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Gal Yadid

Publications and source records attributed to Gal Yadid.

At least 19 recordsLinked to original sources
PubMed2006

Dopamine-2 receptors in the arcuate nucleus modulate cocaine-seeking behavior.

Beta-endorphin is an endogenous opioid peptide, implicated in the behavioral effects of drugs of abuse. It is synthesized in the arcuate nucleus and secreted into the nucleus accumbens. In the present study, we examined the interaction between arcuate nucleus dopaminergic cells and accumbal beta-endorphin, during cocaine exposure. Using microdialysis, we found that blockade of arcuate dopamine-2 receptors with a selective antagonist significantly attenuated cocaine-induced increases of beta-endorphin levels in the nucleus accumbens. Moreover, rats chronically exposed to cocaine using the self-administration paradigm displayed extinction-like behavior following blockade of dopamine-2 receptors. These findings indicate that dopaminergic neurons in the arcuate nucleus may induce the secretion of beta-endorphin in the nucleus accumbens, and that they are implicated in the cocaine reward pathway.

Animals↗
PubMed2006

DHEA, a neurosteroid, decreases cocaine self-administration and reinstatement of cocaine-seeking behavior in rats.

Dehydroepiandrosterone (DHEA), which can act as a potential antidepressant in both animals and humans, appears to lower distress involved with cocaine withdrawal. In fact, a role for neurosteroids in modulation of substance-seeking behavior is becoming increasingly clear. Therefore, we tested the effects of DHEA on the self-administration of cocaine (1 mg/kg/infusion) by rats. At maintenance, a relatively low dose of exogenous DHEA (2 mg/kg; i.p.) attenuated cocaine self-administration after several days of chronic treatment. More than 2 weeks (19 days) of daily DHEA injections were required to decrease the cocaine-seeking behavior of rats to less than 20% of their maintenance levels. DHEA does not seem to decrease cocaine self-administration by increasing the reinforcing properties of the drug, as indicated by a cocaine dose-response determination. After being subjected to extinction conditions in the presence of DHEA, rats demonstrated a minimal response to acute exposure to cocaine (10 mg/kg), which indicated a protective effect of DHEA on relapse to cocaine usage. Our results suggest a potential role for the neurosteroid DHEA in controlling cocaine-seeking behavior, by reducing both the desire for cocaine usage and the incidence of relapse.

Adjuvants, Immunologic↗
PubMed2006

Dopamine-1 receptor agonist, but not cocaine, modulates sigma(1) gene expression in SVG cells.

It has been hypothesized that sigma(1) receptors (sigma(1)Rs) are involved in the effects of cocaine abuse. Many in vitro and in vivo studies have already indicated an influence of sigma(1)R ligands on dopaminergic transmission; however, the direct effect on the brain is poorly understood. Herein we describe the effects of cocaine and the selective dopamine-1 receptor (D(1)R) agonist, (+)-SKF38393, on gene expression of the sigma(1)R in a human fetal astrocyte cell line (SVG cells). This study provides the first evidence for the expression of sigma(1)RmRNAin these cells. Our results show that treatment of SVG cells with various cocaine concentrations for several time durations showed no significant alterations in sigma(1)R gene expression, as detected by real-time quantitative RT-PCR, whereas treating cells for 24 h with (+)-SKF38393 caused a significant down-regulation in sigma(1) transcripts. This (+)-SKF38393-induced effect was blocked by the D(1)R selective antagonist (+)-SCH23390. These results suggest that the effect of cocaine on sigma(1) gene expression in the brain might be indirect and mediated through D(1)R.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2006

Modulation of dopamine transmission by 5HT2C and 5HT3 receptors: a role in the antidepressant response.

