu release in the foetal hippocampus, presumably as a consequence of increased GR expression. These effects of CPEE, coupled with increased glutamate release and increased NMDA receptor expression, may predispose the near-term foetal hippocampus to GR and Glu-NMDA receptor-mediated neurodevelopmental toxicity.

Adrenocorticotropic Hormone↗

PubMed2005

Chronic prenatal ethanol exposure increases apoptosis in the hippocampus of the term fetal guinea pig.

It is hypothesized that chronic prenatal ethanol exposure (CPEE), via maternal ethanol administration, increases mitochondrial-directed apoptosis in the hippocampus of the term fetus that precedes loss of hippocampal CA1 pyramidal cells. To test this hypothesis, timed pregnant guinea pigs received chronic oral administration of: 4 g ethanol/kg maternal body weight/day, isocaloric-sucrose/pair-feeding or water throughout gestation. At gestational day 65 (term fetus) and postnatal day 0 (neonate), individual offspring were euthanized, and the brain was excised and dissected. CPEE, compared with the isocaloric-sucrose/pair-fed and water control groups, decreased the brain weight of the term fetus and neonate. CPEE did not alter the density of CA1 pyramidal cells in the hippocampus of the term fetus and neonate. In the term fetus, CPEE increased cytochrome c content in the cytosolic fraction of the hippocampus, altered the mitochondrial localization of cytochrome c in cells of the dorsal hippocampus, and increased the percentage of cells in the dorsal hippocampus containing activated caspase-3 and cleaved poly(ADP-ribose) polymerase. The data indicate that CPEE increases neuroapoptosis in the hippocampus of term fetus, which appears to occur via an intrinsic, mitochondrial-directed mechanism initiated by leakage of pro-apoptotic cytochrome c from mitochondria into the cytoplasm.

Animals↗

PubMed2005

Chronic prenatal ethanol exposure alters glucocorticoid signalling in the hippocampus of the postnatal Guinea pig.

The present study tested the hypothesis that chronic prenatal ethanol exposure causes long-lasting changes in glucocorticoid signalling in postnatal offspring. Pregnant guinea pigs were treated with ethanol (4 g/kg maternal body weight/day), isocaloric-sucrose/pair-feeding or water throughout gestation, and maternal saliva cortisol concentration was determined 2 h after treatment at different stages of gestation. Electrically-stimulated release of glutamate and GABA, in the presence or absence of dexamethasone, as well as glucocorticoid and mineralocorticoid receptor mRNA expression, was determined in the hippocampus and prefrontal cortex of adult offspring of treated pregnant guinea pigs. Maternal saliva cortisol concentration increased throughout pregnancy, which was associated with increased foetal plasma and amniotic fluid cortisol concentration. Ethanol administration to pregnant guinea pigs increased maternal saliva cortisol concentration during early and mid-gestation. In late gestation, ethanol administration did not increase saliva cortisol concentration above that induced by pregnancy. Chronic prenatal ethanol exposure had no effect on stimulated glutamate or GABA release, but selectively prevented dexamethasone-mediated suppression of stimulated glutamate release, and decreased expression of mineralocorticoid, but not glucocorticoid, receptor mRNA in the hippocampus of adult offspring. These data indicate that maternal ethanol administration leads to excessively increased maternal cortisol concentration that can impact negatively the developing foetal brain, leading to persistent postnatal deficits in glucocorticoid regulation of glutamate signalling in the adult hippocampus.

Amniotic Fluid↗

PubMed2004

Chronic prenatal ethanol exposure alters hippocampal GABA(A) receptors and impairs spatial learning in the guinea pig.

