- Jun 2019
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SAHA helps restore some of the memory deficits in these mice
In cocaine-treated animals, LTP is impaired. SAHA helped in rescuing certain aspects of LTP in cocaine-treated animals.
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Thus, most cocaine users smoked cigarettes before they started using cocaine, and, in addition, they started using cocaine while they were actively smoking cigarettes
This study shows that the key determinants for sequential drug use are the onset of age and the frequency of drug usage
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Because an important step in the molecular sequence leading to the expression of the addictive phenotype in mice is increased FosB expression in the striatum
The authors use DNA expression array techniques to identify genes that are modified by drugs of abuse and their mechanism of action.
FosB is shown to regulate gene expression in cocaine-treated animals.
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The addiction process is also mediated through histone acetylation of the promoter of the transcription factor ΔFosB
CBP is instructed to FosB promoter to acetylate H4 histones, thereby regulating the expression of FosB gene in cocaine-treated animals
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An acute cocaine injection increases acetylation of histone H4 but not H3 at the FosB promoter
This paper shows that chromatin remodeling is a key mechanism that contributes to cocaine-induced synaptic plasticity.
Here the authors show that the cocaine can cause acetylation of histones via histone acetyl transferase (HAT) at a particular promoter site leading to chromatin acetylation and remodeling.
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the consequent activation of a downstream cascade of gene expression initiated by CREB [cyclic adenosine 3′,5′-monophosphate (cAMP) response element–binding protein]. This cascade is dependent upon the acetylation of histone tails by the CREB-binding protein (CBP), a histone acetyl transferase (HAT)
The authors show that the impairment in LTP and chromatin acetylation was observed in the animals.
By manipulating the CREB binding protein (CBP), some of these deficits were able to be restored. This suggests that LTP depends on the regulation of CBP.
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The molecular pathways involved in addiction share some of the same molecular logic and even some of the same molecular steps encountered in long-term memory storage
Cocaine induces long term depression (LTD), a form of synaptic plasticity in the nucleus accumbens. This impairment in LTD causes deficits in the memory storage in this brain region.
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Reduction of excitatory input to the NAc is thought to decrease inhibitory output from the NAc to the VTA and thereby contribute, through disinhibition, to the increased reward and enhanced locomotion activation observed after cocaine administration
After administering cocaine to animals, there is a decreased excitatory input from the prefrontal cortex to Nucleus accumbens.
This change in inputs leads to a lack of restraint on the inhibitory output from the nucleus accumbens to the ventral tegmental area, as the inhibitory output remains the same.
This leads to increased dopaminergic activity in VTA, leading to an increase in motor activity and in reward pathways.
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For example, in 2009 in the United States (4), among adults aged 18 to 34 who had used cocaine at least once, 90.4% had smoked cigarettes before they began to use cocaine, 4.7% began using both drugs at the same age, 2.4% used cocaine first, and 2.5% had never smoked
This survey was conducted in the US to identify the usage and correlation of drugs of abuse. Questions were provided as a survey to the participating individuals, and the results are summarized in the report.
Examples of queries are age, drug usage, and frequency, lifestyle, smoking, and drinking frequency.
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Accumulation of this transcription factor is a crucial step in the establishment of addiction to most drugs of abuse and has been used as a molecular marker for these processes.
The study has identified genetic changes that occur in mice treated with cocaine.
Read the summary of research findings in Science Daily: https://www.sciencedaily.com/releases/2018/05/180531102706.htm
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In human populations, cigarettes and alcohol generally serve as gateway drugs, which people use first before progressing to marijuana, cocaine, or other illicit substances
See the NIH spotlight on the findings of the current paper at NIH Research matters: https://www.nih.gov/news-events/nih-research-matters/why-nicotine-gateway-drug
and in science daily: https://www.sciencedaily.com/releases/2011/11/111102190400.htm
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Is the hyperacetylation produced by nicotine also a molecular explanation of drug action shared by the two other gateway drugs, alcohol and marijuana?
