Dopamine and cyclic AMP-regulated phosphoprotein-32 phosphorylation pattern in cocaine and morphine-sensitized rats

This study reports some of the modifications in dopaminergic signalling that accompany cocaine and morphine behavioural sensitization. Cocaine-sensitized rats showed increased phosphorylation of dopamine- and cyclic AMP-regulated phosphoprotein Mr 32 kDa (DARPP-32) at threonine-75 (Thr75) and decreased DARPP-32 phosphorylation at Thr34, in the caudate-putamen (CPu) and nucleus accumbens (NAc) 7 days after sensitization assessment. Conversely, in morphine-sensitized rats, no apparent modifications in DARPP-32 phosphorylation pattern were observed. Morphine-sensitized rats have increased binding and coupling of micro -opioid receptors and increased dopaminergic transmission in striatal areas and, upon morphine challenge, exhibit dopamine D1 receptor-dependent stereotypies. Thus, the DARPP-32 phosphorylation pattern was studied in morphine-sensitized rats at different times after morphine challenge. Morphine challenge increased levels of phospho-Thr75 DARPP-32 and decreased levels of phospho-Thr34 DARPP-32 in a time-dependent manner in the CPu and NAc. In order to assess whether these modifications were related to modified cyclic AMP-dependent protein kinase (PKA) activity, the phosphorylation levels of two other PKA substrates were examined, the GluR1 and NR1 subunits of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate and NMDA receptors respectively. The phosphorylation levels of GluR1 and NR1 subunits decreased in parallel with those of phospho-Thr-34 DARPP-32, supporting the hypothesis that morphine challenge elicited a decrease in PKA activity in morphine-sensitized rats.     

Regulation of Cytochrome c Oxidase Subunit mRNA and Enzyme Activity in Rat Brain Reward Regions During Withdrawal from Chronic Cocaine

Abstract: A subtractive hybridization and differential screening procedure was used to detect up-regulation of cytochrome c oxidase (CO) subunits I, III, and IV mRNA in the nucleus accumbens (NAc) of rats chronically treated with cocaine. Northern blot analyses of mRNA isolated from individual rats confirmed that CO subunit I was up-regulated by chronic, but not acute, cocaine in two brain regions, the NAc (33%) and caudate-putamen (CP)(35%). CO activity, used as a measure of metabolic activity, was increased by 88% in the NAc, and decreased by 20% in the medial prefrontal cortex (mPFC), the day after chronic treatment was terminated. CO enzyme activity was not regulated in the CP, or in other brain regions not involved in drug reward. CO activity in both the NAc and mPFC showed unique time-dependent patterns of regulation during the week after chronic cocaine treatment.     

Deep brain stimulation of the accumbens increases dopamine,serotonin, and noradrenaline in the prefrontal cortex

Deep brain stimulation (DBS) of the nucleus accumbens (NAc) is effective in treatment‐refractory obsessive‐compulsive disorder and major depressive disorder. However, little is known about the neurobiological mechanisms underlying the rapid and effective changes of DBS. One of the hypotheses is that DBS modulates activity of monoamine neurotransmitters. In this study, we evaluated the effects of DBS in the NAc core on the extracellular concentration of monoaminergic neurotransmitters in the medial (mPFC) and orbital prefrontal cortex (OFC). Freely moving rats were bilaterally stimulated in the NAc core for 2 h while dopamine, serotonin, and noradrenaline were measured using in vivo microdialysis in the mPFC and the OFC. We report rapid increases in the release of dopamine and serotonin to a maximum of 177% and 127% in the mPFC and an increase up to 171% and 166% for dopamine and noradrenaline in the OFC after onset of stimulation in the NAc core. These results provide further evidence for the distal effects of DBS and corroborate previous clinical and pre‐clinical findings of altered neuronal activity in prefrontal areas.     