Chronic prenatal ethanol exposure (CPEE) can injure the developing brain, and may lead to the fetal alcohol syndrome (FAS). Previous studies have demonstrated that CPEE upregulates gamma-aminobutyric acid type A (GABA(A)) receptor expression in the cerebral cortex, and decreases functional synaptic plasticity in the hippocampus, in the adult guinea pig. This study tested the hypothesis that CPEE increases GABA(A) receptor expression in the hippocampus of guinea pig offspring that exhibit cognitive deficits in a hippocampal-dependent spatial learning task. Timed, pregnant guinea pigs were treated with ethanol (4 g/kg maternal body weight per day), isocaloric-sucrose/pair-feeding, or water throughout gestation. GABA(A) receptor subunit protein expression in the hippocampus was measured at two development ages: near-term fetus and young adult. In young adult guinea pig offspring, CPEE increased spontaneous locomotor activity in the open-field and impaired task acquisition in the Morris water maze. CPEE did not change GABA(A) receptor subunit protein expression in the near-term fetal hippocampus, but increased expression of the beta2/3-subunit of the GABA(A) receptor in the hippocampus of young adult offspring. CPEE did not change either [(3)H]flunitrazepam binding or GABA potentiation of [(3)H]flunitrazepam binding, but decreased the efficacy of allopregnanolone potentiation of [(3)H]flunitrazepam binding, to hippocampal GABA(A) receptors in adult offspring. Correlational analysis revealed a relationship between increased spontaneous locomotor activity and growth restriction in the hippocampus induced by CPEE. Similarly, an inverse relationship was found between performance in the water maze and the efficacy of allopregnanolone potentiation of [(3)H]flunitrazepam binding in the hippocampus. These data suggest that alterations in hippocampal GABA(A) receptor expression and pharmacological properties contribute to hippocampal-related behavioral and cognitive deficits associated with CPEE.

Animals↗

PubMed2003

Chronic prenatal ethanol exposure impairs conditioned responding and enhances GABA release in the hippocampus of the adult guinea pig.

In this study, we assessed the effects of chronic prenatal ethanol exposure (CPEE) on spatial navigation in the water maze, conditioned responding using food-reinforced lever pressing, and amino acid neurotransmitter release from the hippocampus of the adult guinea pig. Pregnant guinea pigs were treated with ethanol (3 g/kg of maternal body weight/day), isocaloric-sucrose/pair-feeding, or water throughout gestation. Adult offspring were trained in two-lever operant chambers to respond for sucrose pellets, with one lever designated as the reward lever. There were no group differences in response acquisition or lever discrimination on a fixed-ratio 1 (FR-1) schedule. During extinction sessions, CPEE offspring maintained higher levels of responding on the previously reinforced lever, suggesting that CPEE increases perseveration and/or impairs response inhibition but does not affect operant responding for an appetitive reinforcer or the ability to discriminate rewarding from nonrewarding stimuli. In contrast, there was no effect of CPEE on performance in the water maze in the maternal ethanol regimen used in this study. CPEE did not alter electrically evoked glutamate or GABA release from hippocampal brain slices. However, when slices were tested after delivery of a tetanizing stimulation (five 5-s trains at 100 Hz), post-tetanic potentiation of electrically stimulated GABA release was greater in hippocampal slices obtained from CPEE offspring, whereas post-tetanic potentiation of electrically stimulated glutamate release was unaffected. These data suggest that conditioned learning is a sensitive behavioral measure of CPEE-induced brain injury. Increased activity-dependent potentiation of GABA release in the hippocampus may contribute to alterations in synaptic plasticity observed in CPEE offspring.

Animals↗

PubMed2002

Impaired acquisition in the water maze and hippocampal long-term potentiation after chronic prenatal ethanol exposure in the guinea-pig.

In the hippocampus, the CA1 region is selectively vulnerable to the effects of chronic prenatal ethanol exposure. In the guinea-pig, the number of CA1 pyramidal cells is decreased after chronic prenatal ethanol exposure. We tested the hypotheses that chronic prenatal ethanol exposure (through maternal ethanol ingestion) results in impairments in spatial learning and short- and long-term plasticity in the CA1 region of the postnatal guinea-pig hippocampus. Timed, pregnant guinea-pigs were treated with ethanol (4 g/kg maternal body weight/day), isocaloric sucrose/pair-feeding, or water throughout gestation. Offspring were studied between postnatal days 40 and 80. In the Morris water maze, animals exposed to ethanol prenatally showed slower acquisition of an escape response to a hidden platform over 5 days of training. The amplitude of the field excitatory postsynaptic potential in the CA1 region in response to contralateral CA3 stimulation was decreased in offspring exposed to ethanol prenatally. Two forms of short-term plasticity (paired-pulse and frequency facilitation) were unaffected by chronic prenatal ethanol exposure. Long-term potentiation (LTP) in response to high-frequency CA3 stimulation was induced reliably and maintained over 60 min in isocaloric-sucrose and water control animals. However, LTP failed to be induced in the CA1 area of the hippocampus in prenatal ethanol-exposed offspring. These data show that chronic prenatal ethanol exposure, through maternal ethanol administration, impairs spatial performance and LTP in CA1 neurons. Hippocampal dysfunction could contribute importantly to the cognitive and behavioural deficits resulting from chronic prenatal ethanol exposure.

