Cognitive function modulation during aging: a focus on L-alpha-GPE.

OBJECTIVE: The objectives of this review are to explore the neuronal pathways and cellular and molecular mechanisms involved in both healthy and impaired cognitive function and to discuss the role of nootropics, in particular, those with cholinergic activity, as promising interventions to preserve and/or improve cognitive performance in patients in the symptomatic pre-dementia stage, known as mild cognitive impairment (MCI). MATERIALS AND METHODS: Papers were retrieved by a PubMed search, using different combinations of keywords (e.g., cognitive function AND aging AND nootropics), without limitations in terms of publication date or language. RESULTS: Nootropics modulate the activities of specific brain pathways involving neurotransmitters and neuromodulators that have distinct roles in the cognitive processes. The nootropic L-a-glyceryl-phosphoryl-ethanolamine (L-a GPE), by virtue of its action as a phospholipid (PL) precursor and acetylcholine (Ach) donor, targets neural stem cell aging, cholinergic depletion, oxidative stress and microglia activation, loss of entorhinal cortex neurons, and reduced hippocampal volume. Cognitive reserve levels may be linked to the resilience and adaptability of the brain to cope with age-related cognitive decline. L-a GPE may contribute to cognitive reserve preservation via its neuronal well-being promoting action. CONCLUSIONS: The substantial burden of age-related cognitive decline demands effective long-term and well-tolerated interventions aimed at maximizing the span of effective functioning. The use of inappropriate medication may lower cognitive reserve, thus hastening the onset of symptomatic AD, while the use of nootropics, such as L-a GPE may contribute to cognitive reserve preservation via its neuronal well-being promoting action.

Treatment with gut bifidobacteria improves hippocampal plasticity and cognitive behavior in adult healthy rats.

At the present time, gut microbiota inspires great interest in the field of neuroscience as a function of its role in normal physiology and involvement in brain function. This aspect suggests a specific gut-brain pathway, mainly modulated by gut microbiota activity. Among the multiple actions controlled by microbiota at the brain level, neuronal plasticity and cognitive function represent two of the most interesting aspects of this cross-talk communication. We address the possible action of two-months implementation of gut Bifidobacteria using a mixture of three different strains (B-MIX) on hippocampal plasticity and related cognitive behavior in adult healthy Sprague Dawley rats. B-MIX treatment increases the hippocampal BDNF with a parallel gain in dendritic spines' density of hippocampal CA1 pyramidal neurons. Electrophysiological experiments revealed a significant increment of HFS-induced LTP formation on the CA1 hippocampal region in B-MIX treated rats. All these effects are accompanied by a better cognitive performance observed in B-MIX treated animals with no impairments in locomotion activity. Therefore, in adult rats, the treatment with different strains of bifidobacteria is able to markedly enhance neuronal plasticity and the CNS function influencing cognitive behavior, an effect that may suggest a potential therapeutic treatment in brain diseases associated with cognitive functions.

Social enrichment reverses the isolation-induced deficits of neuronal plasticity in the hippocampus of male rats.

Environmental enrichment is known to improve brain plasticity and protect synaptic function from negative insults. In the present study we used the exposure to social enrichment to ameliorate the negative effect observed in post weaning isolated male rats in which neurotrophic factors, neurogenesis, neuronal dendritic trees and spines were altered markedly in the hippocampus. After the 4 weeks of post-weaning social isolation followed by 4 weeks of reunion, different neuronal growth markers as well as neuronal morphology were evaluated using different experimental approaches. Social enrichment restored the reduction of BDNF, NGF and Arc gene expression in the whole hippocampus of social isolated rats. This effect was paralleled by an increase in density and morphology of dendritic spines, as well as in neuronal tree arborisation in granule cells of the dentate gyrus. These changes were associated with a marked increase in neuronal proliferation and neurogenesis in the same hippocampal subregion that were reduced by social isolation stress. These results further suggest that the exposure to social enrichment, by abolishing the negative effect of social isolation stress on hippocampal plasticity, may improve neuronal resilience with a beneficial effect on cognitive function.

