10 research outputs found
Effort-Related Choice Behavior is Affected by Pharmacological Manipulations Associated with Depression: the Effects of Tetrabenazine
In humans, psychiatric symptoms such as anergia and psychomotor retardation reflect pathologies in behavioral activation. These motivational symptoms are fundamental aspects of depression and other disorders. Drugs such as reserpine and tetrabenazine deplete monoamines, including dopamine, and induce depressive like behaviors in humans. Our results indicate that administration of low doses of tetrabenazine can alter effort-related choice behavior, biasing animals towards low effort alternatives. These findings may be related to the ability of monoamine depleting agents such as tetrabenazine to blunt behavioral activation and induce psychomotor retardation, anergia and fatigue in humans, and this research could be useful for the development of drug treatments for effort-related motivational symptoms in humans
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Alterations in Brain-Derived Neurotrophic Factor in the Mouse Hippocampus Following Acute but Not Repeated Benzodiazepine Treatment
Benzodiazepines (BZs) are safe drugs for treating anxiety, sleep, and seizure disorders, but their use also results in unwanted effects including memory impairment, abuse, and dependence. The present study aimed to reveal the molecular mechanisms that may contribute to the effects of BZs in the hippocampus (HIP), an area involved in drug-related plasticity, by investigating the regulation of immediate early genes following BZ administration. Previous studies have demonstrated that both brain derived neurotrophic factor (BDNF) and c-Fos contribute to memory- and abuse-related processes that occur within the HIP, and their expression is altered in response to BZ exposure. In the current study, mice received acute or repeated administration of BZs and HIP tissue was analyzed for alterations in BDNF and c-Fos expression. Although no significant changes in BDNF or c-Fos were observed in response to twice-daily intraperitoneal (i.p.) injections of diazepam (10 mg/kg + 5 mg/kg) or zolpidem (ZP; 2.5 mg/kg + 2.5 mg/kg), acute i.p. administration of both triazolam (0.03 mg/kg) and ZP (1.0 mg/kg) decreased BDNF protein levels within the HIP relative to vehicle, without any effect on c-Fos. ZP specifically reduced exon IV-containing BDNF transcripts with a concomitant increase in the association of methyl-CpG binding protein 2 (MeCP2) with BDNF promoter IV, suggesting that MeCP2 activity at this promoter may represent a ZP-specific mechanism for reducing BDNF expression. ZP also increased the association of phosphorylated cAMP response element binding protein (pCREB) with BDNF promoter I. Future work should examine the interaction between ZP and DNA as the cause for altered gene expression in the HIP, given that BZs can enter the nucleus and intercalate into DNA directly
Effort-Related Choice Behavior is Affected by Pharmacological Manipulations Associated with Depression: the Effects of Tetrabenazine
In humans, psychiatric symptoms such as anergia and psychomotor retardation reflect pathologies in behavioral activation. These motivational symptoms are fundamental aspects of depression and other disorders. Drugs such as reserpine and tetrabenazine deplete monoamines, including dopamine, and induce depressive like behaviors in humans. Our results indicate that administration of low doses of tetrabenazine can alter effort-related choice behavior, biasing animals towards low effort alternatives. These findings may be related to the ability of monoamine depleting agents such as tetrabenazine to blunt behavioral activation and induce psychomotor retardation, anergia and fatigue in humans, and this research could be useful for the development of drug treatments for effort-related motivational symptoms in humans
Synapse density and dendritic complexity are reduced in the prefrontal cortex following seven days of forced abstinence from cocaine self-administration.
Chronic cocaine exposure in both human addicts and in rodent models of addiction reduces prefrontal cortical activity, which subsequently dysregulates reward processing and higher order executive function. The net effect of this impaired gating of behavior is enhanced vulnerability to relapse. Previously we have shown that cocaine-induced increases in brain-derived neurotrophic factor (BDNF) expression in the medial prefrontal cortex (PFC) is a neuroadaptive mechanism that blunts the reinforcing efficacy of cocaine. As BDNF is known to affect neuronal survival and synaptic plasticity, we tested the hypothesis that abstinence from cocaine self-administration would lead to alterations in neuronal morphology and synaptic density in the PFC. Using a novel technique, array tomography and Golgi staining, morphological changes in the rat PFC were analyzed following 14 days of cocaine self-administration and 7 days of forced abstinence. Our results indicate that overall dendritic branching and total synaptic density are significantly reduced in the rat PFC. In contrast, the density of thin dendritic spines are significantly increased on layer V pyramidal neurons of the PFC. These findings indicate that dynamic structural changes occur during cocaine abstinence that may contribute to the observed hypo-activity of the PFC in cocaine-addicted individuals
Dynamic alterations in Hippo signaling pathway and YAP activation during liver regeneration
Reversal Learning Deficits Associated with Increased Frontal Cortical Brain-Derived Neurotrophic Factor Tyrosine Kinase B Signaling in a Prenatal Cocaine Exposure Mouse Model
Single section Golgi analysis reveals alterations in dendritic branching and spine formation in the PFC following 7 days of abstinence from cocaine.
<p>(<b>A</b>) Representative photomicrograph of a Golgi stain pyramidal neuron and tracing from yoked-saline control (top left, top right) and cocaine (bottom left, bottom right) treated rats scale bar  = 50 µm (<b>B</b>) Sholl plot analysis of animals self-administering saline (open circles) and cocaine (black-filled circles) (<b>C</b>) Representative basal dendritic segment from a yoked-saline (top) and cocaine (bottom) neuron scale bar  = 10 µm (<b>D</b>) Quantitative analysis of total spine number and spine density classified by spine sub-type from 4–5 segments from 5–7 neurons from each animal, n = 4 animals/group. *, <i>p</i><0.05; ***, <i>p</i><0.001.</p
No change in histone acetylation in the HIP following acute BZ treatment.
<p>(A) There is no change in total AcH3 protein levels in the HIP following BZ treatment as measured by western blots (n= 3); (B) There is no change in AcH3 association with BDNF promoters in the HIP following ZP treatment as measured by ChIP (n= 4). IDV: integrated density values.</p
Array tomography reveals alterations in synapse density in the PFC following 7 days of abstinence from cocaine.
<p>(<b>A</b>) Ribbons of 70 nm sections were stained with postsynaptic marker PSD95 (red), presynaptic marker synaptophysin (green), and DAPI to label nuclei (blue) (<b>B</b>) Another set of ribbons were stained with synaptophysin (green) and GAD65 (magenta) to determine the percentage of inhibitory synapses. Raw images of single sections from saline (left) and cocaine treated (right) rats are shown in the top row of panels <b>A</b> and <b>B</b>. Images were aligned, processed to remove noise, and synapses detected in three-dimensional volumes as shown in the 3D rendering of 5 serial sections (bottom rows <b>A</b> and <b>B</b>) (<b>C</b>) Quantification of presynaptic terminals (<b>D</b>) Quantification of PSD95 positive postsynaptic terminals (<b>E</b>) Quantification of GAD65 positive terminals. Graphs show mean + S.E.M. * p<0.05 t-test; n = 5 animals/group; scale bar  = 10 µm top panels, and 2 µm bottom panels.</p
Increased MeCP2 association with BDNF promoter IV in the HIP following acute BZ treatment.
<p>(A) There is no change in total MeCP2 protein levels in the HIP following BZ treatment as measured by western blots (n= 3); (B) There is a significant increase in MeCP2 association with BDNF promoter IV in the HIP following ZP treatment as measured by ChIP (n= 3-4). * <i>p</i>< 0.05; IDV: integrated density values.</p