Alcohol-Induced Disorders, Nervous System↗

PubMed2001

Spatial learning in the guinea pig: cued versus non-cued learning, sex differences, and comparison with rats.

This paper provides the first report of spatial learning in guinea pigs using the Morris water maze (MWM). Male and female guinea pigs were trained for 5 consecutive days (8 trials/day; acquisition phase) in either the visible (cued) or the hidden (non-cued) platform version of the MWM. In both tests, guinea pigs learned to navigate to the escape platform, as indicated by a decrease in escape latency over the 5 training days. There were no sex differences in either test version. A comparison of guinea pigs and male Wistar rats showed that performance during acquisition training was not different for the two species in the visible platform test, but rats performed better during the early training days in the hidden platform test. A retention test (probe trial) was given 5 days after the last acquisition training day. Again, there was no sex difference, and no difference between guinea pigs and rats. Finally, acquisition of a new escape response to a shifted platform location was equivalent for rats and guinea pigs of both sexes. These results demonstrate that guinea pigs show robust cued and non-cued learning in the MWM. Both acquisition and retention performance in guinea pigs is similar to that in rats, even though rats appear to have a slight advantage in the acquisition of non-cued, spatial information in this test. We conclude that the MWM provides a valuable paradigm to assess behavior and learning/memory in the guinea pig.

Animals↗

PubMed2001

A cellular mechanism of reward-related learning.

Positive reinforcement helps to control the acquisition of learned behaviours. Here we report a cellular mechanism in the brain that may underlie the behavioural effects of positive reinforcement. We used intracranial self-stimulation (ICSS) as a model of reinforcement learning, in which each rat learns to press a lever that applies reinforcing electrical stimulation to its own substantia nigra. The outputs from neurons of the substantia nigra terminate on neurons in the striatum in close proximity to inputs from the cerebral cortex on the same striatal neurons. We measured the effect of substantia nigra stimulation on these inputs from the cortex to striatal neurons and also on how quickly the rats learned to press the lever. We found that stimulation of the substantia nigra (with the optimal parameters for lever-pressing behaviour) induced potentiation of synapses between the cortex and the striatum, which required activation of dopamine receptors. The degree of potentiation within ten minutes of the ICSS trains was correlated with the time taken by the rats to learn ICSS behaviour. We propose that stimulation of the substantia nigra when the lever is pressed induces a similar potentiation of cortical inputs to the striatum, positively reinforcing the learning of the behaviour by the rats.

Animals↗

PubMed2001

Chronic prenatal ethanol exposure increases GABA(A) receptor subunit protein expression in the adult guinea pig cerebral cortex.

Excessive consumption of ethanol during pregnancy can produce teratogenic effects in offspring and is the leading cause of mental deficiency in the Western world. The objective of this study was to examine the effects of chronic prenatal ethanol exposure on the number of GABA(A) receptors and relative protein levels for GABA(A) receptor alpha1 and beta2/3 subunits in the adult guinea pig cerebral cortex. Timed pregnant Dunkin-Hartley strain guinea pigs were given one of the following oral treatments daily throughout gestation: 4 gm of ethanol per kilogram of maternal body weight, isocaloric-sucrose with pair feeding, or isovolumetric water with ad libitum access to food. The ethanol treatment resulted in a peak maternal blood ethanol concentration of 328 +/- 55 mg/dl (71.3 +/- 12.0 mm) on gestational day 57 (term, approximately 68 d). Chronic prenatal exposure to ethanol resulted in increased spontaneous locomotor activity throughout development and decreased cerebral cortical weight in adult offspring. The number of cerebral cortical [(3)H]muscimol binding sites was increased in adult offspring from the ethanol treatment group, and there was a corresponding increase in the amount of GABA(A) receptor alpha1 and beta2/3 subunit proteins in these same animals. For individual offspring, there were correlations between locomotor activity and cerebral cortical weight, as well as between cerebral cortical weight and GABA(A) receptor neurochemistry. There was no effect of chronic prenatal ethanol exposure on [(3)H]MK-801 binding in this tissue. These data demonstrate that chronic prenatal ethanol exposure has long-term consequences on the regulation of GABA(A) receptor expression in the cerebral cortex.

