Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Few and often contradictory reports exist on the long-term neurobiological consequences of cannabinoid consumption in adolescents. The endocannabinoid system plays an important role during the different stages of brain development as cannabinoids influence the release and action of different neurotransmitters and promote neurogenesis. This study tested whether long-lasting interference by cannabinoids with the developing endogenous cannabinoid system during adolescence caused persistent behavioral alterations in adult rats. Adolescent female and male rats were treated with increasing doses of Delta(9)-tetrahydrocannabinol (THC) for 11 days (postnatal day (PND) 35-45) and left undisturbed until adulthood (PND 75) when behavioral and biochemical assays were carried out. CB1 receptor level and CB1/G-protein coupling were significantly reduced by THC exposure in the amygdala (Amyg), ventral tegmental area (VTA) and nucleus accumbens (NAc) of female rats, whereas male rats had significant alterations only in the amygdala and hippocampal formation. Neither female nor male rats showed any changes in anxiety responses (elevated plus maze and open-field tests) but female rats presented significant 'behavioral despair' (forced swim test) paralleled by anhedonia (sucrose preference). In contrast, male rats showed no behavioral despair but did present anhedonia. This different behavioral picture was supported by biochemical parameters of depression, namely CREB alteration. Only female rats had low CREB activity in the hippocampal formation and prefrontal cortex and high activity in the NAc paralleled by increases in dynorphin expression. These results suggest that heavy cannabis consumption in adolescence may induce subtle alterations in the emotional circuit in female rats, ending in depressive-like behavior, whereas male rats show altered sensitivity to rewarding stimuli.
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PMID:Chronic delta 9-tetrahydrocannabinol during adolescence provokes sex-dependent changes in the emotional profile in adult rats: behavioral and biochemical correlates. 1817 30

Despite limited understanding of the pathophysiology of depression and the underlying mechanisms mediating antidepressant effects, there are several efficient treatments. The anhedonia symptoms of depression are characterized by decreased motivation and drive and imply possible malfunctioning of the mesolimbic dopamine system, whereas cognitive deficits might reflect decreased plasticity in hippocampus. In female Flinders Sensitive Line (FSL) rats, a model of depression, we compared the effects of three long-term antidepressant treatments: voluntary running, escitalopram and the combination of both on antidepressant-like behaviour in the Porsolt swim test (PST), and on regulation of mRNA for dopamine and neuropeptides in striatal dopamine pathways and brain-derived neurotrophic factor (BDNF) in hippocampus. Escitalopram diet attenuated running behaviour in FSL rats but not in non-depressed controls rats. In the PST the running group had increased climbing activity (noradrenergic/dopaminergic response), whereas the combination of escitalopram and running-wheel access increased swimming (serotonergic response). Running elevated mRNA for dynorphin in caudate putamen and BDNF in hippocampus. The combined treatment down-regulated D1 receptor and enkephalin mRNA in accumbens. Escitalopram alone did not affect behaviour or mRNA levels. We demonstrate a novel behavioural effect of escitalopram, i.e. attenuation of running in 'depressed' rats. The antidepressant-like effect of escitalopram was dependent on the presence of a running wheel, but not actual running indicating that the environment influenced the antidepressant effect of escitalopram. Different patterns of mRNA changes in hippocampus and brain reward pathways and responses in the PST by running and escitalopram suggest that antidepressant-like responses by running and escitalopram are achieved by different mechanisms.
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PMID:Housing conditions modulate escitalopram effects on antidepressive-like behaviour and brain neurochemistry. 1857 Jul 3