Morphology, Morphometry and Spatial Distribution of Secondary Osteons in Equine Femur.

A high number of differences exist in bone histological features depending on the species, breed, age and bone. Moreover, osteon distribution may vary in the different sides of a bone as a consequence of different biomechanical strains. The aim of this work was to study the distribution and morphology of osteons in different sides of the equine femoral diaphysis with the attempt to correlate them to the main strains operating on them. The following parameters of secondary osteons and Haversian canals were measured in the transverse sections of diaphyses: perimeter, area, minimum and maximum diameter, eccentricity and osteon population density. A typical Haversian tissue was observed with elliptic secondary osteons consisting in about 10 well-defined lamellae surrounding a circular Haversian canal. Quantitative analysis displays a different population density of secondary osteons depending on the side. The caudal and medial sides, where compression strains are higher, have more secondary osteons in comparison with the cranial and lateral sides, where tension strains are prevalent. These data suggest that secondary osteon population density may depend on the predominant strains. Even the elliptical shape of secondary osteons may be related to biomechanical strains, as their major axes are oriented cranio-caudally parallel to prevalent strains.

Italian Study on Depressive Disorders (STudio Italiano MAlattia Depressiva, or STIMA-D): a nationwide snapshot of the status of treatment for major depression.

INTRODUCTION: Major depression is a worldwide problem and often remains undetected and untreated. Given the low rates of detection plus the need to intervene in a short time, it is important to identify factors which are likely to improve treatment outcomes. METHODS: STIMA-D was designed to provide the profile of patients with major depression in Italy (focusing on pathway to care, patient characteristics, drug therapy and treatment outcomes). The patients enrolled (M/F, aged between 18 and 65) experienced single/multiple episodes of major depression (DSM-IV-TR). Patients with lifetime or current bipolar syndrome or other mental disorders were excluded. RESULTS: 44 of the 50 invited centers sent data concerning 1 140 patients. The majority of patients were women. Among working individuals, 52.5% of them were absent from work due to depression in the previous 6 months. Recurrent episodes of major depression were very common and were associated with persistence of residual post-episodic symptoms, a family history of mood disorders and presence of anxiety. 59.6% of the patients were treated with monotherapy (SSRI or SNRI), while 19.2% of them were treated with SSRI plus SNRI. Only the 25.5% on monotherapy had a complete response compared to 12.4% of patients on dual therapy. DISCUSSION: Poor outcomes in major depression have profound implications on patients' quality of life and cost burden. New pharmacological approaches with novel modes of action are therefore urgently needed.

Brain excitatory/inhibitory circuits cross-talking with chromogranin A during hypertensive and hibernating states.

To date, many scientific attempts have been directed towards the development of experimental models for the identification of neuronal mechanisms evoking cardiovascular and hemodynamic dysfunctions. The spontaneously hypertensive rat (SHR), a genetic model of essential hypertension, has become a valuable rodent for the characterization of molecular markers in hypertensive-related diseases. Recently, growing interests have also been directed to a new experimental paradigm i.e. hibernation, a physiological state consenting the hamster (Mesocricetus auratus) to activate protective mechanisms against ischemic-like complications during the arousal phase. With this intention, the present review will focus attention on specific neurosignaling systems involved with the preservation of hemodynamic conditions in those brain areas that play a pivotal role on such a feature. It is widely known that healthy neurons conserve their structural and responsiveness properties in presence of a constant blood supply, which is assured by their coupling to microvessels and perivascular astrocytes as well as by secretory proteins such as chromogranin A (CgA). So, it will be interesting to establish if this protein alone or with the participation of excitatory/inhibitory neurosignals is capable of influencing some brain areas controlling cardiovascular conditions in both SHRs and hibernating hamsters. In this context, the present work will deliver the most important findings regarding neuronal CgA and its cross-talking ability with major inhibitory (GABA/adenosine) and/or excitatory (glutamate) neuroreceptor systems in relation to hypertensive/hypotensive states of both animal models. Indications deriving from such approaches may provide clinically useful insights regarding their role as protective factors of hemodynamic and neurological disorders.