Dopaminergic mesolimbic and mesocortical systems are fundamental in hedonia and motivation. Therefore their regulation should be central in understanding depression treatment. This review highlights the dopaminergic activity in relation to depressive behavior and suggests two putative receptors as potential targets for research and development of future antidepressants. In this article we review data that describe the role of serotonin in regulating dopamine release, via 5HT2C and 5HT3 receptors. This action of serotonin appears to be linked to depressive-like behavior and to onset of behavioral effects of antidepressants in an animal model of depression. We suggest that drugs or strategies that decrease 5HT2C and increase 5HT3 receptor-mediated dopamine release in the limbic areas of the brain may provide a fast onset of therapeutic effect. Clinical and basic research data supporting this hypothesis are discussed.

Animals↗
PubMed2005

Dehydroepiandrosterone (DHEA) attenuates cocaine-seeking behavior in the self-administration model in rats.

The aim of this study was to determine the possible involvement of the neurosteroid dehydroepiandrosterone (DHEA) in cocaine-seeking behavior in a self-administration model in rats. DHEA pretreatment (continued thereafter concomitantly with cocaine self-administration) attenuated cocaine-seeking behavior and elevated the levels of dopamine and serotonin in several brain regions relevant to cocaine addiction. Chronic cocaine self-administration induced elevation in brain DHEA, its sulfate ester, DHEAS, and pregnenolone. The increased brain DHEA following cocaine self-administration may serve as a compensatory protective mechanism geared to attenuate the craving for cocaine. Such anti-craving activity is further enhanced by DHEA treatment before and during cocaine self-administration.

Affect↗
PubMed2005

Two different putative genetic animal models of childhood depression.

BACKGROUND: In an attempt to model childhood depression, we examined whether existing genetic animal models of depression in adult rats are also valid in prepubertal rats. METHODS: Two different "depressed" rat lines were studied: the Flinders Sensitive Line (FSL) and their controls, Sprague-Dawley (SD); and the Wistar Kyoto (WKY) line and their controls, Wistar. We hypothesized that male prepubertal FSL and WKY rats would show increased swim test immobility and different patterns of social play and of basal plasma levels of corticosterone and adrenocorticotropic hormone (ACTH) compared with control rats. RESULTS: Prepubertal FSL and WKY rats exhibited significantly longer duration of immobility than control rats in the swim test. The FSL rats demonstrated significantly higher levels of social play behaviors and lower levels of corticosterone and ACTH compared with SD control rats, whereas WKY rats demonstrated significantly lower levels of social play behaviors and higher plasma levels of corticosterone and ACTH compared with Wistar control rats. CONCLUSIONS: The results might suggest that prepubertal FSL and WKY rats are both putative genetic animal models of childhood depression, exhibiting separate patterns and symptoms of childhood depression.

Adrenocorticotropic Hormone↗
PubMed2005

The Flinders Sensitive Line rat: a selectively bred putative animal model of depression.

The Flinders Sensitive Line (FSL) rats were originally selectively bred for increased responses to an anticholinesterase agent. The FSL rat partially resembles depressed individuals because it exhibits reduced appetite and psychomotor function but exhibits normal hedonic responses and cognitive function. The FSL rat also exhibits sleep and immune abnormalities that are observed in depressed individuals. Neurochemical and/or pharmacological evidence suggests that the FSL rat exhibits changes consistent with the cholinergic, serotonergic, dopaminergic, NPY, and circadian rhythm models but not the noradrenergic, HPA axis or GABAergic models of depression. However, evidence for the genetic basis of these changes is lacking and it remains to be determined which, if any, of the neurochemical changes are primary to the behavioral alterations. The FSL rat model has been very useful as a screen for antidepressants because known antidepressants reduced swim test immobility when given chronically and psychomotor stimulants did not. Furthermore, rolipram and a melatonin agonist were shown to have anti-immobility effects in the FSL rats and later to have antidepressant effects in humans. Thus, the FSL rat model of depression exhibits some behavioral, neurochemical, and pharmacological features that have been reported in depressed individuals and has been very effective in detecting antidepressants.

Animals↗
PubMed2005

Variability of the mesolimbic neuronal activity in a rat model of depression.

