Differential effects of chronic stress in young-adult and old female mice: cognitive-behavioral manifestations and neurobiological correlates.

Stress-related psychopathology is highly prevalent among elderly individuals and is associated with detrimental effects on mood, appetite and cognition. Conversely, under certain circumstances repeated mild-to-moderate stressors have been shown to enhance cognitive performance in rodents and exert stress-inoculating effects in humans. As most stress-related favorable outcomes have been reported in adolescence and young-adulthood, this apparent disparity could result from fundamental differences in how aging organisms respond to stress. Furthermore, given prominent age-related alterations in sex hormones, the effect of chronic stress in aging females remains a highly relevant yet little studied issue. In the present study, female C57BL/6 mice aged 3 (young-adult) and 20-23 (old) months were subjected to 8 weeks of chronic unpredictable stress (CUS). Behavioral outcomes were measured during the last 3 weeks of the CUS protocol, followed by brain dissection for histological and molecular end points. We found that in young-adult female mice, CUS resulted in decreased anxiety-like behavior and enhanced cognitive performance, whereas in old female mice it led to weight loss, dysregulated locomotion and memory impairment. These phenotypes were paralleled by differential changes in the expression of hypothalamic insulin and melanocortin-4 receptors and were consistent with an age-dependent reduction in the dynamic range of stress-related changes in the hippocampal transcriptome. Supported by an integrated microRNA (miRNA)-mRNA expression analysis, the present study proposes that, when confronted with ongoing stress, neuroprotective mechanisms involving the upregulation of neurogenesis, Wnt signaling and miR-375 can be harnessed more effectively during young-adulthood. Conversely, we suggest that aging alters the pattern of immune activation elicited by stress. Ultimately, interventions that modulate these processes could reduce the burden of stress-related psychopathology in late life.

Changes in resting-state brain networks after cognitive-behavioral therapy for chronic pain.

BACKGROUND: Cognitive-behavioral therapy (CBT) is thought to be useful for chronic pain, with the pathology of the latter being closely associated with cognitive-emotional components. However, there are few resting-state functional magnetic resonance imaging (R-fMRI) studies. We used the independent component analysis method to examine neural changes after CBT and to assess whether brain regions predict treatment response. METHODS: We performed R-fMRI on a group of 29 chronic pain (somatoform pain disorder) patients and 30 age-matched healthy controls (T1). Patients were enrolled in a weekly 12-session group CBT (T2). We assessed selected regions of interest that exhibited differences in intrinsic connectivity network (ICN) connectivity strength between the patients and controls at T1, and compared T1 and T2. We also examined the correlations between treatment effects and rs-fMRI data. RESULTS: Abnormal ICN connectivity of the orbitofrontal cortex (OFC) and inferior parietal lobule within the dorsal attention network (DAN) and of the paracentral lobule within the sensorimotor network in patients with chronic pain normalized after CBT. Higher ICN connectivity strength in the OFC indicated greater improvements in pain intensity. Furthermore, ICN connectivity strength in the dorsal posterior cingulate cortex (PCC) within the DAN at T1 was negatively correlated with CBT-related clinical improvements. CONCLUSIONS: We conclude that the OFC is crucial for CBT-related improvement of pain intensity, and that the dorsal PCC activation at pretreatment also plays an important role in improvement of clinical symptoms via CBT.

Initial severity of major depression and efficacy of new generation antidepressants: individual participant data meta-analysis.

