Publications from the Neuronal Ensembles in Drug Addiction.
2012
Koya, Eisuke; Cruz, Fabio C; Ator, Robert; Golden, Sam A; Hoffman, Alexander F; Lupica, Carl R; Hope, Bruce T
Silent synapses in selectively activated nucleus accumbens neurons following cocaine sensitization. Journal Article
In: Nat Neurosci, vol. 15, no. 11, pp. 1556–1562, 2012, ISSN: 1546-1726 (Electronic); 1097-6256 (Linking).
@article{Koya2012,
title = {Silent synapses in selectively activated nucleus accumbens neurons following cocaine sensitization.},
author = {Eisuke Koya and Fabio C Cruz and Robert Ator and Sam A Golden and Alexander F Hoffman and Carl R Lupica and Bruce T Hope},
url = {https://www.ncbi.nlm.nih.gov/pubmed/23023294},
doi = {10.1038/nn.3232},
issn = {1546-1726 (Electronic); 1097-6256 (Linking)},
year = {2012},
date = {2012-11-01},
journal = {Nat Neurosci},
volume = {15},
number = {11},
pages = {1556--1562},
address = {Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, US National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland, USA.},
abstract = {Cocaine-induced alterations in synaptic glutamate function in nucleus accumbens are thought to mediate drug-related behaviors such as psychomotor sensitization. However, previous studies have examined global alterations in randomly selected accumbens neurons regardless of their activation state during cocaine-induced behavior. We recently found that a minority of strongly activated Fos-expressing accumbens neurons are necessary for cocaine-induced psychomotor sensitization, whereas the majority of accumbens neurons are less directly involved. We assessed synaptic alterations in these strongly activated accumbens neurons in Fos-GFP mice, which express a fusion protein of Fos and GFP in strongly activated neurons, and compared these alterations with those in surrounding non-activated neurons. Cocaine sensitization produced higher levels of 'silent synapses', which contained functional NMDA receptors and nonfunctional AMPA receptors only in GFP-positive neurons, 6-11 d after sensitization. Thus, distinct synaptic alterations are induced in the most strongly activated accumbens neurons that mediate psychomotor sensitization.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Cocaine-induced alterations in synaptic glutamate function in nucleus accumbens are thought to mediate drug-related behaviors such as psychomotor sensitization. However, previous studies have examined global alterations in randomly selected accumbens neurons regardless of their activation state during cocaine-induced behavior. We recently found that a minority of strongly activated Fos-expressing accumbens neurons are necessary for cocaine-induced psychomotor sensitization, whereas the majority of accumbens neurons are less directly involved. We assessed synaptic alterations in these strongly activated accumbens neurons in Fos-GFP mice, which express a fusion protein of Fos and GFP in strongly activated neurons, and compared these alterations with those in surrounding non-activated neurons. Cocaine sensitization produced higher levels of 'silent synapses', which contained functional NMDA receptors and nonfunctional AMPA receptors only in GFP-positive neurons, 6-11 d after sensitization. Thus, distinct synaptic alterations are induced in the most strongly activated accumbens neurons that mediate psychomotor sensitization.
Guez-Barber, Danielle; Fanous, Sanya; Harvey, Brandon K; Zhang, Yongqing; Lehrmann, Elin; Becker, Kevin G; Picciotto, Marina R; Hope, Bruce T
FACS purification of immunolabeled cell types from adult rat brain. Journal Article
In: J Neurosci Methods, vol. 203, no. 1, pp. 10–18, 2012, ISSN: 1872-678X (Electronic); 0165-0270 (Linking).