Enhanced expression of the neuronal K+/Cl- cotransporter, KCC2, in spontaneously depressed Flinders Sensitive Line rats.

We used Flinder Sensitive Line (FSL) rats, a genetic model of unipolar depression, to examine whether changes in central GABAergic transmission are associated with a depressed phenotype. FSL rats showed an increased behavioral response to low doses of diazepam, as compared to either Sprague Dawley (SD) or Flinder Resistant Line (FRL) rats used as controls. Diazepam at a dose of 0.3 mg/kg, i.p., induced a robust impairment of motor coordination in FSL rats, but was virtually inactive in SD or FRL rats. The increased responsiveness of FSL rats was not due to changes in the brain levels of diazepam or its active metabolites, or to increases in the number or affinity of benzodiazepine recognition sites, as shown by the analysis of [(3)H]-flunitrazepam binding in the hippocampus, cerebral cortex or cerebellum. We therefore examined whether FSL rats differed from control rats for the expression levels of the K(+)/Cl(-) cotransporter, KCC2, which transports Cl(-) ions out of neurons, thus creating the concentration gradient that allows Cl(-) influx through the anion channel associated with GABA(A) receptors. Combined immunoblot and immunohistochemical data showed a widespread increase in KCC2 expression in FSL rats, as compared with control rats. The increase was more prominent in the cerebellum, where KCC2 was largely expressed in the granular layer. These data raise the interesting possibility that a spontaneous depressive state in animals is associated with an amplified GABAergic transmission in the CNS resulting from an enhanced expression of KCC2.

Isoniazid-induced reduction in GABAergic neurotransmission alters the function of the cerebellar cortical circuit.

The cerebellar cortex contributes to the control of movement, coordination, and certain cognitive functions. The cerebellar network is composed of five different types of neurons that are wired together in a repetitive module. Given that four of these five neurons synthesize and release GABA, this inhibitory neurotransmitter plays a central role in regulation of the excitability and correct functioning of the cerebellar cortex. We have now used isoniazid, an inhibitor of glutamic acid decarboxylase, the enzyme responsible for the synthesis of GABA, to evaluate the contribution of GABAergic transmission in different types of cerebellar cortical neurons to the functioning of the cerebellar circuit. Parasagittal cerebellar slices were prepared from 28- to 40-day-old male rats and were subjected to patch-clamp recording in the voltage- or current-clamp mode. Exposure of the tissue slices to isoniazid (10 mM) resulted in a decrease in the level of GABAergic transmission in Purkinje cells and a consequent increase in the firing rate of spontaneous action potentials that was apparent after 40 min. In granule neurons, isoniazid reduced both tonic and phasic GABAergic currents and thereby altered the flow of information across the cerebellar cortex. Our data support the notion that the amount of GABA at the synaptic level is a major determinant of the excitability of the cerebellar cortex, and they suggest that isoniazid may be a useful tool with which to study the function of the cerebellar network.

Social isolation stress and neuroactive steroids.

Social isolation of rats immediately after weaning is associated to a reduction in the cerebrocortical and plasma concentrations of progesterone and its metabolites 3alpha,5alpha-TH PROG and 3alpha,5alpha-THDOC. Although we found that the basal plasma concentration of adrenocorticotropic hormone in isolated rats was slightly decreased compared with that in group-housed animals no other significant changes were found in the steroidogenic machinery (peripheral benzodiazepine receptors, steroidogenic regulatory protein (StAR)). However, the functional response of the hypothalamic-pituitary-adrenal axis HPA axis to an acute stressful stimulus (foot shock), or to an acute injection of ethanol or isoniazid is markedly increased in isolated rats. Behavioral studies have also indicated that the ability of ethanol to inhibit isoniazid-induced convulsions is greater in isolated rats than in group-housed animals and this effect of isolation is prevented by treatment with the 5alpha-reductase inhibitor finasteride. Social isolation modified the effects of ethanol on the amounts of StAR mRNA and protein in the brain suggesting an alteration in the mechanism of cholesterol transport in mitochondria. Moreover, the amounts of the alpha4 and delta subunits of the GABA(A) receptor in the hippocampus were increased in isolated rats, and these effects were accompanied by an increase in GABA(A) receptor-mediated tonic inhibitory currents in granule cells of the dentate gyrus. Ethanol also increased the amplitude of GABA(A) receptor-mediated miniature inhibitory postsynaptic currents (mIPSC) recorded from CA1 pyramidal neurons with a greater potency in hippocampal slices prepared from socially isolated rats than in those from group-housed, an effect inhibited by finasteride.