The Flinders Sensitive Line of rats is a widely accepted and validated model of depression. These rats demonstrate abnormalities in limbic dopamine neurotransmission, suggesting disturbed neuronal activity in the ventral tegmental area. Interspike interval time series were recorded from the ventral tegmental area of the control Sprague-Dawley and Flinders Sensitive Line rats. These data were analyzed for the variance of interspike interval for each group of animals. We found that FSL rats show a significant decrease in the variance of 0.25-0.5-s-long interspike intervals. Moreover, these abnormalities were normalized following 14-day treatment with desipramine. We suggest that the interspike intervals at this range may have an important role in the information encoding of mesolimbic dopaminergic activity. Impaired variance of the length of interspike intervals in this area may correspond to the pathophysiology of depression, and hence be a possible marker for the analysis of the efficiency of antidepressant treatment.

Action Potentials↗
PubMed2005

Increased arachidonic acid concentration in the brain of Flinders Sensitive Line rats, an animal model of depression.

Depression may be associated with impaired membrane PUFA composition, especially decreased n-3 PUFA. This assumption has not been tested at the level of brain tissue. Moreover, most studies were confounded by dietary variability. We examined the FA composition of selected brain areas in an animal model of depression, the Flinders Sensitive Line (FSL) rat, and compared the findings with those in controls fed identical diets. In all brain regions studied, the concentration of arachidonic acid (AA) was significantly higher in the FSL rats: in the hypothalamus by 21%, in the nucleus accumbens by 24%, in the prefrontal cortex by 31%, and in the striatum by 23%. No significant differences were observed for n-3 PUFA or for the saturated and monounsaturated FAs. Our results confirm the existence of altered brain PUFA composition in an animal model of depression. The finding of increased AA, an n-6 PUFA, rather than decreased n-3 PUFA, emphasizes the importance of both PUFA families in the pathophysiological processes underlying depression. The FSL rat is a useful tool for further elucidation of the FA disturbances in depression.

Animals↗
PubMed2005

Abnormal patterns of maternal behavior in a genetic animal model of depression.

The Flinders Sensitive Line (FSL) model is considered a genetic animal model of depression. Among other characteristics, FSL rats express stress-induced anhedonia and an abnormal dopaminergic system. Our hypothesis was that FSL rats would show abnormal maternal behaviors, especially reduced motivation to reach and care for pups and reduced licking and non-nutritive contact, based on their anhedonic characteristics. Mother-infant interactions were assessed by time limited observations in FSL and Sprague-Dawley (SD) controls. In study 1, differences were found in consummatory behaviors: FSL dams compared to SD dams showed less licking and significant decrease in non-nutritive contact from the first to the third postpartum weeks. In addition, shorter duration of nursing postures was seen in FSL compared to SD dams in the first week postpartum, and this difference was significantly increased by the third week postpartum. In study 2, after exposure to acute swim stress, differences emerged in appetitive behaviors: latencies to reach and care for pups were longer in FSL dams compared to controls, suggesting a stress-induced motivational deficit in FSL dams. Possible explanations, especially regarding the FSL dams' reward system are discussed.

Analysis of Variance↗
PubMed2005

Immobility in the swim test and observations of maternal behavior in lactating Flinders sensitive line rats.

In order to elucidate the relationship between maternal behavior and depression, the Flinders sensitive line (FSL) model of depression was studied and compared to Sprague-Dawley (SD) controls. Immobility in the swim test was measured, as an index for depressive-like behavior, and frequencies of maternal and non-maternal behaviors were recorded using short un-intrusive observations in the home cage. Lactating FSL rats displayed higher levels of immobility in the swim test compared to controls, indicating depressive-like behavior. In addition, compared to SD rats, FSL dams showed less frequent pup licking and non-nutritive contact with pups during the first and third weeks of lactation. In the third postpartum week, FSL dams showed less frequent nursing postures and more frequent self-directed behaviors. Thus, lactating FSL dams exhibit both depressed-like behavior and some abnormalities in maternal behavior.

