BDNF-TrkB signaling through Erk1/2 MAPK phosphorylation mediates the enhancement of fear memory induced by glucocorticoids.

Activation of glucocorticoid receptors (GR) by glucocorticoid hormones (GC) enhances contextual fear memories through the activation of the Erk1/2(MAPK) signaling pathway. However, the molecular mechanism mediating this effect of GC remains unknown. Here we used complementary molecular and behavioral approaches in mice and rats and in genetically modified mice in which the GR was conditionally deleted (GR(NesCre)).

The enhancement of stress-related memory by glucocorticoids depends on synapsin-Ia/Ib.

The activation of glucocorticoid receptors (GR) by glucocorticoids increases stress-related memory through the activation of the MAPK signaling pathway and the downstream transcription factor Egr-1. Here, using converging in vitro and in vivo approaches, respectively, GR-expressing cell lines, culture of hippocampal neurons, and GR genetically modified mice (GR(NesCre)), we identified synapsin-Ia/Ib as one of the effectors of the glucocorticoid signaling cascade. Stress and glucocorticoid-induced activation of the GR modulate synapsin-Ia/Ib through two complementary mechanisms.

Transcriptional effects of glucocorticoid receptors in the dentate gyrus increase anxiety-related behaviors.

The Glucocorticoid Receptor (GR) is a transcription factor ubiquitously expressed in the brain. Activation of brain GRs by high levels of glucocorticoid (GC) hormones modifies a large variety of physiological and pathological-related behaviors. Unfortunately the specific cellular targets of GR-mediated behavioral effects of GC are still largely unknown.

In vivo evidence that constitutive activity of serotonin2C receptors in the medial prefrontal cortex participates in the control of dopamine release in the rat nucleus accumbens: differential effects of inverse agonist versus antagonist.

Control of the mesoaccumbens dopamine (DA) pathway by central serotonin(2C) receptors (5-HT(2C)Rs) involves different 5-HT(2C)R populations located within multiple brain areas. Here, using in vivo microdialysis in halothane-anesthetized rats, we assessed the role of medial prefrontal cortex (mPFC) 5-HT(2C)Rs in the control of basal and activated accumbal DA outflow, to identify the modalities of their recruitment and the role of 5-HT(2C)R constitutive activity. Intra-mPFC injection of the 5-HT(2C)R inverse agonist SB 206553 (0.

The MAPK pathway and Egr-1 mediate stress-related behavioral effects of glucocorticoids.

Many of the behavioral consequences of stress are mediated by the activation of the glucocorticoid receptor by stress-induced high levels of glucocorticoid hormones. To explore the molecular mechanisms of these effects, we combined in vivo and in vitro approaches. We analyzed mice carrying a brain-specific mutation (GR(NesCre)) in the glucocorticoid receptor gene (GR, also called Nr3c1) and cell lines that either express endogenous glucocorticoid receptor or carry a constitutively active form of the receptor (DeltaGR) that can be transiently induced.

The neurosteroid allopregnanolone increases dopamine release and dopaminergic response to morphine in the rat nucleus accumbens.

Neurosteroids are a subclass of steroids that can be synthesized in the central nervous system independently from peripheral sources. Clinical studies in humans have associated these hormones with depression and postpartum mood disorders. In rodents, allopregnanolone (AlloP) has been shown to have anxiolytic and rewarding properties.

Changes in extracellular dopamine induced by morphine and cocaine: crucial control by D2 receptors.

An increase of extracellular dopamine (DA) concentration is a major neurobiological substrate of the addictive properties of drugs of abuse. In this article we investigated the contribution of the DA D2 receptor (D2R) in the control of this response. Extracellular DA levels were measured in the striatum of mice lacking D2R expression (D2R-/-) by in vivo microdialysis after administration of the psychostimulant cocaine and the opioid morphine.

Influence of glucocorticoids on dopaminergic transmission in the rat dorsolateral striatum.

Glucocorticoid hormones exert strong influences on central neurotransmitter systems. In the present work, we examined the functional consequences of corticosterone suppression on the dopaminergic transmission in the dorsolateral striatum by studying the expression of Fos-like proteins and extracellular dopamine levels. Glucocorticoid hormones were suppressed by adrenalectomy, and the specificity of the effects assessed by restoring physiological plasmatic corticosterone concentrations.