Administration, Oral↗

PubMed2001

In vitro ethanol exposure decreases potassium-stimulated, but not veratridine-stimulated, glutamate release in the guinea pig hippocampus.

In this study we determined the effect of in vitro ethanol exposure on stimulated glutamate release in transverse hippocampal slices (400-microm thickness) of the young postnatal guinea pig (PD 12) by using two chemical stimuli with different mechanisms of action. Ethanol (50 mM) decreased K+ (45 mM)-, but not veratridine (10 microM)-, stimulated glutamate release. The study findings demonstrate that in vitro ethanol exposure produces differential inhibition of stimulated glutamate release in the hippocampus, dependent on the stimulating agent.

Animals↗

PubMed2001

Positive allosteric modulators of AMPA receptors reduce proton-induced receptor desensitization in rat hippocampal neurons.

Whole-cell or outside-out patch recordings were used to investigate the effects of protons and positive modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors on the desensitization of glutamate-evoked AMPA receptor currents in isolated hippocampal CA1 neurons. Protons inhibited glutamate-evoked currents (IC(50) of 6.2 pH units) but also enhanced the apparent rate and extent of AMPA receptor desensitization. The proton-induced enhancement of desensitization could not be attributed to a reduction in the rate of recovery from desensitization or to a change in the kinetics of deactivation. Non-stationary variance analysis indicated that protons reduced maximum open probability without changing the conductance of AMPA channels. The positive modulators of AMPA receptor desensitization, cyclothiazide and GT-21-005 (an organic nitrate), reduced the proton sensitivity of AMPA receptor desensitization, which suggests that they interact with protons to diminish desensitization. In contrast, the effects of wheat germ agglutinin and aniracetam on AMPA receptor desensitization were independent of pH. These results demonstrate that a reduction in the proton sensitivity of receptor desensitization contributes to the mechanism of action of some positive modulators of AMPA receptors.

Allosteric Regulation↗

PubMed2001

Modulation of AMPA receptors by a novel organic nitrate.

Positive modulators of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) channels reduce desensitization and alter their gating kinetics. We have discovered a novel compound nitric oxide-mimetic that similarly modulates the AMPA receptor by reducing desensitization. This, designated GT-005, belongs to the organic nitrate family that includes the nitrovasodilator nitroglycerine. In acutely isolated hippocampal neurons, GT-005 enhanced kainate (100 microM)-evoked currents with an EC50 of 1.7+/-0.2 mM and a 176+/-10% maximal increase in the steady-state current response. Similar results were found in cultured hippocampal neurons (EC50 of 1.3+/-0.2 mM and a maximal 83+/-14% increase in the steady-state current response). GT-005 reduced the desensitization of glutamate-evoked currents and slowed the onset of desensitization. This compound also increased the rate of recovery from the desensitized state. With respect to alteration of the excitatory synaptic transmission, GT-005 delayed the decay and increased the frequency of spontaneous miniature excitatory postsynaptic currents (mepsc) recorded in cultured hippocampal neurons.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed2000

A novel nitrate ester reverses the cognitive impairment caused by scopolamine in the Morris water maze.

The objective of this study was to test the hypothesis that activation of soluble guanylyl cyclase and increased cGMP formation in the brain would improve task acquisition in cognitively impaired animals. We evaluated the effects of a novel nitrate ester, GT 715 (2,3-dinitrooxy-(2,3-bis-nitrooxypropyldisulfanyl)-propane), in scopolamine-induced impairment of task acquisition in the Morris water maze. GT 715 improved task acquisition in scopolamine-pretreated animals in a time- and dose-dependent manner, whereas the prototypical nitrate ester, glyceryl trinitrate (GTN), was ineffective. GT 715 also was more effective and more potent than GTN for activation of hippocampal guanylyl cyclase. The results of this study therefore suggest that stimulation of cerebral soluble guanylyl cyclase activity may be an effective strategy to improve learning and memory performance in individuals in whom cognitive abilities are impaired by injury, disease, or ageing.

Animals↗

PubMed2000

Substantia nigra dopamine regulates synaptic plasticity and membrane potential fluctuations in the rat neostriatum, in vivo.