OBJECTIVE: The role of baseline severity as effect modifier in various psychiatric disorders is a topic of controversy and of clinical import. This study aims to examine whether baseline severity modifies the efficacy of various antidepressants for major depression through individual participant data (IPD) meta-analysis. METHOD: We identified all placebo-controlled, double-blind randomised trials of new generation antidepressants in the acute phase treatment of major depression conducted in Japan and requested their IPD through the public-private partnerships (PPPs) between the relevant academic societies and the pharmaceutical companies. The effect modification by baseline depression severity was examined through six increasingly complex competing mixed-effects models for repeated measures. RESULTS: We identified eleven eligible trials and obtained IPD from six, which compared duloxetine, escitalopram, mirtazapine, paroxetine or bupropion against placebo (total n = 2464). The best-fitting model revealed that the interaction between baseline severity and treatment was not statistically significant (coefficient = -0.04, 95% confidence interval: -0.16 to 0.08, P = 0.49). Several sensitivity analyses confirmed the robustness of the findings. CONCLUSION: We may expect as much benefit from antidepressant treatments for mild, moderate or severe major depression. Clinical practice guidelines will need to take these findings into consideration.

Effects of behavioural activation on the neural basis of other perspective self-referential processing in subthreshold depression: a functional magnetic resonance imaging study.

BACKGROUND: It has been demonstrated that negatively distorted self-referential processing, in which individuals evaluate one's own self, is a pathogenic mechanism in subthreshold depression that has a considerable impact on the quality of life and carries an elevated risk of developing major depression. Behavioural activation (BA) is an effective intervention for depression, including subthreshold depression. However, brain mechanisms underlying BA are not fully understood. We sought to examine the effect of BA on neural activation during other perspective self-referential processing in subthreshold depression. METHOD: A total of 56 subjects underwent functional magnetic resonance imaging scans during a self-referential task with two viewpoints (self/other) and two emotional valences (positive/negative) on two occasions. Between scans, while the intervention group (n = 27) received BA therapy, the control group (n = 29) did not. RESULTS: The intervention group showed improvement in depressive symptoms, increased activation in the dorsal medial prefrontal cortex (dmPFC), and increased reaction times during other perspective self-referential processing for positive words after the intervention. Also, there was a positive correlation between increased activation in the dmPFC and improvement of depressive symptoms. Additionally, there was a positive correlation between improvement of depressive symptoms and increased reaction times. CONCLUSIONS: BA increased dmPFC activation during other perspective self-referential processing with improvement of depressive symptoms and increased reaction times which were associated with improvement of self-monitoring function. Our results suggest that BA improved depressive symptoms and objective monitoring function for subthreshold depression.

Long-term prognosis of patients with major depression and silent cerebral infarction.

OBJECTIVE: Many studies have examined the effects of cerebrovascular changes on treatment response in geriatric depression. However, few such studies have examined the relationship between cerebrovascular changes and long-term prognosis. We examined the effects of cerebrovascular changes on the course of geriatric depressive symptoms, dementia rates, and mortality over a follow-up period of approximately 10 years. METHOD: Participants were 84 patients with major depression (age of onset over 50 years); patients suffering from strokes, neurological disorders, and other psychiatric disorders were excluded. Magnetic resonance imaging findings were used to classify all patients into silent cerebral infarction (SCI)-positive (n = 37) or SCI-negative groups (n = 47). Prognoses were ascertained using a review of clinical charts and mailed questionnaires. RESULTS: Only 5% of patients with SCI were able to maintain remission whereas 36% of patients without SCI were able to do so. Total duration of depressive episodes was significantly longer in the SCI-positive group than in the SCI-negative group. SCI was also associated with a higher risk of dementia. CONCLUSION: The results of this long-term follow-up study demonstrate that the presence of SCI is associated with a relatively poor prognosis in geriatric depression.

Neonatal tactile stimulation reverses the effect of neonatal isolation on open-field and anxiety-like behavior, and pain sensitivity in male and female adult Sprague-Dawley rats.

