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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chronic mild stress (CMS) model of depression has high validity but has in the past been criticized for being difficult to replicate. However, a large number of recent publications have confirmed that CMS causes behavioural changes in rodents that parallel symptoms of depression. This review summarizes studies from over sixty independent research groups that have reported decreases in reactivity to rewards, and a variety of other depression-like behaviours, in rats or mice, following exposure to CMS. Together, these changes are referred to as a 'depressive' behavioural profile. Almost every study that has examined the effects of chronic antidepressant treatment in these procedures has reported that antidepressants were effective in reversing or preventing these 'depressive' behavioural changes. (The single exception is a study in which the duration of treatment was too brief to constitute an adequate trial.) There are also a handful of reports of CMS causing significant effects in the opposite direction, termed here an 'anomalous' behavioural profile. There are six neurobiological parameters that have been studied in both 'anhedonic' and 'anomalous' animals: psychostimulant and place-conditioning effects of dopamine agonists; dopamine D2 receptor number and message; inhibition of dopamine turnover by quinpirole, and beta-adrenergic receptor binding. On all six measures, CMS caused opposite effects in animals displaying 'depressive' and 'anomalous' profiles. Thus, there is overwhelming evidence that under appropriate experimental conditions, CMS can cause antidepressant-reversible depressive-like effects in rodents; however, the 'anomalous' profile that is occasionally reported appears to be a genuine phenomenon, and these two sets of behavioural effects appear to be associated with opposite patterns of neurobiological changes.
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PMID:Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS. 1603 78

Prostate apoptosis response 4 (Par-4) is a leucine zipper containing protein that plays a role in apoptosis. Although Par-4 is expressed in neurons, its physiological role in the nervous system is unknown. Here we identify Par-4 as a regulatory component in dopamine signaling. Par-4 directly interacts with the dopamine D2 receptor (D2DR) via the calmodulin binding motif in the third cytoplasmic loop. Calmodulin can effectively compete with Par-4 binding in a Ca2+-dependent manner, providing a route for Ca2+-mediated downregulation of D2DR efficacy. To examine the importance of the Par-4/D2DR interaction in dopamine signaling in vivo, we used a mutant mouse lacking the D2DR interaction domain of Par-4, Par-4DeltaLZ. Primary neurons from Par-4DeltaLZ embryos exhibit an enhanced dopamine-cAMP-CREB signaling pathway, indicating an impairment in dopamine signaling in these cells. Remarkably, Par-4DeltaLZ mice display significantly increased depression-like behaviors. Collectively, these results provide evidence that Par-4 constitutes a molecular link between impaired dopamine signaling and depression.
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PMID:Par-4 links dopamine signaling and depression. 1605 Nov 41

The antinociceptive effect of ribavirin, an antiviral drug, was studied after systemic injection using several pain tests in mice. In the hot-plate test of thermal pain, capsaicin-induced chemogenic pain, formalin test and abdominal stretching assay induced by the i.p. injection of 0.6% acetic acid, ribavirin produced a dose-related reduction in nociceptive responses. The visceral antinociceptive effect of ribavirin was unaffected by co-treatment with yohimbine, atropine or theophylline, but partially reversed by naloxone. Antinociception by ribavirin was augmented by treatment with prazosin, doxazosin, propranolol, guanethidine, glibenclamide, baclofen, indomethacin or cysteamine. Further, the ribavirin induced antinociception was enhanced by D2 receptor antagonists haloperidol, sulpiride, clozapine or domperidone and by the dopamine D2 receptor agonist bromocryptine. Ribavirin did not exhibit depression-like effect, nor it influenced the effect of amitriptyline in the forced swimming test. It did not impair cognitive performance in the Morris water Maze test. The present data demonstrate that ribavirin administered via systemic route possesses visceral and thermal anti-nociceptive properties. The ribavirin analgesic effect was partially reversed by naloxone, an opioid antagonist.
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PMID:Antinociceptive and behavioral effects of ribavirin in mice. 1656 75

The striatum is a major forebrain nucleus that integrates cortical and thalamic afferents and forms the input nucleus of the basal ganglia. Striatal projection neurons target the substantia nigra pars reticulata (direct pathway) or the lateral globus pallidus (indirect pathway). Imbalances between neural activity in these two pathways have been proposed to underlie the profound motor deficits observed in Parkinson's disease and Huntington's disease. However, little is known about differences in cellular and synaptic properties in these circuits. Indeed, current hypotheses suggest that these cells express similar forms of synaptic plasticity. Here we show that excitatory synapses onto indirect-pathway medium spiny neurons (MSNs) exhibit higher release probability and larger N-methyl-d-aspartate receptor currents than direct-pathway synapses. Moreover, indirect-pathway MSNs selectively express endocannabinoid-mediated long-term depression (eCB-LTD), which requires dopamine D2 receptor activation. In models of Parkinson's disease, indirect-pathway eCB-LTD is absent but is rescued by a D2 receptor agonist or inhibitors of endocannabinoid degradation. Administration of these drugs together in vivo reduces parkinsonian motor deficits, suggesting that endocannabinoid-mediated depression of indirect-pathway synapses has a critical role in the control of movement. These findings have implications for understanding the normal functions of the basal ganglia, and also suggest approaches for the development of therapeutic drugs for the treatment of striatal-based brain disorders.
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PMID:Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson's disease models. 1728 9