Analysis of Variance↗
PubMed2005

The involvement of dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) in blocking the therapeutic effect of electroconvulsive shocks in an animal model of depression.

Depressed patients with resistance to electroconvulsive treatment (ECT) had high basal serum levels of dehydroepiandrosterone (DHEA) sulfate (DHEAS). To clarify the role of DHEA/S in the ECT resistance, Flinder Sensitive Line (FSL) rats, which are a genetic animal model of depression, were injected i.p. with 2 mg/kg DHEA daily for 13 days to overload their serum and brain DHEA/S levels. Thereafter, rats were exposed to electroconvulsive shock (ECS), which is analogue to ECT in humans. Both ECS and DHEA displayed an antidepressive-like effect, as assessed by immobility time in forced swim test. However, combined DHEA and ECS treatment abolished these antidepressive-like effects. In addition, the levels of neurosteroids, corticosterone and adrenocorticotropin in selected brain regions were evaluated and compared to serum levels. The present study supports our assumption that high basal levels of DHEA/S play a role in the resistance to ECS and maybe ECT in humans.

Adrenocorticotropic Hormone↗
PubMed2005

Hyperfunctionality of serotonin-2C receptor-mediated inhibition of accumbal dopamine release in an animal model of depression is reversed by antidepressant treatment.

Dopamine release in the nucleus accumbens mediates motivation and reward, making it a likely candidate to be involved in anhedonia, one of the major symptoms of depression. In the current study, alterations in basal extracellular dopamine levels and 5HT2C receptor-mediated inhibition of accumbal dopamine release in Flinders Sensitive Line (FSL) rats, an animal model of depression, were investigated. We found that FSL rats have decreased extracellular dopamine levels in the nucleus accumbens and an increased inhibitory-like effect of 5HT2C receptors on accumbal dopamine release. However, neither basal 5HT levels nor the accumbal 5HT response to the local 5HT2C receptor antagonist (RS 102221) differed between Sprague-Dawley and FSL rats. Seven-day treatment with the nefazodone (a serotonin/noradrenaline reuptake inhibitor and 5HT2C antagonist) as well as 7-day and 14-day treatments with a tricyclic antidepressant desipramine increased extracellular dopamine levels in the nucleus accumbens of FSL rats. However, only 14-day treatment with desipramine or 7-day treatment with nefazodone, but not 7-day treatment with desipramine, decreased 5HT2C receptor-mediated inhibition of accumbal dopamine release. Based on a possible correlation between the onset of 5HT2C receptor-mediated inhibition and the behavioral effects of desipramine and nefazodone treatment that was described in our previous studies, we suggest that 5HT2C receptor activation may be important for the onset of the behavioral effects of antidepressant treatment.

Analysis of Variance↗
PubMed2004

Dimensional complexity of the neuronal activity in a rat model of depression.

The Flinders sensitive line of rats is a widely accepted and validated model of depression. These rats demonstrate abnormalities in limbic dopamine neurotransmission, suggesting disturbed neuronal activity in the ventral tegmental area. Interspike interval time-series were recorded from the ventral tegmental area of control Sprague-Dawley and Flinder sensitive line rats. These data were analyzed using standard measures (mean firing rate, bursting activity and spectral analysis) as well as the pointwise correlation dimension, a nonlinear measurement characterizing the complexity degree of dynamic systems. Pointwise correlation dimension, but not standard analysis revealed a significant difference between the animal lines. Our results suggest that nonlinear analyses can detect dysregulation of the mesolimbic dopaminergic system and shed light on the pathophysiology of depression.

Action Potentials↗
PubMed2004

The serotonin-dopamine interaction is critical for fast-onset action of antidepressant treatment: in vivo studies in an animal model of depression.