It is well known that early life events induce long-lasting psychophysiological and psychobiological influences in later life. In rodent studies, environmental enrichment after weaning prevents the adulthood behavioral and emotional disturbances in response to early adversities. We compared the behavioral effect of neonatal isolation (NI) with the effect of NI accompanied by tactile stimulation (NTS) to determine whether NTS could reverse or prevent the effects of NI on the adulthood behavioral and emotional responses to environmental stimuli. In addition, we also examined the sex difference of the NTS effect. Measurements of body weights, an open-field locomotor test, an elevated plus maze test, a hot-plate test, and a contextual fear-conditioning test were performed on postnatal day 60. As compared with rats subjected to NI, rats subjected to NTS showed significantly higher activity and exploration in the open-field locomotor test, lower anxiety-like behavior in the elevated plus maze test, and significantly prolonged latencies in the hot-plate test, and this effect was equal among males and females. In the contextual fear-conditioning test, whereas NTS significantly reduced the enhanced freezing time due to NI in females, no significant difference in the freezing time between NI and NTS was found in males. These findings indicate that adequate tactile stimulation in early life plays an important role in the prevention of disturbances in the behavioral and emotional responses to environmental stimuli in adulthood induced by early adverse experiences.

Humans can adopt optimal discounting strategy under real-time constraints.

Critical to our many daily choices between larger delayed rewards, and smaller more immediate rewards, are the shape and the steepness of the function that discounts rewards with time. Although research in artificial intelligence favors exponential discounting in uncertain environments, studies with humans and animals have consistently shown hyperbolic discounting. We investigated how humans perform in a reward decision task with temporal constraints, in which each choice affects the time remaining for later trials, and in which the delays vary at each trial. We demonstrated that most of our subjects adopted exponential discounting in this experiment. Further, we confirmed analytically that exponential discounting, with a decay rate comparable to that used by our subjects, maximized the total reward gain in our task. Our results suggest that the particular shape and steepness of temporal discounting is determined by the task that the subject is facing, and question the notion of hyperbolic reward discounting as a universal principle.

Crossover of aging dynamics in polymer glass: from cumulative aging to noncumulative aging.

The aging behavior of polymer glass, poly(methyl methacrylate), has been investigated through the measurement of the ac-dielectric susceptibility at a fixed frequency after a temperature shift deltaT (< or = 20 K) between two temperatures T1 and T2. A crossover from cumulative aging to noncumulative aging could be observed with increasing deltaT using a twin-temperature (T-) shift measurement. Based on the growth law of a dynamical coherent length given by activated dynamics, we obtain a unique coherent length for positive and negative T shifts. The possibility of the existence of temperature chaos in polymer glasses is discussed.

Monoclonal antibodies that detect different antigenic determinants of the same human osteosarcoma-associated antigen.

Monoclonal antibodies (MoAbs) against human osteosarcoma cells were obtained by the fusion of NS/1 mouse myeloma cells with spleen cells from the human osteosarcoma cell line-immunized BALB/c mice. Two hybrid clones were established and designated as 2H10 and 2D3. Both MoAbs reacted strongly with all osteosarcoma tissues but not with other bone and soft tissue tumors such as chondrosarcoma, malignant fibrous histiocytoma, liposarcoma, leiomyosarcoma, and rhabdomyosarcoma. In addition, neither MoAb reacted with tumor cell lines and tissues obtained from other cancers. Immunohistochemical analysis demonstrated that 2H10 and 2D3 reacted with endothelial cells in sarcoma tissues, but not with those of other tumors and normal tissues. 2H10 also reacted with cells on the basal layer of epidermis of the skin. 2H10- and 2D3-defined antigen has an approximate molecular weight of 75,000 under nonreducing and reducing conditions, indicating that the antigen has a single chain structure and there is no intramolecular disulfide bond. 2H10- and 2D3-defined antigen has a pI value between 5.5 and 6.2. Sequential immunoprecipitation analysis clearly demonstrated that 2H10 and 2D3 recognized the same antigen molecule. However, further analysis suggested the possibility that 2H10 and 2D3 MoAbs recognized the different antigenic determinants on the same antigen molecule.

Association of thalamic hyperactivity with treatment-resistant depression and poor response in early treatment for major depression: a resting-state fMRI study using fractional amplitude of low-frequency fluctuations.