Increase in 20-50 Hz (gamma frequencies) power spectrum and synchronization after chronic vagal nerve stimulation.

OBJECTIVE: Though vagus nerve stimulation (VNS) is an important option in pharmaco-resistant epilepsy, its mechanism of action remains unclear. The observation that VNS desynchronised the EEG activity in animals suggested that this mechanism could be involved in VNS antiepileptic effects in humans. Indeed VNS decreases spiking bursts, whereas its effects on the EEG background remain uncertain. The objective of the present study is to investigate how VNS affects local and inter regional syncronization in different frequencies in pharmaco-resistant partial epilepsy. METHODS: Digital recordings acquired in 11 epileptic subjects 1 year and 1 week before VNS surgery were compared with that obtained 1 month and 1 year after VNS activation. Power spectrum and synchronization were then analyzed and compared with an epileptic group of 10 patients treated with AEDs only. RESULTS: VNS decreases the synchronization of theta frequencies (P < 0.01), whereas it increases gamma power spectrum and synchronization (< 0.001 and 0.01, respectively). CONCLUSIONS: The reduction of theta frequencies and the increase in power spectrum and synchronization of gamma bands can be related to VNS anticonvulsant mechanism. In addition, gamma modulation could also play a seizure-independent role in improving attentional performances. SIGNIFICANCE: These results suggest that some antiepileptic mechanisms affected by VNS can be modulated by or be the reflection of EEG changes.

Social isolation-induced changes in the hypothalamic-pituitary-adrenal axis in the rat.

Social isolation of rats both reduces the cerebrocortical and plasma concentrations of 3a-hydroxy-5a-pregnan-20-one (3a,5a-TH PROG) and 3a,5a-tetrahydrodeoxycorticosterone and potentiates the positive effects of acute stress and ethanol on the concentrations of these neuroactive steroids. We now show that social isolation decreased the plasma level of adrenocorticotropin (ACTH), moreover, intracerebroventricular administration of corticotropin releasing factor (CRF) induced a marked increase in the plasma corticosterone level in both isolated and group-housed rats, but this effect was significantly greater in the isolated rats (+121%) than in the group-housed rats (+86%). In addition, in isolated rats, a low dose of dexamethasone had no effect on the plasma corticosterone concentration, whereas, a high dose significantly reduced it; both doses of dexamethasone reduced plasma corticosterone in group-housed rats. Furthermore, the corticosterone level after injection of dexamethasone at the high dose was significantly greater in the isolated animals than in the group-housed rats. These results suggest that social isolation increased sensitivity of the pituitary to CRF and impaired negative feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis.

Valproic acid-hydrophilic cyclodextrin complexes and valproic acid-solid dispersions: evaluation of their potential pharmaceutical use.

The purpose of this study was to evaluate the potential use of two novel solid formulations of valproic acid (VPA) prepared by complexation with hydrophilic cyclodextrins (CDs) as hydroxypropyl-beta- and sulfobutylether-beta-cyclodextrin and by solid dispersion (SD) in hydrophilic carriers as polyethylene glycol 6000 (PEG 6000) and polyvinylpyrrolidone K-30 (PVP K-30). The corresponding cyclodextrin-based complexes were prepared by the freeze-drying method while the solid dispersions were obtained by the solvent method. Valproic acid solubility improved by CDs complexation and solid dispersion techniques. Comparison of dissolution profiles with that of VPA sodium salt (NaVP) was made by using release parameters such as dissolution efficiency, percent of drug dissolved after 60 min, and difference and similarity factors. Based on difference and similarity factors, it can be concluded that all the VPA formulations possess dissolution profiles essentially equivalent to those of NaVP at pH 6. However, this conclusion is not confirmed by using the analysis of variance (ANOVA) approach, indicating some significant differences between some SD-based formulations and NaVP at that pH value. Preliminary pharmacological studies in the pentylenetetrazole test in rats showed some important differences among the SD-based formulations, NaVP, and VPA as oil/water emulsion. Some implications and limitations of the investigated formulations are discussed.