@article{Guez-Barber2012,
title = {FACS purification of immunolabeled cell types from adult rat brain.},
author = {Danielle Guez-Barber and Sanya Fanous and Brandon K Harvey and Yongqing Zhang and Elin Lehrmann and Kevin G Becker and Marina R Picciotto and Bruce T Hope},
url = {https://www.ncbi.nlm.nih.gov/pubmed/21911005},
doi = {10.1016/j.jneumeth.2011.08.045},
issn = {1872-678X (Electronic); 0165-0270 (Linking)},
year = {2012},
date = {2012-01-15},
journal = {J Neurosci Methods},
volume = {203},
number = {1},
pages = {10--18},
address = {Behavioral Neuroscience Branch, IRP/NIDA/NIH/DHHS, 251 Bayview Boulevard, Baltimore, MD 21224, USA. danielle.guez@yale.edu},
abstract = {Molecular analysis of brain tissue is greatly complicated by having many different classes of neurons and glia interspersed throughout the brain. Fluorescence-activated cell sorting (FACS) has been used to purify selected cell types from brain tissue. However, its use has been limited to brain tissue from embryos or transgenic mice with promoter-driven reporter genes. To overcome these limitations, we developed a FACS procedure for dissociating intact cell bodies from adult wild-type rat brains and sorting them using commercially available antibodies against intracellular and extracellular proteins. As an example, we isolated neurons using a NeuN antibody and confirmed their identity using microarray and real time PCR of mRNA from the sorted cells. Our FACS procedure allows rapid, high-throughput, quantitative assays of molecular alterations in identified cell types with widespread applications in neuroscience.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Molecular analysis of brain tissue is greatly complicated by having many different classes of neurons and glia interspersed throughout the brain. Fluorescence-activated cell sorting (FACS) has been used to purify selected cell types from brain tissue. However, its use has been limited to brain tissue from embryos or transgenic mice with promoter-driven reporter genes. To overcome these limitations, we developed a FACS procedure for dissociating intact cell bodies from adult wild-type rat brains and sorting them using commercially available antibodies against intracellular and extracellular proteins. As an example, we isolated neurons using a NeuN antibody and confirmed their identity using microarray and real time PCR of mRNA from the sorted cells. Our FACS procedure allows rapid, high-throughput, quantitative assays of molecular alterations in identified cell types with widespread applications in neuroscience.
2011
Bossert, Jennifer M; Stern, Anna L; Theberge, Florence R M; Cifani, Carlo; Koya, Eisuke; Hope, Bruce T; Shaham, Yavin
Ventral medial prefrontal cortex neuronal ensembles mediate context-induced relapse to heroin. Journal Article
In: Nat Neurosci, vol. 14, no. 4, pp. 420–422, 2011, ISSN: 1546-1726 (Electronic); 1097-6256 (Linking).
@article{Bossert2011,
title = {Ventral medial prefrontal cortex neuronal ensembles mediate context-induced relapse to heroin.},
author = {Jennifer M Bossert and Anna L Stern and Florence R M Theberge and Carlo Cifani and Eisuke Koya and Bruce T Hope and Yavin Shaham},
url = {https://www.ncbi.nlm.nih.gov/pubmed/21336273},
doi = {10.1038/nn.2758},
issn = {1546-1726 (Electronic); 1097-6256 (Linking)},
year = {2011},
date = {2011-04-01},
journal = {Nat Neurosci},
volume = {14},
number = {4},
pages = {420--422},
address = {Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, US National Institutes of Health/Department of Health and Human Services, Baltimore, Maryland, USA.},
abstract = {In a rat model of context-induced relapse to heroin, we identified sparsely distributed ventral medial prefrontal cortex (mPFC) neurons that were activated by the heroin-associated context. Selective pharmacogenetic inactivation of these neurons inhibited context-induced drug relapse. A small subset of ventral mPFC neurons formed neuronal ensembles that encode the learned associations between heroin reward and heroin-associated contexts; re-activation of these neuronal ensembles by drug-associated contexts during abstinence provoked drug relapse.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
In a rat model of context-induced relapse to heroin, we identified sparsely distributed ventral medial prefrontal cortex (mPFC) neurons that were activated by the heroin-associated context. Selective pharmacogenetic inactivation of these neurons inhibited context-induced drug relapse. A small subset of ventral mPFC neurons formed neuronal ensembles that encode the learned associations between heroin reward and heroin-associated contexts; re-activation of these neuronal ensembles by drug-associated contexts during abstinence provoked drug relapse.