Blockade of TrkB receptors in the nucleus accumbens prior to heterotypic stress alters corticotropin-releasing hormone (CRH), vesicular glutamate transporter 2 (vGluT2) and glucocorticoid receptor (GR) within the mesolimbic pathway

Inhibition of stress-induced elevations in brain-derived neurotrophic factor (BDNF) or its primary receptor tyrosine-related kinase B (TrkB) within the reward pathway may modulate vulnerability to anxiety and mood disorders. The current study examined the role of BDNF/TrkB signaling on biochemistry and behavior under basal conditions and following exposure to a 10-day heterotypic stress paradigm in male rats. Effects of intra-accumbal administration of TrkB antagonist ANA-12 (0.25 μg/0.5 μl/min) on anxiety, and expression of Trk-B, corticotropin-releasing hormone (CRH), vesicular glutamate transporter 2 (vGluT2) and glucocorticoid receptor (GR) within the mesolimbic pathway were determined. Notably, ANA-12 attenuated anxiety-like behavior in stress rats while increasing anxiety in the non-stress group in the elevated plus maze (EPM). At the neurochemical level, ANA-12 blocked the increased vGluT2 and CRH expressions in the hypothalamic PVN and basolateral amygdala in stress rats, while it enhanced vGluT2 and CRH expressions in non-stress rats. ANA-12 also showed state-dependent effects at the NAc core, attenuating TrkB-ir in non-stress rats while reversing reduced expression in stressed rats. At the cingulate cortex, ANA-12 normalized stress-induced increase in TrkB expression. Notably, ANA-12 showed region-specific effects on GR-ir at the NAc core and shell, with increased GR-ir in non-stress rats, although the drug attenuated stress-induced GR-ir expression only in the core portion of the NAc, while having no impact at the cingulate cortex. Elevated blood CORT levels post-stress was not influenced by ANA-12 treatment. Together, these findings suggest that BDNF-mediated TrkB activation exerts differential impact in regulating emotional response under basal and stress conditions.     

The dopamine D1 receptor is a critical mediator for cocaine-induced gene expression

The dopamine D1 receptor plays a major role in mediating behavioral responses to cocaine administration. The time course for the acquisition and the relative stability for the expression of behavioral responses suggest the involvement of enduring neuroadaptations in response to repeated cocaine exposure. Changes in gene expression through the D1 receptors may accompany and mediate the development of such neuroadaptations to repeated cocaine stimulation. To test this possibility, we systematically compared the expression of the fos and Jun family immediate early genes in the nucleus accumbens and caudoputamen in D1 receptor mutant and wild-type control mice after acute and repeated cocaine exposure. Moreover, we compared the expression of three molecules that have been implicated in mediating the actions of cocaine, Galphaolf, beta-catenin and brain-derived neurotrophic factor, in the two groups of mice before and after cocaine administration. We found that there is a lack of induction of c-Fos, FosB, Fra-2 and JunB by acute cocaine exposure, and of DeltaFosB by repeated cocaine administration in both the NAc and CPu of D1 receptor mutant mice compared with wild-type control mice. Moreover, the D1 receptor is differentially required for mediating Galphaolf, beta-catenin and BDNF expression in the NAc and CPu upon cocaine exposure. These results suggest that the D1 receptor is a critical mediator for cocaine-induced expression of these genes.     

Combined brain‐derived neurotrophic factor with extinction training alleviate impaired fear extinction in an animal model of post‐traumatic stress disorder

Impaired fear memory extinction (Ext) is one of the hallmark symptoms of post‐traumatic stress disorder (PTSD). However, since the precise mechanism of impaired Ext remains unknown, effective interventions have not yet been established. Recently, hippocampal‐prefrontal brain‐derived neurotrophic factor (BDNF) activity was shown to be crucial for Ext in naïve rats. We therefore examined whether decreased hippocampal‐prefrontal BDNF activity is also involved in the Ext of rats subjected to a single prolonged stress (SPS) as a model of PTSD. BDNF levels were measured by enzyme‐linked immunosorbent assay (ELISA), and phosphorylation of TrkB was measured by immunohistochemistry in the hippocampus and medial prefrontal cortex (mPFC) of SPS rats. We also examined whether BDNF infusion into the ventral mPFC or hippocampus alleviated the impaired Ext of SPS rats in the contextual fear conditioning paradigm. SPS significantly decreased the levels of BDNF in both the hippocampus and mPFC and TrkB phosphorylation in the ventral mPFC. Infusion of BDNF 24 hours after conditioning in the infralimbic cortex (ILC), but not the prelimbic cortex (PLC) nor hippocampus, alleviated the impairment of Ext. Since amelioration of impaired Ext by BDNF infusion did not occur without extinction training, it seems the two interventions must occur consecutively to alleviate impaired Ext. Additionally, BDNF infusion markedly increased TrkB phosphorylation in the ILC of SPS rats. These findings suggest that decreased BDNF signal transduction might be involved in the impaired Ext of SPS rats, and that activation of the BDNF‐TrkB signal might be a novel therapeutic strategy for the impaired Ext by stress.     