There is accumulating evidence that the nucleus accumbens (NAc) plays an important role in the pathophysiology of depression. Given that clinical depression is marked by anhedonia (diminished interest or pleasure), dysfunction of the brain reward pathway has been suggested as contributing to the pathophysiology of depression.Since the NAc is the center of reward and learning, it is hypothesized that anhedonia might be produced by hampering the function of the NAc. Indeed, it has been reported that stress, drug exposure and drug withdrawal, all of which produce a depressive-phenotype, alter various functions within the NAc, leading to inhibited dopaminergic activity in the NAc.In this review, we describe various factors as possible candidates within the NAc for the initiation of depressive symptoms. First, we discuss the roles of several neurotransmitters and neuropeptides in the functioning of the NAc, including dopamine, glutamate, gamma-aminobutyric acid (GABA), acetylcholine, serotonin, dynorphin, enkephaline, brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), melanin-concentrating hormone (MCH) and cocaine- and amphetamine-regulated transcript (CART). Second, based on previous studies, we propose hypothetical relationships among these substances and the shell and core subregions of the NAc.
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PMID:Neurochemistry of the nucleus accumbens and its relevance to depression and antidepressant action in rodents. 1865 37

Stress and anxiety are mainly regulated by amygdala and hypothalamic circuitries involving several neurotransmitter systems and providing physiological responses to peripheral organs via the hypothalamic-pituitary-adrenal axis and other pathways. The role of endogenous opioid peptides in this process is largely unknown. Here we show for the first time that anxiolytic parameters of explorative behavior in mice lacking prodynorphin were increased 2-4-fold in the open field, the elevated plus maze and the light-dark test. Consistent with this, treatment of wild-type mice with selective kappa-opioid receptor antagonists GNTI or norbinaltorphimine showed the same effects. Furthermore, treatment of prodynorphin knockout animals with U-50488H, a selective kappa-opioid receptor agonist, fully reversed their anxiolytic phenotype. These behavioral data are supported by an approximal 30% reduction in corticotropin-releasing hormone (CRH) mRNA expression in the hypothalamic paraventricular nucleus and central amygdala and an accompanying 30-40% decrease in corticosterone serum levels in prodynorphin knockout mice. Although stress-induced increases in corticosterone levels were attenuated in prodynorphin knockout mice, they were associated with minor increases in depression-like behavior in the tail suspension and forced swim tests. Taken together, our data suggest a pronounced impact of endogenous prodynorphin-derived peptides on anxiety, but not stress coping ability and that these effects are mediated via kappa-opioid receptors. The delay in the behavioral response to kappa-opioid receptor agonists and antagonist treatment suggests an indirect control level for the action of dynorphin, probably by modulating the expression of CRH or neuropeptide Y, and subsequently influencing behavior.
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PMID:Prodynorphin-derived peptides are critical modulators of anxiety and regulate neurochemistry and corticosterone. 1880 67

Methylphenidate (MPH) is commonly prescribed in childhood and adolescence for the treatment of attention-deficit/hyperactivity disorders. In rodents, MPH exposure during preadolescence (postnatal days (PD) 20-35) causes decreased sensitivity to drug and natural rewards, while enhancing a negative emotional state characterized by increased sensitivity to aversive situations later in adulthood. It has been proposed that this behavioral profile may be mediated, at least in part, by changes in the expression of dynorphin, the endogenous ligand for kappa-opioid receptors (KORs). Because increases in dynorphin activity and activation of KOR induce aversive states, we examined the possibility that these behavioral deficits may be mediated by changes in KOR function, and that MPH-exposed rats would demonstrate increased sensitivity to the kappa-agonist U-50488. Sprague-Dawley male rats were treated with MPH (2 mg/kg) or its saline vehicle (VEH) during PD20-35. When adults (PD90+), these rats were divided into groups receiving saline, U-50488 (5 mg/kg), or nor-binaltorphimine (20 mg/kg), a kappa-antagonist, and their behavioral reactivity to various emotion-eliciting stimuli was assessed. Results show that MPH exposure decreases cocaine place conditioning and sucrose preference, while increasing vulnerability to anxiety (elevated plus maze)- and stress (forced swimming)-eliciting situations, and that these behavioral deficits can be intensified by U-50488, while being normalized by nor-binaltorphimine treatment. These results are consistent with the notion that dysregulated dynorphin/kappa-opioid systems may mediate deficits in behavioral responding after developmental MPH exposure. Moreover, these findings further support the idea of kappa-antagonists as potential pharmacotherapy for the treatment of anxiety- and depression-related disorders.
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PMID:Kappa-opioid system regulates the long-lasting behavioral adaptations induced by early-life exposure to methylphenidate. 1892 99