Changes in GABAA receptor gamma 2 subunit gene expression induced by long-term administration of oral contraceptives in rats.

The effects of oral contraceptives (OCs) on neurosteroid concentrations were evaluated in female rats and women. In rats, ethynylestradiol and levonorgestrel (0.030 and 0.125 mg, respectively, subcutaneously) administered daily for 6 weeks reduced the concentrations of pregnenolone (-41%) progesterone (-74%) and allopregnanolone (-79%) in the cerebral cortex; the plasma concentrations of these steroids were also reduced but by smaller extents. OC administration for 3 months also reduced the serum concentrations of pregnenolone, progesterone and allopregnanolone in women. Chronic administration of OCs in rats increased the abundance of gamma-aminobutyric acid type A (GABA(A)) receptor gamma 2L and gamma 2S subunit mRNAs and the relative protein in the cerebral cortex, while the amounts of various alpha and beta subunit mRNAs were unaffected. Ovariectomy did not modify the effect of OCs administration on the concentrations of neurosteroids in the rat cerebral cortex (but not in the plasma) as well as on the GABA(A) receptor gene expression, suggesting a direct effect of OCs in brain. Finally, rats treated with OCs exhibited an anxiety-like behavior in the elevated plus-maze test. These results indicate that long-term treatment with OCs induced a persistent reduction in the concentrations of pregnenolone, progesterone and its GABA(A) receptor-active metabolite, allopregnanolone, both in rats and women. In rats this effect was associated with a plastic adaptation of GABA(A) receptor gene expression in the rat cerebral cortex.

Changes in GABA(A) receptor gene expression induced by withdrawal of, but not by long-term exposure to, zaleplon or zolpidem.

The effects of long-term treatment with and subsequent withdrawal of the two hypnotic drugs zaleplon and zolpidem on the abundance of gamma-aminobutyric acid type A (GABA(A)) receptor subunit mRNAs in cultured rat cerebellar granule cells were investigated. Incubation of neurons with either drug at a concentration of 10 microM for 5 days did not significantly affect the amounts of mRNAs encoding the alpha(1), alpha(4), beta(1), beta(2), beta(3), gamma(2)L, or gamma(2)S subunits. As expected, similar treatment with the nonselective benzodiazepine diazepam resulted in a decrease in the abundance of alpha(1), beta(2), gamma(2)L, and gamma(2)S subunit mRNAs as well as an increase in that of the beta(1) subunit mRNA. Withdrawal of zaleplon or zolpidem, like that of diazepam, induced a marked increase in the amount of the alpha(4) subunit mRNA. In addition, discontinuation of treatment with either hypnotic drug resulted in a decrease in the amounts of alpha(1), beta(2), gamma(2)L, and gamma(2)S subunit mRNAs as well as an increase in that of the beta(1) subunit mRNA. These effects of zaleplon and zolpidem on GABA(A) receptor gene expression are consistent with the reduced tolerance liability of these drugs, compared with that of diazepam, as well as with their ability to induce both physical dependence and withdrawal syndrome.

Role of allopregnanolone in regulation of GABA(A) receptor plasticity during long-term exposure to and withdrawal from progesterone.