Despite novel antidepressant development, 10-30% of patients with major depressive disorder (MDD) have antidepressant treatment-resistant depression (TRD). Although new therapies are needed, lack of knowledge regarding the neural mechanisms underlying TRD hinders development of new therapeutic options. We aimed to identify brain regions in which spontaneous neural activity is not only altered in TRD but also associated with early treatment resistance in MDD. Sixteen patients with TRD, 16 patients with early-phase non-TRD and 26 healthy control (HC) subjects underwent resting-state functional magnetic resonance imaging. To identify brain region differences in spontaneous neural activity between patients with and without TRD, we assessed fractional amplitude of low-frequency fluctuations (fALFF). We also calculated correlations between the percent change in the Hamilton Rating Scale for Depression (HRSD17) scores and fALFF values in brain regions with differing activity for patients with and without TRD. Patients with TRD had increased right-thalamic fALFF values compared with patients without TRD. The percent change in HRSD17 scores negatively correlated with fALFF values in patients with non-TRD. In addition, patients with TRD showed increased fALFF values in the right inferior frontal gyrus (IFG), inferior parietal lobule (IPL) and vermis, compared with patients with non-TRD and HC subjects. Our results show that spontaneous activity in the right thalamus correlates with antidepressant treatment response. We also demonstrate that spontaneous activity in the right IFG, IPL and vermis may be specifically implicated in the neural pathophysiology of TRD.

Lithium decreases 5-HT1 receptors but increases 5-HT-sensitive adenylate cyclase activity in rat hippocampus.

The effect of lithium (Li) treatment on serotonin1 (5-HT1) receptors and 5-HT-sensitive adenylate cyclase (ACase) activity in rat hippocampus was studied. [3H]5-HT binding to 5-HT1 receptors was decreased after either subacute (5 days) or chronic (3 weeks) treatment. In contrast, 5-HT-stimulated [3H]cyclic adenosine monophosphate ([3H]cAMP) formation was unchanged after 5 days of Li treatment, but was increased after 3 weeks of treatment. There was no difference in the inhibitory effects of guanosine triphosphate (GTP) on [3H]5-HT binding between the subacute Li and control groups. In addition, [3H]cAMP formation induced by GTP was not changed in the subacute group, whereas chronic treatment decreased it. These results suggested that chronic Li treatment caused the facilitation of 5-HT-sensitive ACase activity in spite of a decrease in the density of 5-HT1 receptors in the hippocampus. The enhancement of the coupling between receptor and ACase seemed not to be involved in these Li effects.

Decreased inositol 1,4,5-trisphosphate-specific binding in platelets from alcoholic subjects.

We measured the degree of inositol 1,4,5-triphosphate (IP3)-specific binding in platelets from alcoholic and nonalcoholic subjects. IP3-specific binding in alcoholic subjects was 45% less than that in nonalcoholic subjects. There was no significant difference in the number of IP3 receptors as detected immunologically in the platelet membrane fractions from alcoholic and nonalcoholic subjects. These results indicate that the decrease in IP3-specific binding in alcoholic subjects may have been due to a decreased affinity, but not number of IP3 binding sites. In contrast to the decrease in IP3 receptor binding, there were no significant changes in phospholipase-C activity or immunoreactivity of phospholipase C-beta 1 in platelet membranes from alcoholic subjects. The decreased IP3-specific binding in platelets may allow for the development of biological markers for alcoholism.

Possible involvement of presynaptic 5-HT autoreceptors in effect of lithium on 5-HT release in hippocampus of rat.

The effects of subacute treatment with lithium on the stimulation-induced release of serotonin (5-HT) and the function of 5-HT autoreceptors in the hippocampus and frontal cortex of the rat were studied. In the rats treated with lithium for 3 days, the high K+-evoked release of endogenous 5-HT from the slices of hippocampus, but not the slices of frontal cortex, was significantly increased. High K+-induced release of [3H]5-HT from the slices of hippocampus of control rats preloaded with [3H]5-HT was decreased when the slices were exposed to 5-HT, while it was increased when they were exposed to methiothepin. In the slices of hippocampus from the lithium-treated rats, this inhibitory effect of 5-HT on the release of [3H]5-HT, evoked by either high K+ or electrical stimulation was significantly attenuated. On the other hand, it was not modified in the slices of frontal cortex. The results suggest that lithium may inhibit the function of 5-HT autoreceptors to regulate the release of 5-HT. This action may, in part, trigger the development of the down-regulation of 5-HT1 receptors occurring in the hippocampus but not in the frontal cortex after chronic treatment with lithium.