The dynorphin (DYN)-kappa opioid receptor (kappaOR) system has been implicated in stress modulation, depression, and relapse to drug-seeking behaviors. Previous anatomical and physiological data have indicated that the noradrenergic nucleus locus coeruleus (LC) is one site at which DYN may contribute to these effects. Using light microscopy, immunofluorescence, and electron microscopy, the present study investigated the cellular substrates for pre- and postsynaptic interactions of kappaOR in the LC. Dual immunocytochemical labeling for kappaOR and tyrosine hydroxylase (TH) or kappaOR and preprodynorphin (ppDYN) was examined in the same section of tissue. Light microscopic analysis revealed prominent kappaOR immunoreactivity in the nuclear core of the LC and in the peri-coerulear region where noradrenergic dendrites extend. Fluorescence and electron microscopy revealed kappaOR immunoreactivity within TH-immunoreactive somata and dendrites in the LC as well as localized to ppDYN-immunoreactive processes. In sections processed for kappaOR and TH, approximately 29% (200/688) of the kappaOR-containing axon terminals identified targeted TH-containing profiles. Approximately 49% (98/200) of the kappaOR-labeled axon terminals formed asymmetric synapses with TH-labeled dendrites. Sections processed for kappaOR and ppDYN showed that, of the axon terminals exhibiting kappaOR, 47% (223/477) also exhibited ppDYN. These findings indicate that kappaORs are poised to modulate LC activity by their localization to somata and dendrites. Furthermore, kappaORs are strategically localized to presynaptically modulate DYN afferent input to catecholamine-containing neurons in the LC. These data add to the growing literature showing that kappaORs can modulate diverse afferent signaling to the LC.
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PMID:Subcellular targeting of kappa-opioid receptors in the rat nucleus locus coeruleus. 1900 91

Several lines of evidence suggest that D-amphetamine (D-AMPH) withdrawal induces a syndrome with symptoms similar to major depressive disorder (MDD). Upregulation of dynorphin (DYN) may underlie the symptoms of MDD and contribute to the negative emotional symptoms associated with psychostimulant withdrawal. Changes in the serotonin transporter (SERT) have also been reported in MDD, and changes in the immediate early gene c-fos have been observed in the context of psychostimulant withdrawal. This study examined the effects of chronic, escalating doses of D-AMPH followed by 24 h of withdrawal on the expression of prodynorphin (PD) and c-fos mRNA in limbic regions of the brain, caudate putamen (CPu), and brainstem and SERT mRNA expression in the dorsal raphe nucleus (DRN). Male Sprague-Dawley rats were treated three times a day for 4 days with escalating doses of D-AMPH (1-10 mg/kg) and sacrificed 24 h after the last injection. Following 24 h of withdrawal, there was an increase in PD and c-fos mRNA expression in the CPu and nucleus accumbens (NAc), and a decrease in PD and c-fos expression in hippocampus and amygdala. SERT mRNA expression was decreased in the DRN, and PD mRNA expression was increased in the adjacent ventrolateral periaqueductal gray (VLPAG) following D-AMPH withdrawal. These data indicate that region-specific changes in PD and c-fos expression occur after withdrawal, while SERT mRNA expression is suppressed, similar to what has been reported in MDD. Alterations in PD, c-fos, and SERT expression could contribute to the depression-like syndrome associated with psychostimulant withdrawal.
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PMID:Differential regulation of prodynophin, c-fos, and serotonin transporter mRNA following withdrawal from a chronic, escalating dose regimen of D-amphetamine. 1911 47