Prolonged use of alcohol, another gateway drug also leads to repetitive use of cocaine.
Read the summary of the research findings in Technology Networks:
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Our results showing how nicotine may act as a gateway drug on the brain—an effect likely to occur whether nicotine exposure is from smoked, passive, or nonsmoked forms—emphasize the need for developing more effective public health prevention programs for all products that contain nicotine, especially those targeted toward young people
The idea and formulation of the gateway hypothesis and how the hypothesis can be tested in animals are explained in the special article written by Dr.Kandel.
Read the article “A molecular basis for nicotine as a gateway drug” in the New England Journal of Medicine:
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In the general population of the United States and other Western societies, there is a well-defined sequence of drug usage in which the use of tobacco or alcohol precedes the use of marijuana, which in turn precedes the use of cocaine and other illicit drugs
The National Institute of Drug Abuse provides the statistics, trends, and the health effects of cocaine.
Read more in Drug Abuse website: https://www.drugabuse.gov/drugs-abuse/cocaine
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D. B. Kandel, Stages and Pathways of Drug Involvement: Examining the Gateway Hypothesis (Cambridge Univ. Press, Cambridge, UK, 2002), pp. 3–15
The book chapter introduces the concept of gateway hypothesis – a model to inform how teenagers initiate and progress in the usage of illicit drugs. The chapter addresses these crucial questions from various fronts – neurobiology, animal studies, and epidemiological studies.
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F. E. Pontieri, G. Tanda, F. Orzi, G. Di Chiara, Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature 382, 255–257 (1996).
The article addresses a fundamental question: is nicotine a habit-forming drug or an addictive drug? The authors performed experiments in mice and concluded that nicotine shares several biological aspects with the drugs of abuse.
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J. A. Kauer, R. C. Malenka, Synaptic plasticity and addiction. Nat. Rev. Neurosci. 8, 844–858 (2007)
The review presents the available evidence that the drugs of abuse can alter the synaptic plasticity mechanisms in the dopaminergic circuit, the key pathway to processing reward in the brain.
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A. Kumar, K. H. Choi, W. Renthal, N. M. Tsankova, D. E. Theobald, H. T. Truong, S. J. Russo, Q. Laplant, T. S. Sasaki, K. N. Whistler, R. L. Neve, D. W. Self, E. J. Nestler, Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum. Neuron 48, 303–314 (2005)
The authors show that the cocaine, a drug of abuse, can activate genes at core histones, which can lead to a restructuring of chromatin. This restructuring could have an effect on long-lasting changes in the animal, for instance, modulating the body movements
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A. A. Levine, Z. Guan, A. Barco, S. Xu, E. R. Kandel, J. H. Schwartz, CREB-binding protein controls response to cocaine by acetylating histones at the fosB promoter in the mouse striatum. Proc. Natl. Acad. Sci. U.S.A. 102, 19186–19191 (2005).
The authors show that the cAMP response element binding protein (CREB)-binding protein (CBP) acetylate histones at the FosB promoter in the mouse striatum, thereby regulating the responses to cocaine.
The authors confirmed this finding by repeating this experiment in mice lacking a copy of the CBP gene. These mice exhibited a decrease response to cocaine than the animals that had an intact copy of the CBP gene.
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- Apr 2019
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sympathoadrenal
Relates to both sympathetic nervous system and the adrenal medulla.
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lability
Ability to change.
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neonatal
Newborn or shortly after birth.
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cardiorespiration
Relates to both cardiac (heart) and respiration (lungs) functions. Helps in the maintenance of oxygen and breathing.
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- Mar 2019
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E. J. Furshpan, P. R. MacLeish, P. H. O'Lague, D. D. Potter, Proc. Natl. Acad. Sci. U.S.A. 73, 4225 (1976)
In this study, Furshpan et al. were interested in identifying the neurotransmitter that is being released in response to different liquids or drugs. His group noted that neurons release acetylcholine, catecholamine or both in response to the drugs.
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excitatory
Neurotransmitters that have increased effects on the neuron.