Brain Region-Specific Effects of Short-Term Treatment with Duloxetine,Venlafaxine, Milnacipran and Sertraline on Monoamine Metabolism in Rats

We examined brain region-specific changes in monoamines and metabolites, and their ratios, after short-term administration of antidepressants to rats. Serotonin noradrenaline reuptake inhibitors (SNRIs; duloxetine, venlafaxine, milnacipran) and a serotonin-selective reuptake inhibitor (SSRI; sertraline) elevated serotonin (5-HT) levels in the midbrain (MB). Duloxetine and venlafaxine increased 5-HT levels in the brainstem and 5-HT terminal areas, whereas milnacipran and sertraline increased levels in the brainstem only. Significant reductions in 5-HT turnover were observed in various forebrain regions, including the hippocampus and hypothalamus, after treatment with all of the tested drugs except for milnacipran. In addition, there was reduced 5-HT turnover in the dorsolateral frontal cortex (dlFC), the medial prefrontal cortex (mPFC), and both the dlFC and the mPFC after treatment with duloxetine, sertraline, and venlafaxine, respectively. Venlafaxine significantly increased dopamine (DA) levels in the nucleus accumbens (NAc) and the substantia nigra and decreased DA turnover in the NAc. Similar changes were observed after treatment with duloxetine and sertraline in the NAc, whereas milnacipran increased DA levels in the mPFC. Limited increases in noradrenaline levels were detected after treatment with duloxetine, venlafaxine, or sertraline, but not after treatment with milnacipran. These results show that SNRIs and SSRIs induced region-specific monoaminergic changes after short-term treatment.     

Signaling via dopamine D1 and D3 receptors oppositely regulates cocaine-induced structural remodeling of dendrites and spines

Repeated exposure to cocaine can induce persistent alterations in the brain. The structural remodeling of dendrites and dendritic spines is thought to play a critical role in cocaine addiction. We previously demonstrated that signaling via dopamine D1 and D3 receptors have opposite effects on cocaine-induced gene expression. Here, we show that cocaine-induced structural remodeling in the nucleus accumbens (NAc) and caudoputamen (CPu) is mediated by D1 receptors and inhibited by D3 receptors. In addition, chronic exposure to cocaine results in an altered number of asymmetric spine synapses via the actions of both D1 and D3 receptors. The contradictory effects of D1 and D3 receptor signaling on cocaine-induced structural remodeling is associated with NMDA-receptor R1 subunit (NR1) phosphorylation, and is dependent upon the activation of extracellular signal-regulated kinase (ERK). In addition, we found that D1 and D3 receptor signaling has contradictory effects upon the activation of the myocyte enhancer factor 2 (MEF2), which is involved in the dendritic remodeling after cocaine treatment. Together, these data suggest that dopamine D1 and D3 receptors differentially regulate the cocaine-induced structural remodeling of dendrites and spines via mechanisms involving the consecutive actions of NR1 phosphorylation, ERK activation, and MEF2 activity in the NAc and CPu.     

Selective modifications in the nucleus accumbens of dopamine synaptic transmission in rats exposed to chronic stress

Stressful events are accompanied by modifications in dopaminergic transmission in distinct brain regions. As the activity of the neuronal dopamine (DA) transporter (DAT) is considered to be a critical mechanism for determining the extent of DA receptor activation, we investigated whether a 3-week exposure to unavoidable stress, which produces a reduction in DA output in the nucleus accumbens shell (NAcS) and medial prefrontal cortex (mPFC), would affect DAT density and DA D1 receptor complex activity in the NAcS, mPFC and caudate-putamen (CPu). Rats exposed to unavoidable stress showed a decreased DA output in the NAcS accompanied by a decrease in the number of DAT binding sites, and an increase in the number of DA D1 binding sites and Vmax of SKF 38393-stimulated adenylyl cyclase. In the mPFC, stress exposure produced a decrease in DA output with no modification in DAT binding or in DA D1 receptor complex activity. Moreover, in the CPu stress exposure induced no changes in DA output or in the other neurochemical variables examined. This study shows that exposure to a chronic unavoidable stress that produces a decrease in DA output in frontomesolimbic areas induced several adaptive neurochemical modifications selectively in the nucleus accumbens.     