Guez-Barber, Danielle; Fanous, Sanya; Golden, Sam A; Schrama, Regina; Koya, Eisuke; Stern, Anna L; Bossert, Jennifer M; Harvey, Brandon K; Picciotto, Marina R; Hope, Bruce T
FACS identifies unique cocaine-induced gene regulation in selectively activated adult striatal neurons. Journal Article
In: J Neurosci, vol. 31, no. 11, pp. 4251–4259, 2011, ISSN: 1529-2401 (Electronic); 0270-6474 (Linking).
@article{Guez-Barber2011,
title = {FACS identifies unique cocaine-induced gene regulation in selectively activated adult striatal neurons.},
author = {Danielle Guez-Barber and Sanya Fanous and Sam A Golden and Regina Schrama and Eisuke Koya and Anna L Stern and Jennifer M Bossert and Brandon K Harvey and Marina R Picciotto and Bruce T Hope},
url = {https://www.ncbi.nlm.nih.gov/pubmed/21411666},
doi = {10.1523/JNEUROSCI.6195-10.2011},
issn = {1529-2401 (Electronic); 0270-6474 (Linking)},
year = {2011},
date = {2011-03-16},
journal = {J Neurosci},
volume = {31},
number = {11},
pages = {4251--4259},
address = {Behavioral Neuroscience Branch, Intramural Research Program/National Institute on Drug Abuse/National Institutes of Health/Department of Health and Human Services, Baltimore, Maryland 21224, USA.},
abstract = {Numerous studies with the neural activity marker Fos indicate that cocaine activates only a small proportion of sparsely distributed striatal neurons. Until now, efficient methods were not available to assess neuroadaptations induced specifically within these activated neurons. We used fluorescence-activated cell sorting (FACS) to purify striatal neurons activated during cocaine-induced locomotion in naive and cocaine-sensitized cfos-lacZ transgenic rats. Activated neurons were labeled with an antibody against beta-galactosidase, the protein product of the lacZ gene. Cocaine induced a unique gene expression profile selectively in the small proportion of activated neurons that was not observed in the nonactivated majority of neurons. These genes included altered levels of the immediate early genes arc, fosB, and nr4a3, as well as genes involved in p38 MAPK signaling and cell-type specificity. We propose that this FACS method can be used to study molecular neuroadaptations in specific neurons encoding the behavioral effects of abused drugs and other learned behaviors.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Numerous studies with the neural activity marker Fos indicate that cocaine activates only a small proportion of sparsely distributed striatal neurons. Until now, efficient methods were not available to assess neuroadaptations induced specifically within these activated neurons. We used fluorescence-activated cell sorting (FACS) to purify striatal neurons activated during cocaine-induced locomotion in naive and cocaine-sensitized cfos-lacZ transgenic rats. Activated neurons were labeled with an antibody against beta-galactosidase, the protein product of the lacZ gene. Cocaine induced a unique gene expression profile selectively in the small proportion of activated neurons that was not observed in the nonactivated majority of neurons. These genes included altered levels of the immediate early genes arc, fosB, and nr4a3, as well as genes involved in p38 MAPK signaling and cell-type specificity. We propose that this FACS method can be used to study molecular neuroadaptations in specific neurons encoding the behavioral effects of abused drugs and other learned behaviors.
2009
Marin, Marcelo T; Berkow, Alexander; Golden, Sam A; Koya, Eisuke; Planeta, Cleopatra S; Hope, Bruce T
Context-specific modulation of cocaine-induced locomotor sensitization and ERK and CREB phosphorylation in the rat nucleus accumbens. Journal Article
In: Eur J Neurosci, vol. 30, no. 10, pp. 1931–1940, 2009, ISSN: 1460-9568 (Electronic); 0953-816X (Linking).