Distinct functions of the two isoforms of dopamine D2 receptors.

Signalling through dopamine D2 receptors governs physiological functions related to locomotion, hormone production and drug abuse. D2 receptors are also known targets of antipsychotic drugs that are used to treat neuropsychiatric disorders such as schizophrenia. By a mechanism of alternative splicing, the D2 receptor gene encodes two molecularly distinct isoforms, D2S and D2L, previously thought to have the same function.

Vertical shifts in self-administration dose-response functions predict a drug-vulnerable phenotype predisposed to addiction.

The role of individual differences in the etiology of addiction is a very controversial issue. Neuroendocrine phenotypes that are able to predispose an individual to the development of drug intake have been identified previously. However, such information has been gathered by comparing individuals who differ in their sensitivity to low doses of the drug.

The dopaminergic hyper-responsiveness of the shell of the nucleus accumbens is hormone-dependent.

The dopaminergic projection to the shell of the nucleus accumbens is the most reactive to stress, reward and drugs of abuse and this subregion of the nucleus accumbens is also considered a target of therapeutic effects of atypical antipsychotic drugs (APD). In this report we show, by means of in vivo microdialysis and Fos immunohistochemistry, that the hyper-responsiveness which characterizes the dopaminergic transmission to the shell is dependent on glucocorticoid hormones. In Sprague-Dawley rats, after suppression of endogenous glucocorticoids by adrenalectomy, extracellular dopamine levels selectively decreased in the shell, whilst they remained unchanged in the core.

Release of endogenous dopamine in cultured mesencephalic neurons: influence of dopaminergic agonists and glucocorticoid antagonists.

Several electrochemical techniques allow the measurement of dopamine release in freely moving animals and brain slices. In this report, we applied one of these techniques, coulometry, coupled to high-performance liquid chromatography (HPLC), to the study of dopamine release in primary cultures of embryonic mesencephalic dopaminergic neurons. Between day 9 and 33 of culture, concentrations of dopamine, above the detection threshold, were found in the incubation buffer (Krebs ringer buffer, KRB).

Functional heterogeneity in dopamine release and in the expression of Fos-like proteins within the rat striatal complex.

The dorsolateral striatum, and the core and shell of the nucleus accumbens are three major anatomical regions of the striatal complex. The shell is considered as a part of the extended amygdala, and is involved in the control of motivation and reward. The core and the striatum are considered central to sensory motor integration.

Individual differences in stress-induced dopamine release in the nucleus accumbens are influenced by corticosterone.

Stressful experiences, glucocorticoids hormones and dopaminergic neurons seems to interact in determining a higher propensity to develop drug abuse. In this report, we studied the acute interaction between these three factors. For this purpose, we compared stress-induced dopamine release in intact rats and in rats in which stress-induced corticosterone secretion was experimentally blocked.

Glucocorticoids and behavioral effects of psychostimulants. I: locomotor response to cocaine depends on basal levels of glucocorticoids.

In this study, we explored the influence of corticosterone, the major glucocorticoid in the rat, on the locomotor response to cocaine. In particular, in a first series of experiments, we determined the effects of suppressing endogenous glucocorticoids by adrenalectomy on a full dose-response curve of cocaine-induced locomotion and the influence, on this behavioral response, of different corticosterone concentrations, by implanting different corticosterone pellets in adrenalectomized rats. Adrenalectomy decreased the locomotor response to cocaine, inducing a vertical shift in the dose-response curve, and corticosterone dose-dependently reversed the decrease induced by adrenalectomy.

Acute blockade of corticosterone secretion decreases the psychomotor stimulant effects of cocaine.

Previous reports have shown that long-term blockade of corticosterone secretion, by either adrenalectomy or repeated treatment with an inhibitor of corticosterone synthesis, metyrapone, profoundly reduces sensitivity to drugs of abuse. In this report we investigated whether acute blockade of corticosterone secretion has similar effects. Animals received a single injection of metyrapone (50 mg/kg SC) and were tested for their locomotor response to cocaine (15 mg/kg IP) 3 hours later.

Suppression of glucocorticoid secretion and antipsychotic drugs have similar effects on the mesolimbic dopaminergic transmission.