Rat Strain Differences in Responses of Plasma Prolactin and PRL mRNA Expression After Acute Amphetamine Treatment or Restraint Stress

1. The aim of this study was to compare the effects of acute amphetamine (AMPH) treatment and restraint stress on plasma level of prolactin (PRL) and PRL mRNA expression in the adenohypophysis in Sprague–Dawley and Lewis male rats, the latter known to have a deficient hypothalamo–pituitary-adrenal (HPA) axis.2. Both restraint stress and AMPH treatment (i.p. in a dose of 8 mg/kg of b.w.) were applied 15 or 30 min before termination of the experiment. Plasma PRL and corticosterone (CORT) were determined by radioimmunoassay. PRL mRNA expression was estimated by a dot-blot hybridization.3. Restraint stress and AMPH treatment induced a significant increase in theCORT plasma level, as an indicator of stress response. Compared to Sprague–Dawley rats, the magnitude of CORT increase after both stimuli was significantly lower in Lewis rats.4. Although restraint stress significantly increased the PRL plasma levels in both rat strains, AMPH treatment reduced the PRL levels in both rat strains. However, the changes of PRL plasma levels had another pattern in Lewis rats than in Sprague–Dawley rats. Control plasma PRL levels were significantly higher in Lewis rats, and in this rat strain AMPH treatment for 30 min increased the PRL levels as compared to the values obtained after AMPH treatment for 15 min.5. Expression of PRL mRNA in adenohypophysis by restraint stress and AMPH treatment had a similar pattern. After a 15-min lasting restraint stress, the expression of PRL mRNA was decreased insignificantly in both rat strains. AMPH treatment induced in Sprague–Dawley rats a significant decrease of PRL mRNA after a 15-min interval while after 30 min there was a significant increase. However, in Lewis rats AMPH failed to significantly change PRL mRNA.6. The results from the present study indicate that the mechanisms mediatingthe effects of acute restraint stress and acute AMPH treatment differ in PRL response in Sprague–Dawley and Lewis male rat strains. Differences in the observed responses in Lewis rats could be related to the deficient activity of HPA axis in this rat strain.     

Increases in cytoplasmic dopamine compromise the normal resistance of the nucleus accumbens to methamphetamine neurotoxicity

Methamphetamine (METH) is a neurotoxic drug of abuse that damages the dopamine (DA) neuronal system in a highly delimited manner. The brain structure most affected by METH is the caudate–putamen (CPu) where long-term DA depletion and microglial activation are most evident. Even damage within the CPu is remarkably heterogenous with lateral and ventral aspects showing the greatest deficits. The nucleus accumbens (NAc) is largely spared of the damage that accompanies binge METH intoxication. Increases in cytoplasmic DA produced by reserpine, l -DOPA or clorgyline prior to METH uncover damage in the NAc as evidenced by microglial activation and depletion of DA, tyrosine hydroxylase (TH), and the DA transporter. These effects do not occur in the NAc after treatment with METH alone. In contrast to the CPu where DA, TH, and DA transporter levels remain depleted chronically, DA nerve ending alterations in the NAc show a partial recovery over time. None of the treatments that enhance METH toxicity in the NAc and CPu lead to losses of TH protein or DA cell bodies in the substantia nigra or the ventral tegmentum. These data show that increases in cytoplasmic DA dramatically broaden the neurotoxic profile of METH to include brain structures not normally targeted for damage by METH alone. The resistance of the NAc to METH-induced neurotoxicity and its ability to recover reveal a fundamentally different neuroplasticity by comparison to the CPu. Recruitment of the NAc as a target of METH neurotoxicity by alterations in DA homeostasis is significant in light of the important roles played by this brain structure.     