@article{Marin2009,
title = {Context-specific modulation of cocaine-induced locomotor sensitization and ERK and CREB phosphorylation in the rat nucleus accumbens.},
author = {Marcelo T Marin and Alexander Berkow and Sam A Golden and Eisuke Koya and Cleopatra S Planeta and Bruce T Hope},
url = {https://www.ncbi.nlm.nih.gov/pubmed/19912338},
doi = {10.1111/j.1460-9568.2009.06982.x},
issn = {1460-9568 (Electronic); 0953-816X (Linking)},
year = {2009},
date = {2009-11-01},
journal = {Eur J Neurosci},
volume = {30},
number = {10},
pages = {1931--1940},
address = {School of Pharmaceutical Sciences, Sao Paulo State University (UNESP), Araraquara-SP, Brazil.},
abstract = {Learned associations are hypothesized to develop between drug effects and contextual stimuli during repeated drug administration to produce context-specific sensitization that is expressed only in the drug-associated environment and not in a non-drug-paired environment. The neuroadaptations that mediate such context-specific behavior are largely unknown. We investigated context-specific modulation of cAMP-response element-binding protein (CREB) phosphorylation and that of four upstream kinases in the nucleus accumbens that phosphorylate CREB, including extracellular signal-regulated kinase (ERK), cAMP-dependent protein kinase, calcium/calmodulin-dependent kinase (CaMK) II and CaMKIV. Rats received seven once-daily injections of cocaine or saline in one of two distinct environments outside their home cages. Seven days later, test injections of cocaine or saline were administered in either the paired or the non-paired environment. CREB and ERK phosphorylation were assessed with immunohistochemistry, and phosphorylation of the remaining kinases, as well as of CREB and ERK, was assessed by western blotting. Repeated cocaine administration produced context-specific sensitized locomotor responses accompanied by context-specific enhancement of the number of cocaine-induced phosphoCREB-immunoreactive and phosphoERK-immunoreactive nuclei in a minority of neurons. In contrast, CREB and CaMKIV phosphorylation in nucleus accumbens homogenates were decreased by cocaine test injections. We have recently shown that a small number of cocaine-activated accumbens neurons mediate the learned association between cocaine effects and the drug administration environment to produce context-specific sensitization. Context-specific phosphorylation of ERK and CREB in the present study suggests that this signal transduction pathway is selectively activated in the same set of cocaine-activated accumbens neurons that mediate this learned association.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Learned associations are hypothesized to develop between drug effects and contextual stimuli during repeated drug administration to produce context-specific sensitization that is expressed only in the drug-associated environment and not in a non-drug-paired environment. The neuroadaptations that mediate such context-specific behavior are largely unknown. We investigated context-specific modulation of cAMP-response element-binding protein (CREB) phosphorylation and that of four upstream kinases in the nucleus accumbens that phosphorylate CREB, including extracellular signal-regulated kinase (ERK), cAMP-dependent protein kinase, calcium/calmodulin-dependent kinase (CaMK) II and CaMKIV. Rats received seven once-daily injections of cocaine or saline in one of two distinct environments outside their home cages. Seven days later, test injections of cocaine or saline were administered in either the paired or the non-paired environment. CREB and ERK phosphorylation were assessed with immunohistochemistry, and phosphorylation of the remaining kinases, as well as of CREB and ERK, was assessed by western blotting. Repeated cocaine administration produced context-specific sensitized locomotor responses accompanied by context-specific enhancement of the number of cocaine-induced phosphoCREB-immunoreactive and phosphoERK-immunoreactive nuclei in a minority of neurons. In contrast, CREB and CaMKIV phosphorylation in nucleus accumbens homogenates were decreased by cocaine test injections. We have recently shown that a small number of cocaine-activated accumbens neurons mediate the learned association between cocaine effects and the drug administration environment to produce context-specific sensitization. Context-specific phosphorylation of ERK and CREB in the present study suggests that this signal transduction pathway is selectively activated in the same set of cocaine-activated accumbens neurons that mediate this learned association.
Koya, Eisuke; Golden, Sam A; Harvey, Brandon K; Guez-Barber, Danielle H; Berkow, Alexander; Simmons, Danielle E; Bossert, Jennifer M; Nair, Sunila G; Uejima, Jamie L; Marin, Marcelo T; Mitchell, Timothy B; Farquhar, David; Ghosh, Sukhen C; Mattson, Brandi J; Hope, Bruce T
Targeted disruption of cocaine-activated nucleus accumbens neurons prevents context-specific sensitization. Journal Article
In: Nat Neurosci, vol. 12, no. 8, pp. 1069–1073, 2009, ISSN: 1546-1726 (Electronic); 1097-6256 (Linking).