Huntington's disease is a fatal neurodegenerative disorder characterised by a progressive motor, psychiatric and cognitive decline and associated with a marked loss of neurons in the cortex and striatum of affected individuals. The disease is inherited in an autosomal dominant fashion and is caused by a trinucleotide (CAG) repeat expansion in the gene encoding the protein huntingtin. Predictive genetic testing has revealed early cognitive deficits in asymptomatic gene carriers such as altered working memory, executive function and recognition memory. The perirhinal cortex is believed to process aspects of recognition memory. Evidence from primate studies suggests that decrements in neuronal firing within this cortical region encode recognition memory and that the underlying mechanism is an activity-dependent long-term depression (LTD) of excitatory neurotransmission, the converse of long-term potentiation (LTP). We have used the R6/1 mouse model of HD to assess synaptic plasticity in the perirhinal cortex. This mouse model provides an ideal tool for investigating early and progressive changes in synaptic function in HD. We report here that LTD at perirhinal synapses is markedly reduced in R6/1 mice. We also provide evidence to suggest that a reduction in dopamine D2 receptor signalling may be implicated.
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PMID:Abnormal cortical synaptic plasticity in a mouse model of Huntington's disease. 1735 33

Social isolation has profound effects on animal behavior and dopamine systems. We investigated the effect of social isolation on the dopamine receptor and neuropeptide mRNAs in the brain reward system in an animal model of depression, the Flinders Sensitive Line rats and Sprague-Dawley controls. We demonstrate that socially isolated but not group housed Flinders sensitive line rats had lower dopamine D2 receptor mRNA levels compared with Sprague-Dawley rats. Isolated and group housed Flinders Sensitive Line rats had higher levels of dopamine D1 receptor and substance P and enkephalin but not dynorphin mRNAs when compared with Sprague-Dawley rats. Our findings of decreased dopamine D2 receptor levels in socially isolated Flinders Sensitive Line rats suggest that low D2 receptor expression may play a role in pathophysiology of depression.
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PMID:Isolated Flinders Sensitive Line rats have decreased dopamine D2 receptor mRNA. 1755 92

Cordyceps sinensis (CS) has been known as a component of traditional medicines that elicit various biological effects such as anti-fatigue, immunomodulatory, and hypoglycemic actions. Since it has been well-established that fatigue is closely related to depression, we used the tail suspension test (TST) in mice to examine the antidepressant-like effects of hot water extract (HWCS) and supercritical fluid extract (SCCS) of CS. Immobility time in the TST was reduced by administration of SCCS (2.5-10 ml/kg, p.o.) dose-dependently though it was not reduced by treatment with HWCS (500-2000 mg/kg, p.o.). Neither HWCS nor SCCS altered locomotor activity in the open field test, excluding the possibility that the effect of SCCS is due to activation of locomotion. Pretreatment with prazosin (an adrenoreceptor antagonist) or sulpiride (a dopamine D2 receptor antagonist) reduced the effect of SCCS on the immobility time. In contrast, pretreatment with p-chlorophenylalanine (p-CPA, a serotonin synthesis inhibitor) did not alter the anti-immobility effect of SCCS. The last finding is consistent with an additional observation that SCCS had no effect on head twitch response induced by 5-hydroxy-L-tryptophan in mice. Taken altogether, these results suggest that SCCS may elicit an antidepressant-like effect by affecting the adrenergic and dopaminergic systems, but not by affecting the serotonergic system.
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PMID:Antidepressant-like effect of Cordyceps sinensis in the mouse tail suspension test. 1782 35