Here we summarize recent data from our laboratory pertaining to the effects of fluctuations in the brain concentrations of the progesterone (PROG) metabolite allopregnanolone (3alpha,5alpha-TH PROG) on the expression and function of gamma-aminobutyric acid type A (GABA(A)) receptors. The effects of long-term exposure to progesterone and of its sudden withdrawal on the activity of GABA(A) receptors and on the abundance of receptor subunit mRNAs were examined in cultured rat cerebellar granule cells and cortical neurons. The effects of a persistent reduction in the brain concentration of 3alpha,5alpha-TH PROG on GABA(A) receptor function and gene expression were examined in vivo in rats subjected to long-term administration of oral contraceptives. Our results demonstrate that long-lasting changes in the exposure of GABA(A) receptors to this PROG metabolite induce marked effects on receptor structure and function. These effects of 3alpha,5alpha-TH PROG appear to be mediated through modulation of GABA(A) receptor signaling mechanisms that control the expression of specific receptor subunit genes. Furthermore, the specific outcomes of such signaling appear to differ among neurons derived from different regions of the brain. Neuroactive steroids such as 3alpha,5alpha-TH PROG might thus exert differential actions on GABA(A) receptor plasticity in distinct neuronal cell populations, likely accounting for some of the physiological effects induced by these compounds.

Binding of [3H]CB 34, a selective ligand for peripheral benzodiazepine receptors, to rat brain membranes.

The 2-phenyl-imidazo[1,2-a]pyridine derivative CB 34 is a ligand for peripheral benzodiazepine receptors. The binding of [3H]CB 34 to rat cerebrocortical membranes was characterized. Specific binding was rapid, reversible, saturable and of high affinity. Kinetic analysis yielded association and dissociation rate constants of 0.2x10(8) M(-1) min(-1) and 0.29 min(-1), respectively. Saturation binding experiments revealed a single class of binding sites with a total binding capacity of 188+/-8 fmol/mg protein and an apparent dissociation constant of 0.19+/-0.02 nM. Specific [3H]CB 34 binding was inhibited by ligands selective for peripheral benzodiazepine receptors, whereas, with the exception of flunitrazepam and diazepam, ligands for central benzodiazepine receptors were inactive. Of the brain regions examined, the density of the [3H]CB 34-binding sites was greatest in the hypothalamus and lowest in the cerebral cortex. [3H]CB 34 is thus a potent and selective ligand for peripheral benzodiazepine receptors and should be proven useful for studies of the roles of these receptors.

Opposite effects of short- versus long-term administration of fluoxetine on the concentrations of neuroactive steroids in rat plasma and brain.

RATIONALE: Recent preclinical and clinical studies have shown that selective serotonin re-uptake inhibitors modulate neurosteroid synthesis in an opposite manner. OBJECTIVES: The action of long-term administration of fluoxetine was investigated on the peripheral and central concentrations of 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-TH PROG) and 3alpha,5alpha-tetrahydrodeoxycorticosterone (of 3alpha,5alpha-TH DOC), progesterone, and pregnenolone in rats. We also investigated the effect of chronic treatment with fluoxetine on the foot-shock stress-induced increase in the plasma and brain concentrations of these steroids. METHODS: Fluoxetine was administered acutely (20 mg/kg) or chronically (10 mg/kg, once daily for 15 days). Steroids were extracted from plasma and brain, separated and purified by means of high-performance liquid chromatography, and quantified by means of radioimmunoassay. RESULTS: A single dose of fluoxetine (20 mg/kg, i.p.) induced in 20 min significant increases in the cerebral cortical and plasma concentrations of 3alpha,5alpha-TH PROG (+96% and +13%, respectively), 3alpha,5alpha-TH DOC (+129 and +31%, respectively), progesterone (+111 and +58%, respectively), and pregnenolone (+151 and +59%, respectively). In addition, the plasma concentration of corticosterone was also significantly increased (+24%) after acute administration of fluoxetine. In contrast, long-term administration of fluoxetine reduced the basal concentrations of these various steroids (ranging from -22 to -43%), measured 48 h after the last drug injection, in both brain and plasma. A challenge injection of fluoxetine (20 mg/kg, i.p.), however, was still able to increase the concentrations of steroids in both the brain and plasma of rats chronically treated with this drug. Acute foot-shock stress increased the cortical and plasma concentrations of steroids in rats chronically treated with fluoxetine to extents similar to those apparent in control rats. CONCLUSIONS: A repetitive increase in the brain concentrations of neuroactive steroids may contribute to the therapeutic action of fluoxetine.