Since the first description of their opioid properties three decades ago, dynorphins have increasingly been thought to play a regulatory role in numerous functional pathways of the brain. Dynorphins are members of the opioid peptide family and preferentially bind to kappa opioid receptors. In line with their localization in the hippocampus, amygdala, hypothalamus, striatum and spinal cord, their functions are related to learning and memory, emotional control, stress response and pain. Pathophysiological mechanisms that may involve dynorphins/kappa opioid receptors include epilepsy, addiction, depression and schizophrenia. Most of these functions were proposed in the 1980s and 1990s following histochemical, pharmacological and electrophysiological experiments using kappa receptor-specific or general opioid receptor agonists and antagonists in animal models. However, at that time, we had little information on the functional relevance of endogenous dynorphins. This was mainly due to the complexity of the opioid system. Besides actions of peptides from all three classical opioid precursors (proenkephalin, prodynorphin, proopiomelanocortin) on the three classical opioid receptors (delta, mu and kappa), dynorphins were also shown to exert non-opioid effects mainly through direct effects on NMDA receptors. Moreover, discrepancies between the distribution of opioid receptor binding sites and dynorphin immunoreactivity contributed to the difficulties in interpretation. In recent years, the generation of prodynorphin- and opioid receptor-deficient mice has provided the tools to investigate open questions on network effects of endogenous dynorphins. This article examines the physiological, pathophysiological and pharmacological implications of dynorphins in the light of new insights in part obtained from genetically modified animals.
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PMID:30 years of dynorphins--new insights on their functions in neuropsychiatric diseases. 1948 70

Stress is a complex experience that carries both aversive and motivating properties. Chronic stress causes an increase in the risk of depression, is well known to increase relapse of drug seeking behavior, and can adversely impact health. Several brain systems have been demonstrated to be critical in mediating the negative affect associated with stress, and recent evidence directly links the actions of the endogenous opioid neuropeptide dynorphin in modulating mood and increasing the rewarding effects of abused drugs. These results suggest that activation of the dynorphin/kappa opioid receptor (KOR) system is likely to play a major role in the pro-addictive effects of stress. This review explores the relationship between dynorphin and corticotropin-releasing factor (CRF) in the induction of dysphoria, the potentiation of drug seeking, and stress-induced reinstatement. We also provide an overview of the signal transduction events responsible for CRF and dynorphin/KOR-dependent behaviors. Understanding the recent work linking activation of CRF and dynorphin/KOR systems and their specific roles in brain stress systems and behavioral models of addiction provides novel insight to neuropeptide systems that regulate affective state.
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PMID:The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors. 1971 11

Stress is most often associated with aversive states. It rapidly induces the release of hormones and neuropeptides including dynorphin, which activates kappa opioid receptors (KORs) in the central and peripheral nervous systems. In animal models, many aversive effects of stress are mimicked or exacerbated by stimulation of KORs in limbic brain regions. Although KOR signaling during acute stress may increase physical ability (by producing analgesia) and motivation to escape a threat (by producing aversion), prolonged KOR signaling in response to chronic or uncontrollable stress can lead to persistent expression of behavioral signs that are characteristic of human depressive disorders (i.e., "prodepressive-like" signs). Accumulating evidence suggests that KORs contribute to the progressive amplification (sensitization) of stress-induced behaviors that occurs with repeated exposure to stress. Many of the aversive effects of stress are blocked by KOR antagonists, suggesting that these agents may have potential as therapeutics for stress-related conditions such as depression and anxiety disorders. This review summarizes current data on how KOR systems contribute to the acute (rapid), delayed, and cumulative molecular and behavioral effects of stress. We focus on behavioral paradigms that provide insight on interactions between stress and KOR function within each of these temporal categories. Using a simplified model, we consider the time course and mechanism of KOR-mediated effects in stress and suggest future directions that may be useful in determining whether KOR antagonists exert their therapeutic effects by preventing the development of stress-induced behaviors, the expression of stress-induced behaviors, or both.
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PMID:Dynorphin, stress, and depression. 1978 55


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