Specific antagonists of central dopaminergic receptors constitute the major class of antipsychotic drugs (APD). Two principal effects of APD are used as criteria for the pre-clinical screening of their antipsychotic action: (i) inhibition of basal and depolarization-induced activity of mesolimbic dopaminergic neurons; (ii) antagonism of the locomotor effects of dopaminergic agonists. Given that glucocorticoid hormones in animals increase dopamine release and dopamine-mediated behaviors and that high levels of glucocorticoids can induce psychotic symptoms in humans, these experiments examined whether inhibition of endogenous glucocorticoids might have APD-like effects on mesolimbic dopaminergic transmission in rats.

Glucocorticoids have state-dependent stimulant effects on the mesencephalic dopaminergic transmission.

An increase in the activity of mesencephalic dopaminergic neurons has been implicated in the appearance of pathological behaviors such as psychosis and drug abuse. Several observations suggest that glucocorticoids might contribute to such an increase in dopaminergic activity. The present experiments therefore analyzed the effects of corticosterone, the major glucocorticoid in the rat, both on dopamine release in the nucleus accumbens of freely moving animals by means of microdialysis, and on locomotor activity, a behavior dependent on accumbens dopamine.

Stress-induced sensitization and glucocorticoids. II. Sensitization of the increase in extracellular dopamine induced by cocaine depends on stress-induced corticosterone secretion.

Secretion of glucocorticoids seems to control stress-induced sensitization of the behavioral effects of drugs of abuse by acting on the mesencephalic dopaminergic transmission, the principal neural substrate of sensitization. In order to investigate the mechanisms of this interaction between glucocorticoids and dopamine, we studied the sensitization of the increase in extracellular concentration of dopamine induced by cocaine in male rats in which corticosterone secretion was either intact or blocked. Extracellular concentrations of dopamine were evaluated in the nucleus accumbens of freely moving animals by means of microdialysis.

Inhibition of corticosterone synthesis by Metyrapone decreases cocaine-induced locomotion and relapse of cocaine self-administration.

Several studies have recently shown that basal and stress-induced secretion of corticosterone may enhance vulnerability to drugs of abuse. In this report, we studied the effects of metyrapone, an inhibitor of the synthesis of corticosterone, on cocaine-induced locomotion and on the relapse of cocaine self-administration. Locomotor response to cocaine was studied because psychomotor effects of drugs have been shown to be related to their reinforcing properties.

Brain monoaminergic, neuroendocrine, and immune responses to an immune challenge in relation to brain and behavioral lateralization.

Host responses to immune challenges involve central neurotransmission, the hypothalamo-pituitary adrenal axis, and the immune system. In the present work, we investigated the possibility of an asymmetry in the modification of brain monoamine metabolism induced by a systemic injection of lipopolysaccharide (LPS) in adult female mice. We also studied the possible influence of behavioral lateralization, as assessed by a paw preference test, on the reactivity of the nervous, neuroendocrine, and immune systems to a LPS challenge.

Basal and stress-induced corticosterone secretion is decreased by lesion of mesencephalic dopaminergic neurons.

There is evidence that certain psychopathological conditions are accompanied by a dysfunction in both the hypothalamo-pituitary-adrenal axis and dopaminergic systems, although the relationship between these two systems is as yet unclear. In the present study we investigated the effect of a specific lesion of dopamine mesencephalic neurons (Ventral Tegmental Area) on basal and stress-induced corticosterone secretion. Three weeks after injection of 6-OHDA, there was a depletion in dopamine in the frontal cortex and in the ventral and dorsal striatum, whereas norepinephrine and serotonin levels were unchanged.

Effects of intracerebral dopaminergic grafts on behavioural deficits induced by neonatal 6-hydroxydopamine lesions of the mesotelencephalic dopaminergic pathway.

The functional capabilities of dopamine neuron-rich grafts implanted into the accumbens and striatal regions in neonatal rats were evaluated in a series of behavioural tests. The ascending mesotelencephalic dopaminergic system of three-day-old rat pups was bilaterally lesioned by injecting 6-hydroxydopamine at the level of the lateral hypothalamus. Five days later a suspension containing dopaminergic neurons obtained from embryonic day 14 mesencephali was injected bilaterally into the striatal complex.