Alterations of BDNF and trkB mRNA Expression in the 6-Hydroxydopamine-Induced Model of Preclinical Stages of Parkinson’s Disease: An Influence of Chronic Pramipexole in Rats

Our recent study has indicated that a moderate lesion of the mesostriatal and mesolimbic pathways in rats, modelling preclinical stages of Parkinson’s disease, induces a depressive-like behaviour which is reversed by chronic treatment with pramipexole. The purpose of the present study was to examine the role of brain derived neurotrophic factor (BDNF) signalling in the aforementioned model of depression. Therefore, we investigated the influence of 6-hydoxydopamine (6-OHDA) administration into the ventral region of the caudate-putamen on mRNA levels of BDNF and tropomyosin-related kinase B (trkB) receptor. The BDNF and trkB mRNA levels were determined in the nigrostriatal and limbic structures by in situ hybridization 2 weeks after the operation. Pramipexole (1 mg/kg sc twice a day) and imipramine (10 mg/kg ip once a day) were injected for 2 weeks. The lesion lowered the BDNF and trkB mRNA levels in the hippocampus [CA1, CA3 and dentate gyrus (DG)] and amygdala (basolateral/lateral) as well as the BDNF mRNA content in the habenula (medial/lateral). The lesion did not influence BDNF and trkB expression in the caudate-putamen, substantia nigra, nucleus accumbens (shell and core) and ventral tegmental area (VTA). Chronic imipramine reversed the lesion-induced decreases in BDNF mRNA in the DG. Chronic pramipexole increased BDNF mRNA, but decreased trkB mRNA in the VTA in lesioned rats. Furthermore, it reduced BDNF and trkB mRNA expression in the shell and core of the nucleus accumbens, BDNF mRNA in the amygdala and trkB mRNA in the caudate-putamen in these animals. The present study indicates that both the 6-OHDA-induced dopaminergic lesion and chronic pramipexole influence BDNF signalling in limbic structures, which may be related to their pro-depressive and antidepressant activity in rats, respectively.     

Effect of ginsenoside Re on depression- and anxiety-like behaviors and cognition memory deficit induced by repeated immobilization in rats

In this study, we assessed the effects of ginsenoside Re (GRe) administration on repeated immobilization stressinduced behavioral alterations using the forced swimming test (FST), the elevated plus maze (EPM), and the active avoidance conditioning test (AAT). Additionally, we examined the effect of GRe on the central adrenergic system by observing changes in neuronal tyrosine hydroxylase (TH) immunoreactivity and brain-derived neurotrophic factor (BDNF) mRNA expression in the rat brain. Male rats received 10, 20, or 50 mg/kg GRe (i.p.) 30 min before daily exposures to repeated immobilization stress (2 h/day) for 10 days. Activation of the hypothalamic-pituitary-adrenal (HPA) axis in response to repeated immobilization was confirmed by measuring serum levels of corticosterone (CORT) and the expression of corticotrophin-releasing factor (CRF) in the hypothalamus. Repeated immobilization stress increased immobility in the FST and reduced openarm exploration in the EPM test. It also increased the probability of escape failures in the AAT test, indicating a reduced avoidance response. Daily administration of GRe during the repeated immobilization stress period significantly inhibited the stress-induced behavioral deficits in these behavioral tests. Administration of GRe also significantly blocked the increase in TH expression in the locus coeruleus (LC) and the decrease in BDNF mRNA expression in the hippocampus. Taken together, these findings indicate that administration of GRe prior to immobilization stress significantly improved helpless behaviors and cognitive impairment, possibly through modulating the central noradrenergic system in rats. These findings suggest that GRe may be a useful agent for treating complex symptoms of depression, anxiety, and cognitive impairment.     

The effects of gestational stress and Selective Serotonin reuptake inhibitor antidepressant treatment on structural plasticity in the postpartum brain — A translational model for postpartum depression