The effects of electroconvulsive shock or imipramine on subtypes of alpha 1-adrenoceptors in the frontal cortex of the rat.

The effects of repeated treatment (14 days) with electroconvulsive shock (ECS) or imipramine on binding sites on alpha 1-adrenoceptors in the rat were studied. The binding of [3H]prazosin studied with WB4101 and phentolamine, as binding inhibitors, showed the existence of two subtypes of alpha 1-adrenoceptor (alpha 1A and alpha 1B). Proportions of the alpha 1A and alpha 1B binding sites were about 3:7 in the frontal cortex and 9:1 in the hippocampus. Pretreatment of the membranes with chlorethylclonidine (CEC) almost abolished the alpha 1B binding sites. Inhibition of the binding of [3H]prazosin studied with antidepressants (imipramine, desipramine, maprotiline and mianserin) showed that these drugs bound to alpha 1-adrenoceptors with low affinity, in an apparent monophasic manner. The characteristics of the alpha 1A and alpha 1B binding sites were studied by the binding assay with [3H]prazosin, in the presence of a small concentration (2 nM) of WB4101 to mask the alpha 1A binding sites, as well as the assay without WB4101, for the total alpha 1-adrenoceptor (alpha 1A and alpha 1B) binding. Repeated treatment with electroconvulsive shock increased but that with imipramine decreased, the density of the alpha 1B binding sites in the frontal cortex, without change of the affinity. Neither treatment affected the alpha 1A binding sites in the frontal cortex. The alpha 1-adrenoceptors (alpha 1A and alpha 1B) in the hippocampus were not affected at all by these repeated treatments. The electroconvulsive shock-induced increase in the alpha 1B binding sites in the frontal cortex of the rat could contribute to differences in clinical effects between electroconvulsive shock and antidepressant drugs.

Morphine antagonizes pentobarbital-induced anesthesia.

Morphine was administered by the intracerebroventricular (i.c.v.) route to pentobarbital-anesthetized rabbits. Small doses of morphine (less than 150 micrograms) potentiated, but larger doses (greater than 250 micrograms) shortened, the duration of anesthesia. In naltrexone-pretreated animals, all doses of morphine employed acted only as an analeptic. Atropine, but not atropine methylbromide, blocked the analeptic effect of morphine, indicating that a central cholinergic mechanism was involved in this response. Tolerance to the analeptic effect was not evident. These results suggest that morphine exerts an arousal action which is usually masked by the dominant narcotic properties, but which becomes evident when administered intracerebroventricularly or in the presence of naltrexone.

Reduction in levels of amphiphysin 1 mRNA in the hippocampus of aged rats subjected to repeated variable stress.

Various neurobiological studies of aging indicate that elevated levels of circulating glucocorticoids lead to hippocampal vulnerability to stress, though little is known about the molecular mechanism underlying stress vulnerability in the elderly. We have compared the gene expression profiles in the hippocampus of aged (20 months) and adult (3 months) rats in response to repeated variable stress (RVS) for 4 days, using a cDNA array technique and real-time quantitative PCR, to identify putative genes involved in the mechanism of stress vulnerability in the elderly. We found a significant decrease in the levels of amphiphysin 1 mRNA in aged rats subjected to RVS compared with treated and untreated adult rats or to untreated aged rats. Similarly, we found a significant decrease in hippocampal levels of amphiphysin 1 mRNA in aged rats subjected to RVS for 8 days, but not in those subjected to a single VS. These findings suggest that the decrease in the hippocampal levels of amphiphysin 1 mRNA in response to repeated stress may be involved in the stress vulnerability in the elderly, and may lead to the disturbance of learning and memory under stressful conditions in the elderly.