Long-term changes in the efficacy of glutamatergic synaptic transmission in the striatal complex are proposed to underlie motor learning and neuroadaptations leading to addiction. Dopamine and glutamate play key roles in the induction of long-term potentiation (LTP) and long-term depression (LTD) in the dorsal striatum, but their contribution to synaptic plasticity in the ventral striatum (nucleus accumbens, NAc) has been less extensively studied. We have examined the role of dopamine, glutamate and GABA in the induction of LTP in mouse brain slices containing the NAc. High-frequency stimulation of glutamatergic inputs elicited LTP of field excitatory postsynaptic potentials/population spikes (fEPSP/PSs) in the core region of the NAc. GABA did not seem to participate in LTP induction because LTP was not altered in the presence of either a GABA(A)- (bicuculline) or a GABA(B)- (CGP 55845) receptor antagonist. However, the dopamine D1 receptor antagonist SCH 23390, but not the dopamine D2 receptor antagonist sulpiride, impaired LTP. The dopamine reuptake blocker nomifensine also inhibited LTP induction. We found that group I metabotropic glutamate receptors (mGluRs) contribute to LTP induction because the mGluR1 antagonist LY 367385, or the mGluR5 antagonist MPEP, blocked LTP induction. Furthermore, the glutamate reuptake blocker DL-TBOA also impaired LTP. The present results demonstrate that dopamine and glutamate play critical roles in the mechanisms of induction of LTP in the NAc through the activation of dopamine D1 receptors and group I mGluRs. However, LTP is negatively regulated when endogenous levels of dopamine or glutamate are elevated.
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PMID:Dopamine D1 receptors and group I metabotropic glutamate receptors contribute to the induction of long-term potentiation in the nucleus accumbens. 1827 87

Abnormal dopamine signal transduction is implicated in the pathophysiology of schizophrenia. A recent study showed that prostate apoptosis response 4 protein (Par-4) interacts with dopamine D2 receptor and plays an important role in dopamine signaling. Par-4 knockout mice showed depression-like behavior, suggesting that Par-4 gene may be associated with mental disorders in human. The study was aimed to determine whether the PRKC, apoptosis, WT1, regulator gene (PAWR) that encodes the human homolog of Par-4 protein is a susceptibility gene for schizophrenia. We systematically screened for mutations at the 5' untranslated region (5'UTR) and all the exonic regions of the PAWR gene in a sample of Han Chinese schizophrenic patients from Taiwan. We identified two missense single nucleotide polymorphisms (SNPs) that are in strong linkage in our sample (D'=0.98), i.e. P78R at exon 2 and I199M at exon 3, respectively. SNP- and haplotype-based analysis showed that these two variants are associated with schizophrenia; there is an overrepresentation of RR homozygotes of P78R (OR=2.00, 95% CI=1.05-3.83) and MM homozygotes of I199M (OR=1.81, 95% CI=0.95-3.54) in schizophrenic patients as compared to control subjects. When subjects were divided by gender, the association is specifically with female patients (OR=2.94 for RR and OR=2.7 for MM), but not with male patients. Our results indicate that the PAWR gene is associated with schizophrenia in our population, and this study provides genetic evidence to support the dopamine hypothesis of schizophrenia.
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PMID:Association of missense variants of the PRKC, apoptosis, WT1, regulator (PAWR) gene with schizophrenia. 1828 Nov 37

The gaseous neurotransmitter nitric oxide plays an important role in the modulation of corticostriatal synaptic transmission. This study examined the impact of frontal cortex stimulation on striatal nitric oxide efflux and neuron activity in urethane-anesthetized rats using amperometric microsensor and single-unit extracellular recordings, respectively. Systemic administration of the neuronal nitric oxide synthase inhibitor 7-nitroindazole decreased spontaneous spike activity without affecting activity evoked by single-pulse stimulation of the ipsilateral cortex. Train (30 Hz) stimulation of the contralateral frontal cortex transiently increased nitric oxide efflux in a robust and reproducible manner. Evoked nitric oxide efflux was attenuated by systemic administration of 7-nitroindazole and the non-selective nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester. Train stimulation of the contralateral cortex, in a manner identical to that used to evoke nitric oxide efflux, had variable effects on spike activity assessed during the train stimulation trial, but induced a short-term depression of cortically evoked activity in the first post-train stimulation trial. Interestingly, 7-nitroindazole potently decreased cortically evoked activity recorded during the train stimulation trial. Moreover, the short-term depression of spike activity induced by train stimulation was enhanced following pretreatment with 7-nitroindazole and attenuated after systemic administration of the dopamine D2 receptor antagonist eticlopride. These results demonstrate that robust activation of frontal cortical afferents in the intact animal activates a powerful nitric oxide-mediated feed-forward excitation which partially offsets concurrent D2 receptor-mediated short-term inhibitory influences on striatal neuron activity. Thus, nitric oxide signaling is likely to play an important role in the integration of corticostriatal sensorimotor information in striatal networks.
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PMID:Feed-forward excitation of striatal neuron activity by frontal cortical activation of nitric oxide signaling in vivo. 1837 Oct 82


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