This article is part of a Special Issue “Parental Care”.Postpartum depression (PPD) is a common complication following childbirth experienced by one in every five new mothers. Although the neural basis of PPD remains unknown, previous research in rats has shown that gestational stress, a risk factor for PPD, induces depressive-like behavior during the postpartum period. Moreover, the effect of gestational stress on postpartum mood is accompanied by structural modifications within the nucleus accumbens (NAc) and the medial prefrontal cortex (mPFC)–limbic regions that have been linked to PPD. Mothers diagnosed with PPD are often prescribed selective serotonin reuptake inhibitor (SSRI) antidepressant medications and yet little is known about their effects in models of PPD. Thus, here we investigated whether postpartum administration of Citalopram, an SSRI commonly used to treat PPD, would ameliorate the behavioral and morphological consequences of gestational stress. In addition, we examined the effects of gestational stress and postpartum administration of Citalopram on structural plasticity within the basolateral amygdala (BLA) which together with the mPFC and NAc forms a circuit that is sensitive to stress and is involved in mood regulation. Our results show that postpartum rats treated with Citalopram do not exhibit gestational stress-induced depressive-like behavior in the forced swim test. In addition, Citalopram was effective in reversing gestational stress-induced structural alterations in the postpartum NAc shell and mPFC. We also found that gestational stress increased spine density within the postpartum BLA, an effect which was not reversed by Citalopram treatment. Overall, these data highlight the usefulness of gestational stress as a valid and informative translational model for PPD. Furthermore, they suggest that structural alterations in the mPFC–NAc pathway may underlie stress-induced depressive-like behavior during the postpartum period and provide much needed information on how SSRIs may act in the maternal brain to treat PPD.     

Honokiol Exerts Antidepressant Effects in Rats Exposed to Chronic Unpredictable Mild Stress by Regulating Brain Derived Neurotrophic Factor Level and Hypothalamus–Pituitary–Adrenal Axis Activity

Honokiol (HNK), the main active component of Magnolia officinalis, has shown a variety of pharmacological activities. In the present study, we measured the antidepressant-like effects of HNK in a rat model of chronic unpredictable mild stress (CUMS) and explored its possible mechanisms. The antidepressant-like effects of HNK were assessed in rats by an open field test (OFT), sucrose preference test (SPT) and forced swimming test (FST). Then, serum levels of corticotrophin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and corticosterone (CORT) and hippocampal brain-derived neurotrophic factor (BDNF) and glucocorticoid receptor α (GRα) levels were assessed to explore the possible mechanisms. We identified that HNK treatment (2, 4, and 8 mg/kg) alleviated the CUMS-induced behavioural deficits. Treatment with HNK also normalized the CUMS-induced hyperactivity of the limbic hypothalamic–pituitary–adrenal (HPA) axis, as indicated by reduced CRH, ACTH and CORT serum levels. In addition, HNK increased the expression of GRα (mRNA and protein) and BDNF (mRNA and protein) in the hippocampus. These data confirmed the antidepressant-like effects of HNK, which may be related to its normalizing the function of the HPA axis and increasing the BDNF level in the hippocampus.     

Abnormal Hippocampal BDNF and miR-16 Expression Is Associated with Depression-Like Behaviors Induced by Stress during Early Life

Some environmental stressors lead to the onset of depression via inhibiting hippocampal BDNF expression, but other environmental stressors-induced depression exhibits no change in BDNF expression. The underlying mechanisms behind the divergence remain unknown. In this study, depression-like behaviors were induced in rats by maternal deprivation (MD) and chronic unpredictable stress (CUPS). Depression-like behaviors were tested by open field test, forced swimming test, and sucrose consumption test. BDNF and miR-16 expressions in the hippocampus were examined by real-time PCR. MD and CUPS rats crawled less distance, exhibited decreased vertical activity, and produced more fecal pellets than control rats in the open field test. However, MD rats crawled less distance and produced significantly less fecal pellets than CUPS rats. In the forced swimming and sucrose consumption tests, CUPS and MD rats exhibited longer floating time and consumed less sucrose than control rats, but MD rats exhibited shorter floating time and consumed less sucrose than CUPS rats. MD but not CUPS rats showed lower BDNF mRNA and higher miR-16 expression than control rats. In MD rats, BDNF mRNA expression negatively correlated with the expression of miR-16. BDNF expression positively correlated with the total distance rats crawled and vertical activity in the open field test while miR-16 expression negatively correlated the two behaviors. BDNF positively correlated with sucrose preference rate while miR-16 negatively correlated with sucrose preference rate of the sucrose consumption test. Our study suggests that MD and CUPS induced different depression-like behaviors in rats. Depression induced by MD but not CUPS was significantly associated with upregulation of miR-16 and possibly subsequent downregulation of BDNF in hippocampus.     