GABAA-receptor plasticity during long-term exposure to and withdrawal from progesterone.

The subunit composition of native gamma-aminobutyric acid type A (GABAA) receptors is an important determinant of the role of these receptors in the physiological and pharmacological modulation of neuronal excitability and associated behavior. GABAA receptors containing the alpha 1 subunit mediate the sedative-hypnotic effects of benzodiazepines (Rudolph et al., 1999; McKernan et al., 2000), whereas the anxiolytic effects of these drugs are mediated by receptors that contain the alpha 2 subunit (Löw et al., 2000). In contrast, GABAA receptors containing the alpha 4 or alpha 6 subunits are insensitive to benzodiazepines (Barnard et al., 1998). Characterization of the functions of GABAA-receptors thus requires an understanding of the mechanisms by which the receptor subunit composition is regulated. The expression of specific GABAA-receptor subunit genes in neurons is affected by endogenous and pharmacological modulators of receptor function. The expression of GABAA-receptor subunit genes is thus regulated by neuroactive steroids both in vitro and in vivo. Such regulation occurs both during physiological conditions, such as pregnancy, and during pharmacologically induced conditions, such as pseudo-pregnancy and long-term treatment with steroid derivatives or anxiolytic-hypnotic drugs. Here, we summarize results obtained by our laboratory and by other groups pertaining to the effects of long-term exposure to, and subsequent withdrawal from, progesterone and its metabolite 3 alpha,5 alpha-tetrahydroprogesterone on both the expression of GABAA-receptor subunits and GABAA-receptor function.

Stress and neuroactive steroids.

The discovery that the endogenous steroid derivatives 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone, or 3 alpha,5 alpha-TH PROG) and 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (allotetrahydrodeoxycorticosterone, or 3 alpha,5 alpha-TH DOC) elicit marked anxiolytic and anti-stress effects and selectively facilitate gamma-aminobutyric acid (GABA)-mediated neurotransmission in the central nervous system (see Chapter 3) has provided new perspectives for our understanding of the physiology and neurobiology of stress and anxiety. Evidence indicating that various stressful conditions that downregulate GABAergic transmission and induce anxiety-like states (Biggio et al., 1990) also induce marked increases in the plasma and brain concentrations of these neuroactive steroids (Biggio et al., 1996, 2000) has led to the view that stress, neurosteroids, and the function of GABAA receptors are intimately related. Changes in the brain concentrations of neurosteroids may play an important role in the modulation of emotional state as well as in the homeostatic mechanisms that counteract the neuronal overexcitation elicited by acute stress. Indeed, neurosteroids not only interact directly with GABAA receptors but also regulate the expression of genes that encode subunits of this receptor complex. This chapter summarizes observations from our laboratories and others, suggesting that neurosteroids and GABAergic transmission are important contributors to the changes in emotional state induced by environmental stress.

Prevention of the stress-induced increase in frontal cortical dopamine efflux of freely moving rats by long-term treatment with antidepressant drugs.

Use of antidepressant drugs in the treatment of anxiety disorders has recently increased due to the anxiolytic effect of some of these agents. Because dopaminergic transmission in the prefrontal cortex is sensitive to anxiogenic or stressful stimuli, the effects of two antidepressant drugs with different mechanisms of action, imipramine and mirtazapine, on the response of rat cortical dopaminergic neurons to stress were investigated. A 2-week (but not single dose) administration of imipramine (10 mg/kg, i.p., twice daily) or mirtazapine (10 mg/kg, i.p., once daily) reduced and completely antagonized, respectively, the increase in dopamine release in the prefrontal cortex elicited by footshock stress. Long-term administration of imipramine or mirtazapine had no marked effect on the stress-induced increases in the brain or plasma concentrations of neuroactive steroids or corticosterone. An attenuation of the response of mesocortical dopaminergic neurons to stress induced by long-term treatment with antidepressants might contribute to the anxiolytic effects of such drugs.