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Depolarization with veratridine after 2 weeks in culture also significantly increased TH, suggesting that mature as well as developing locus ceruleus exhibits plastic responses to depolarization
This experiment was focused on observing the changes in tyrosine hydroxylase (TH) activity in older cultures. Similar to developing cultures, the old cultures were also exposed to veratridine.
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Dot blot analysis
A quantitative method to detect mRNA levels in the explants. Here, mRNA levels of proenkephalin is measured using this method.
Learn more with this video from Abnova.
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neuritic process
Refers to any branches/projections from the cell body of a neuron.
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Denervation
A technique used to separate or eliminate a particular nerve supply to specific area(s) in the nervous system.
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ontogenetic
During the beginning and development of an organism.
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Depolarizing stimuli elicited noradrenergic expression, whereas factors derived from nonneuronal cells evoked cholinergicity
Neurons in the dish were exposed to electrical activity that can cause depolarization of membrane. It is shown that these neurons are noradrenergic while the non-neuronal cells show an expression of acetylcholine.
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introspects
Observation and examination of one's own thoughts.
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prodigious
In this context, meaning huge.
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Transmitter plasticity adds a newly recognized dimension of flexibility to nervous system function.
Learn more about the concept of neuroplasticity with this iBiology video. Nobel Prize-winning neurobiologist Dr. Eric Kandel explains how neuroplasticity modifies our nervous system.
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brain nucleus locus ceruleus
A mid-brain region, involved with the physiological responses to stress. The locus ceruleus is now believed to be the primary site of norepinephrine production.
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sensory neurons
Neurons that perceive stimulation or sensation.
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sodium ion influx
When depolarization occurs, there is an inward flow of sodium ions through the ion channels into the cell. Ion channels are present across the membrane.
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intraneuronal
Occurs within a neuron.
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- Jan 2019
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PNMT
An enzyme responsible for the conversion of norepinephrine to epinephrine.
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leucineenkephalin ([Leu]enkephalin)
Class of opiate neurotransmitter.
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reinnervation
Restoration of the nerves in the area either surgically or spontaneously.
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Fluorescence photomicrograph
The neurons are visualized and imaged with a fluorescent microscopy.
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bifurcating
Splits into two or more branches.
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transmembrane
Across the membrane.
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transsynaptic
Occurs across the nerve cells.
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anlage
A region from where an organ can develop.
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Adrenomedullary chromaffin cells
The cells present in the medulla of the adrenal gland.
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vesicles
Small pockets that store neurotransmitter in a cell.
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postnatally
After birth.
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transient expression of transmitter traits is not restricted to gut cells, but also occurs in cranial nerve ganglia of the embryonic rat
Similar to the gut cells, the nerve ganglia of the rat also show transient expression of catecholamine during development.
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These traits are detectable on embryonic day 11.5 (E-11.5) but have disappeared by E-14.5. However, the specific, high-affinity uptake system for norepinephrine selectively appears in these cells at E-12.5 and persists (8), permitting cellular identification after loss of other endogenous characters
This study focused on the neurotransmitter expression changes in the embryonic stages of development. At embryonic day 11.5, the neurons express the attributes of noradrenergic cells. However, these traits are lost by embryonic day 14.5. The uptake system for norepinephrine remains intact in these neurons.
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J. A. Kessler and I. B. Black, Brain Res. 234, 182 (1982)
In this study, the authors identified factors that regulate the substance P in nerve ganglia. The authors reported that impulse activity and decentralization of neurons (or denervation) can affect positively or negatively the expression of substance P in the nerve ganglia.
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S. C. Landis, Fed. Proc. Fed. Am. Soc. Exp. Biol. 42, 1633 (1983)
This article discusses the evidence of neurotransmitter plasticity in sweat glands of rats. The authors show that the neurons change from a norepinephrine to acetylcholine during development. Though the change of neurotransmitter occurs in the system, it does not alter the uptake and storage of norepinephrine in these neurons.
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