Anxiety-Related Behaviours Associated with microRNA-206-3p and BDNF Expression in Pregnant Female Mice Following Psychological Social Stress

Stress during pregnancy can induce various psychological disorders in women. However, the association linking psychological stress during pregnancy with abnormal behaviours in females remains largely unknown. We employed a novel psychological stress model by introducing pregnant mice to witness the defeat process of their mated partner (WDPMP) and examined the effects of WDPMP on depression-/anxiety-like behaviours and on the expression of brain-derived neurotrophic factor (BDNF) and miR-206-3p in the hippocampus, medial prefrontal cortex (mPFC) and amygdala. Compared to pregnant control (PC) mice, pregnant stressed (PS) mice showed decreased sucrose preference during the late period of gestation, and after lactation, they spent less time in the open arms of the elevated plus maze and in the light chamber of the light/dark box. After lactation, decreased BDNF expression in both the hippocampus and mPFC of PS mice was found to be associated with enhanced miR-206-3p levels; meanwhile, elevated BDNF associated with decreased miR-206-3p expression was evident in the amygdala of the same PS mice. DNA methylation level in the Bdnf promoter did not show difference between PC and PS mice in the hippocampus. Transfection of miR-206-3p resulted in decreased BDNF levels in vitro. These results suggest that WDPMP stress during gestation can induce long-term mood alterations in pregnant mice, which may correlate with changes in miR-206-3p and BDNF expression in the hippocampus, mPFC and amygdala.     

Plasticity in the Rat Prefrontal Cortex: Linking Gene Expression and an Operant Learning with a Computational Theory

The plasticity in the medial Prefrontal Cortex (mPFC) of rodents or lateral prefrontal cortex in non human primates (lPFC), plays a key role neural circuits involved in learning and memory. Several genes, like brain-derived neurotrophic factor (BDNF), cAMP response element binding (CREB), Synapsin I, Calcium/calmodulin-dependent protein kinase II (CamKII), activity-regulated cytoskeleton-associated protein (Arc), c-jun and c-fos have been related to plasticity processes. We analysed differential expression of related plasticity genes and immediate early genes in the mPFC of rats during learning an operant conditioning task. Incompletely and completely trained animals were studied because of the distinct events predicted by our computational model at different learning stages. During learning an operant conditioning task, we measured changes in the mRNA levels by Real-Time RT-PCR during learning; expression of these markers associated to plasticity was incremented while learning and such increments began to decline when the task was learned. The plasticity changes in the lPFC during learning predicted by the model matched up with those of the representative gene BDNF. Herein, we showed for the first time that plasticity in the mPFC in rats during learning of an operant conditioning is higher while learning than when the task is learned, using an integrative approach of a computational model and gene expression.     

In vivo up-regulation of brain-derived neurotrophic factor in specific brain areas by chronic exposure to Delta-tetrahydrocannabinol

Cannabinoids are widely abused drugs. Here we show that chronic administration of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the active psychotropic agent in marijuana and hashish, at 1.5 mg per kg per day intraperitoneally for 7 days, increases the expression, at both mRNA and protein levels, of brain-derived neurotrophic factor (BDNF), in specific rat brain areas, notably in those involved in reward and addiction. Real-time PCR revealed a 10-fold up-regulation of BDNF mRNA in the nucleus accumbens (NAc) upon chronic Delta(9)-THC treatment, but there was no change at 3 or 24 h after a single injection. Smaller increases in mRNA levels were found in the ventral tegmental area (VTA), medial prefrontal cortex and paraventricular nucleus (PVN). Immunohistochemistry showed large increases in BDNF-stained cells in the NAc (5.5-fold), posterior VTA (4-fold) and PVN (1.7-fold), but no change was observed in the anterior VTA, hippocampus or dorsal striatum. Altogether, our study indicates that chronic exposure to Delta(9)-THC up-regulates BDNF in specific brain areas involved with reward, and provides evidence for different BDNF expression in the anterior and posterior VTA. Moreover, BDNF is known to modulate synaptic plasticity and adaptive processes underlying learning and memory, leading to long-term functional and structural modification of synaptic connections. We suggest that Delta(9)-THC up-regulation of BDNF expression has an important role in inducing the neuroadaptive processes taking place upon exposure to cannabinoids.