In the last decade, many new antidepressants have been developed that display a more rapid onset to clinical effects than classical antidepressants. However, the mechanism that enables some drugs to have a faster onset of action than others is poorly understood. The aim of the present study was to determine neural alterations that are specific to fast-acting antidepressant action using Flinders Sensitive Line (FSL) rats, an animal model of depression. Because of the central role of accumbal dopamine in the mediation of motivation and reward, our measurements were focused on dopaminergic neurotransmission in the nucleus accumbens (NAC). The authors found that 7-day treatment with nefazodone (a putative fast-onset antidepressant) but not with desipramine (a classical antidepressant) normalized immobility time in the swim test in FSL rats. Serotonin (5-HT)-induced dopamine release but not basal dopamine levels correlated with the improvement of depressive-like behavior. The authors conclude that the 5-HT-dopamine interaction is critical to the fast-onset action of antidepressant treatment.

Adrenergic Uptake Inhibitors↗
PubMed2003

5-HT(1A) receptor subsensitivity in infancy and supersensitivity in adulthood in an animal model of depression.

Flinders Sensitive Line (FSL) rats, a genetic animal model of depression, exhibit 5-HT abnormalities including an increased sensitivity to serotonergic agonists. Studies of 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT)-induced hypothermia have shown 5-HT(1A) receptor supersensitivity in adult FSL rats. The aims of the present study were to: (a) further characterize the 5-HT(1A) system in adult FSL rats by assessing their behavioral responses to 8-OH-DPAT (the 'serotonergic syndrome'-a pattern of stereotypic behavior on a number of parameters). (b) Examine behavioral and hypothermic responses of neonatal FSL pups to 8-OH-DPAT. In adult FSL rats the 'serotonergic syndrome' was measured (Exp. 1) and in 1-day-old pups body temperature and ultrasonic vocalizations (USV) were also examined (Exp. 2) following administration (s.c. and i.p., respectively) of 8-OH-DPAT (1 mg/kg). Overall, adult FSL rats exhibited a significant supersensitive behavioral response to 8-OH-DPAT compared to Sprague-Dawley controls. Under baseline conditions, body weight, USV and rectal temperature were significantly lower in FSL pups compared to controls. In contrast to the adults, 1-day-old FSL pups exhibited an overall pattern of subsensitive stereotypic response to the agonist. In conclusion, an abnormal pattern of response to 8-OH-DPAT was observable in FSL rats, as early as postnatal day 1. This may contribute to a better understanding of the involvement of the serotonergic system in depression, and lead to pharmacological interventions aiming to modulate 5-HT regulation.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2003

Decreased limbic vesicular monoamine transporter 2 in a genetic rat model of depression.

Psychopharmacological and neurochemical research suggests that alterations in monoamine transporters may be involved in the etiology of depression. We studied the expression of the brain-type vesicular monoamine transporter (VMAT2) in the Flinders sensitive line (FSL) rats, which represent a genetic animal model for clinical depression in humans. VMAT2 expression at the protein level was assessed by autoradiography using [(3)H]dihydrotetrabenazine ([(3)H]TBZOH) binding, in the prefrontal cortex, the striatum and its subregions, nucleus accumbens (NAC), ventral tegmental area (VTA) and the substantia nigra pars compacta (SNC). The VMAT2 mRNA level was analyzed by in situ hybridization, in the VTA, SNC and the dorsal raphe (DR) nucleus. Reduced levels of [(3)H]TBZOH binding were detected in the striatum and its subregions, NAC shell but not in the NAC core. A marked reduction of 21% was found in the VTA while only a slight reduction (13%) was observed in the SNC. The reduced levels of VMAT2 protein binding capacity were not accompanied by a parallel alteration in VMAT2 mRNA levels in the VTA, the SNC and the DR. Since the VMAT2 is responsible for the intracellular storage and regulated release of monoamines, the reduced [(3)H]TBZOH binding levels in limbic brain regions of FSL rats may imply a reduced density of vesicular monoamine transporters, which can result in reduced monoamine transmission. Such reduction in the limbic neurotransmission, especially in NAC shell and VTA regions, may be involved in the depressive features of anhedonia and lack of motivation reported in the FSL rats.

Animals↗