Enhancement of cyclic AMP accumulation mediated by 5-HT after chronic amitriptyline treatment in NG 108-15 cells.

1. The effects of chronic in vitro administration of amitriptyline, a tricyclic antidepressant, on 5-hydroxytryptamine (5-HT) receptor-mediated adenylyl cyclase activity was studied in the neuroblastoma x glioma hybrid cell line, NG 108-15. 2. Treatment of NG 108-15 cells with 8 microM amitriptyline for 3 days increased forskolin-stimulated (0.1 microM) adenosine 3':5'-cyclic monophosphate (cyclic AMP) accumulation. Addition of 5-HT (0.1-100 microM) increased forskolin-stimulated cyclic AMP accumulation in amitriptyline-treated cells in a concentration-dependent manner. However, 5-HT did not affect forskolin-stimulated cyclic AMP accumulation in untreated cells. 3. The 5-HT4 receptor agonist, 5-methoxytryptamine, significantly enhanced forskolin-stimulated cyclic AMP accumulation in amitriptyline-treated cells. In contrast, amitriptyline treatment failed to modify 8-hydroxy-2-(di-n-propylamine) tetralin-induced inhibition of forskolin-stimulated cyclic AMP accumulation. 4. Pretreatment of cells with pertussis toxin did not affect the 5-HT-induced enhancement of cyclic AMP accumulation. 5. The 5-HT-induced enhancement of cyclic AMP accumulation in amitriptyline-treated cells was attenuated by the 5-HT4 receptor antagonists, GR 113808 and ICS 205-930, with relatively low potency. However, spiperone, SCH 23390, and pindolol were completely ineffective against this 5-HT-induced enhancement. 6. Chronic treatment with amitriptyline did not modify the cyclic AMP production stimulated by prostaglandin E1 or cholera toxin. This treatment also had no effect on GTP gamma S-, NaF-, and Mn(2+)-stimulated cyclic AMP accumulation in isolated cell membranes. 7. Chronic treatment with the 5-HT receptor antagonists, pindolol or ICS 205-930, did not inhibit the 5-HT-induced enhancement of cyclic AMP accumulation.8. Chronic treatment with other antidepressant drugs, imipramine, mianserin or paroxetine, elicited the 5-HT-induced enhancement of cyclic AMP accumulation.9. Taken together, these results suggest that chronic amitriptyline treatment of NG 108-15 cells causes 5-HT to enhance forskolin-stimulated cyclic AMP accumulation by enhancing 5-HT receptor-mediated stimulation of adenylyl cyclase and not by reducing 5-HT-mediated inhibition of adenylyl cyclase. The 5-HT-induced enhancement of cyclic AMP accumulation in amitriptyline-treated cells may result from changes at the level of the 5-HT receptor rather than at the level of G, proteins or adenylyl cyclase. It is unlikely that this enhancement of cyclic AMP accumulation is caused by long-term antagonism of the 5-HT receptor by amitriptyline.

Chronic lithium treatment enhances the postsynaptic 5-HT1A receptor-mediated 5-HT behavioral syndrome induced by 8-OH-DPAT in rats via catecholaminergic systems.