@article{Koya2009,
title = {Targeted disruption of cocaine-activated nucleus accumbens neurons prevents context-specific sensitization.},
author = {Eisuke Koya and Sam A Golden and Brandon K Harvey and Danielle H Guez-Barber and Alexander Berkow and Danielle E Simmons and Jennifer M Bossert and Sunila G Nair and Jamie L Uejima and Marcelo T Marin and Timothy B Mitchell and David Farquhar and Sukhen C Ghosh and Brandi J Mattson and Bruce T Hope},
url = {https://www.ncbi.nlm.nih.gov/pubmed/19620976},
doi = {10.1038/nn.2364},
issn = {1546-1726 (Electronic); 1097-6256 (Linking)},
year = {2009},
date = {2009-08-01},
journal = {Nat Neurosci},
volume = {12},
number = {8},
pages = {1069--1073},
address = {Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland, USA.},
abstract = {Learned associations between effects of abused drugs and the drug administration environment are important in drug addiction. Histochemical and electrophysiological studies suggest that these associations are encoded in sparsely distributed nucleus accumbens neurons that are selectively activated by drugs and drug-associated cues. Although correlations have been observed between nucleus accumbens neuronal activity and responsivity to drugs and drug cues, no technique exists for selectively manipulating these activated neurons and establishing their causal role in behavioral effects of drugs and drug cues. Here we describe a new approach, which we term the 'Daun02 inactivation method', that selectively inactivates a minority of neurons previously activated by cocaine in an environment repeatedly paired with cocaine to demonstrate a causal role for these activated neurons in context-specific cocaine-induced psychomotor sensitization in rats. This method provides a new tool for studying the causal roles of selectively activated neurons in behavioral effects of drugs and drug cues and in other learned behaviors.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Learned associations between effects of abused drugs and the drug administration environment are important in drug addiction. Histochemical and electrophysiological studies suggest that these associations are encoded in sparsely distributed nucleus accumbens neurons that are selectively activated by drugs and drug-associated cues. Although correlations have been observed between nucleus accumbens neuronal activity and responsivity to drugs and drug cues, no technique exists for selectively manipulating these activated neurons and establishing their causal role in behavioral effects of drugs and drug cues. Here we describe a new approach, which we term the 'Daun02 inactivation method', that selectively inactivates a minority of neurons previously activated by cocaine in an environment repeatedly paired with cocaine to demonstrate a causal role for these activated neurons in context-specific cocaine-induced psychomotor sensitization in rats. This method provides a new tool for studying the causal roles of selectively activated neurons in behavioral effects of drugs and drug cues and in other learned behaviors.
2008
Mattson, Brandi J; Koya, Eisuke; Simmons, Danielle E; Mitchell, Timothy B; Berkow, Alexander; Crombag, Hans S; Hope, Bruce T
Context-specific sensitization of cocaine-induced locomotor activity and associated neuronal ensembles in rat nucleus accumbens. Journal Article
In: Eur J Neurosci, vol. 27, no. 1, pp. 202–212, 2008, ISSN: 1460-9568 (Electronic); 0953-816X (Linking).