The spiny projection neurons of the neostriatum are a site at which dopamine inputs from the substantia nigra converge with excitatory inputs from the cerebral cortex. These two systems interact in certain learning and motor control mechanisms of the brain. We investigated these interactions using intracellular recording from spiny striatal neurons in urethane-anaesthetized rats. We found that acute dopamine depletion was associated with long-term depression of corticostriatal synaptic input. Electrical stimulation of the cortex which mimicked synchronous cortical input to striatal neurons also induced long-term depression of corticostriatal inputs. In intact control animals, but not in dopamine-depleted animals, this depression was prevented or reversed by concomitant stimulation of the substantia nigra. In agreement with previous in vitro studies, our in vivo findings show that long-term depression occurs in the corticostriatal pathway, and in addition show that it is regulated by dopaminergic inputs from the substantia nigra. This form of synaptic plasticity may therefore be important for understanding disturbances of the motor system seen in humans with Parkinson's disease.

Animals↗

PubMed2000

Effects of chronic prenatal ethanol exposure on hippocampal glutamate release in the postnatal guinea pig.

This study was designed to test the hypothesis that chronic prenatal ethanol exposure decreases basal and stimulated L-glutamate release in the hippocampus of young, postnatal guinea pigs. Timed, pregnant guinea pigs were randomly assigned to one of the following three chronic treatment groups: 4 g ethanol/kg maternal body weight/day, isocaloric-sucrose and pair-feeding to the ethanol group, and water. Each oral treatment was given daily throughout gestation. Spontaneous locomotor activity was increased on postnatal day (PD) 10, and brain and hippocampal weights were decreased on PD 12 in the offspring of the ethanol group compared with the isocaloric-sucrose/pair-fed and water groups. On PD 12, the 45 mM K(+)- and 10 microM veratridine-stimulated release of glutamate in transverse hippocampal slices was decreased in the ethanol group compared with the two control groups. This alteration in glutamate release produced by chronic prenatal ethanol exposure may decrease the efficiency of excitatory synaptic transmission in the hippocampus during postnatal life.

Animals↗

PubMed1999

Ontogeny of nitric oxide synthase I and III protein expression and enzymatic activity in the guinea pig hippocampus.

60. NOS enzymatic activity increased throughout prenatal and postnatal life, and attained highest activity in the adult. The developmental profile of NOS III protein expression was similar to that for NOS enzymatic activity. There was differential expression of NOS I protein, which was low in the GD 50 fetus and increased rapidly during fetal development to attain adult level by GD 62. These data suggest that the guinea pig is a reliable animal model in which to investigate the roles of NO in normal hippocampal development and in mediating neuronal injury in this brain region.

Animals↗

PubMed1999

Neurosteroid modulation of the GABAA receptor in the developing guinea pig cerebral cortex.

Developmental changes in 5alpha-pregnan-3alpha-ol-20-one (allopregnanolone; 5alpha-3alpha-P) potentiation of muscimol and benzodiazepine binding to the GABAA receptor were studied in the guinea pig cerebral cortex at three prenatal ages (gestational day (GD) 40, GD 50, GD 62), and three postnatal ages (postnatal day (PD) 11, PD 21, PD 61) (term, about GD 68). The number and affinity of [3H]flunitrazepam binding sites, and 5alpha-3alpha-P potentiation of [3H]muscimol and [3H]flunitrazepam binding to the GABAA receptor were determined at each age. There was no age effect on the affinity (Kd) for [3H]flunitrazepam. However, the number (Bmax) of [3H]flunitrazepam binding sites doubled between GD 40 and GD 62, and then declined slightly to reach adult levels by PD 11. 5alpha-3alpha-P produced a concentration-dependent potentiation of [3H]muscimol and [3H]flunitrazepam binding at each developmental age examined. The potency (high-affinity) for 5alpha-3alpha-P potentiation of both [3H]muscimol and [3H]flunitrazepam binding was lowest at GD 40, and increased to adult levels by GD 62. In contrast, the efficacy for 5alpha-3alpha-P potentiation of both [3H]muscimol and [3H]flunitrazepam binding was greatest at GD 40, and decreased to adult levels between GD 50 and GD 62. The percentage of high-affinity zolpidem binding sites increased in an age-dependent manner from 34.2+/-2.2% at GD 40, to reach adult levels by GD 62 (59. 4+/-2.5%). These data suggest that 5alpha-3alpha-P can modulate GABAA receptors in the immature cerebral cortex, and that changes in 5alpha-3alpha-P action are temporally related to changes in GABAA receptor benzodiazepine pharmacology late in gestation in the guinea pig.

Animals↗