The effects of antimanic agents, including lithium, carbamazepine, clonazepam and zotepine, on the postsynaptic 5-HT1A receptor-mediated behavioral and hypothermic responses induced by 8-OH-DPAT in rats, and on [3H]8-OH-DPAT binding to 5-HT1A receptors in the rat hippocampus were examined. Treatment with lithium (3 mEq/kg, IP) for 14 days enhanced forepaw treading, one component of the 5-HT behavioral syndrome induced by 8-OH-DPAT, and this enhancement by lithium was abolished by catecholamine depletion with reserpine or alpha-methyl-p-tyrosine, but not by 5-HT depletion with p-chlorophenylalanine. These data suggest that lithium enhances 5-HT1A-mediated behavior via catecholaminergic systems. In contrast, chronic lithium treatment did not alter the hypothermic response to 8-OH-DPAT in untreated rats, as well as in rats treated with reserpine. These findings strengthen the suggestion that lithium has no direct influence on the postsynaptic 5-HT1A-mediated response. Other antimanic agents had no effect on either forepaw treading or hypothermia induced by 8-OH-DPAT. Radioligand binding studies using [3H]-8-OH-DPAT demonstrated that chronic lithium treatment, but not other antimanic agents, caused 5-HT1A receptor down-regulation in rat hippocampus. A discrepancy therefore exists between 5-HT1A receptor down-regulation and unaltered 5-HT1A-mediated behavioral and hypothermic responses in catecholamine-depleted rats after chronic lithium treatment.

5-HT1A receptor-mediated inhibition of nucleus accumbens neurons activated by stimulation of parafascicular nucleus of thalamus.

Electrophysiological studies using chloral hydrate-anesthetized rats were performed to elucidate the role of serotonin1A (5-HT1A) receptors in the regulation of neuronal activity of nucleus accumbens (Acc) neurons receiving input from the parafascicular nucleus of the thalamus (Pf). Extracellular neuronal activities were recorded in Acc using a glass microelectrode attached along a seven-barreled micropipette, each barrel of which was filled with dopamine, 5-HT, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT: 5-HT1A agonist) hydrobromide, 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]-piperazine (NAN-190: 5-HT1A antagonist) hydrobromide, glutamate and 2 M NaCl. These drugs were microiontophoretically applied to the immediate vicinity of the target neuron. Spikes elicited by Pf stimulation were inhibited by iontophoretically applied dopamine, 5-HT and 8-OH-DPAT in a dose-dependent manner. In these neurons, firing induced by iontophoretic application of glutamate was also suppressed by dopamine, 5-HT and 8-OH-DPAT. The 5-HT or 8-OH-DPAT-induced inhibitions of the glutamate-induced firing were antagonized by concomitant application of NAN-190. These findings suggest that the dopamine-sensitive Acc neurons receiving input from Pf are inhibited by 5-HT via 5-HT1A receptors located on postsynaptic Acc neurons.

Chronic lithium treatment increases the expression of brain-derived neurotrophic factor in the rat brain.

RATIONALE: Lithium is the most widely prescribed mood stabilizer, but the precise mechanism of lithium is unresolved. OBJECTIVE: We examine the effects of the administration of therapeutically relevant concentrations of lithium on the expression of brain-derived neurotrophic factor (BDNF) and its receptor, Trk B, as well as glia-derived neurotrophic factor (GDNF) and its receptors, RET and GDNFR-alpha, in the rat brain. In addition, we also examined the effect of another well-prescribed mood stabilizer, valproate, on the expression of BDNF and GDNF. METHODS: Rats were kept on a 0.2% lithium carbonate-containing diet for 1, 7, 14, or 28 days or treated with valproate (400 mg/kg per day i.p.) for 1 or 14 days. After the brains were rapidly removed, the levels of BDNF, GDNF, and their receptors were measured by ELISA or western blot analysis. RESULTS: Chronic lithium treatment for 14 and 28 days significantly increased the expression of BDNF in the hippocampus and temporal cortex. In addition, chronic lithium treatment for 14 days significantly increased the expression of BDNF in the frontal cortex. In contrast, acute or chronic dietary lithium treatment did not alter GDNF expression in these brain regions. In addition, acute or chronic lithium treatments did not change the levels of Trk B, RET, or GDNFR-alpha immunoreactivity. As well as lithium, repeated administration of valproate also increased the expression of BDNF in the frontal cortex and hippocampus. CONCLUSIONS: Our results suggest that the chronic administration of mood stabilizers may produce a neurotrophic effect mediated by the upregulation of BDNF in the rat brain.