@article{Mattson2008,
title = {Context-specific sensitization of cocaine-induced locomotor activity and associated neuronal ensembles in rat nucleus accumbens.},
author = {Brandi J Mattson and Eisuke Koya and Danielle E Simmons and Timothy B Mitchell and Alexander Berkow and Hans S Crombag and Bruce T Hope},
url = {https://www.ncbi.nlm.nih.gov/pubmed/18093170},
doi = {10.1111/j.1460-9568.2007.05984.x},
issn = {1460-9568 (Electronic); 0953-816X (Linking)},
year = {2008},
date = {2008-01-01},
journal = {Eur J Neurosci},
volume = {27},
number = {1},
pages = {202--212},
address = {Behavioral Neuroscience Branch, Intramural Research Program, The National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.},
abstract = {Repeated cocaine administration to rats outside their home cage induces behavioral sensitization that is strongly modulated by the drug administration environment. We hypothesized that stimuli in the drug administration environment activate specific sets of striatal neurons, called neuronal ensembles, for further cocaine-enhanced activation, and that repeated activation of these neuronal ensembles underlies context-specific sensitization. In the present study, we repeatedly administered cocaine or saline to rats on alternate days in two distinct environments outside the home cage, one paired with cocaine and the other with saline. On test day, cocaine challenge injections in the cocaine-paired environment produced strongly enhanced levels of locomotor activity, while cocaine challenge injections in the saline-paired environment did not. The corresponding record of past neuronal activation in nucleus accumbens and caudate-putamen during repeated drug administration was assessed using FosB immunohistochemistry, while acute neuronal activation on test day was assessed using c-fos in situ hybridization. Although only 2% of striatal neurons were FosB labeled, 87% of these FosB-labeled neurons were co-labeled with c-fos when cocaine was injected in the cocaine-paired environment. The degree of co-labeling was significantly less following cocaine or saline challenge injections in the saline-paired environment. Furthermore, the total number of c-fos-labeled neurons was greater with either cocaine or saline challenge injections in the cocaine-paired environment than in the saline-paired environment. These findings demonstrate that the drug administration environment partly determines which striatal neuronal ensembles are activated, and to what extent, following context-specific sensitization to cocaine.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Repeated cocaine administration to rats outside their home cage induces behavioral sensitization that is strongly modulated by the drug administration environment. We hypothesized that stimuli in the drug administration environment activate specific sets of striatal neurons, called neuronal ensembles, for further cocaine-enhanced activation, and that repeated activation of these neuronal ensembles underlies context-specific sensitization. In the present study, we repeatedly administered cocaine or saline to rats on alternate days in two distinct environments outside the home cage, one paired with cocaine and the other with saline. On test day, cocaine challenge injections in the cocaine-paired environment produced strongly enhanced levels of locomotor activity, while cocaine challenge injections in the saline-paired environment did not. The corresponding record of past neuronal activation in nucleus accumbens and caudate-putamen during repeated drug administration was assessed using FosB immunohistochemistry, while acute neuronal activation on test day was assessed using c-fos in situ hybridization. Although only 2% of striatal neurons were FosB labeled, 87% of these FosB-labeled neurons were co-labeled with c-fos when cocaine was injected in the cocaine-paired environment. The degree of co-labeling was significantly less following cocaine or saline challenge injections in the saline-paired environment. Furthermore, the total number of c-fos-labeled neurons was greater with either cocaine or saline challenge injections in the cocaine-paired environment than in the saline-paired environment. These findings demonstrate that the drug administration environment partly determines which striatal neuronal ensembles are activated, and to what extent, following context-specific sensitization to cocaine.
2006
Hope, Bruce T; Simmons, Danielle E; Mitchell, Tim B; Kreuter, Justin D; Mattson, Brandi J
In: Eur J Neurosci, vol. 24, no. 3, pp. 867–875, 2006, ISSN: 0953-816X (Print); 0953-816X (Linking).
@article{Hope2006,
title = {Cocaine-induced locomotor activity and Fos expression in nucleus accumbens are sensitized for 6 months after repeated cocaine administration outside the home cage.},
author = {Bruce T Hope and Danielle E Simmons and Tim B Mitchell and Justin D Kreuter and Brandi J Mattson},
url = {https://www.ncbi.nlm.nih.gov/pubmed/16930414},
doi = {10.1111/j.1460-9568.2006.04969.x},
issn = {0953-816X (Print); 0953-816X (Linking)},
year = {2006},
date = {2006-08-01},
journal = {Eur J Neurosci},
volume = {24},
number = {3},
pages = {867--875},
address = {Behavioural Neuroscience Branch, Intramural Research Program, The National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA. bhope@intra.nida.nih.gov},
abstract = {Induction of the immediate early gene protein product Fos has been used extensively to assess neural activation in the striatum after repeated cocaine administration to rats in their home cages but rarely after repeated administration outside the home cage, which produces more robust locomotor sensitization. In the present study, we found cocaine-induced Fos expression in nucleus accumbens, but not caudate-putamen, was enhanced 1 and 6 months after repeated drug administration in locomotor activity chambers. Double-labelling of Fos protein and enkephalin mRNA indicated that Fos expression in nucleus accumbens was enhanced in enkephalin-positive, but not enkephalin-negative, medium spiny neurons. In contrast, cocaine-induced Fos expression was absent altogether in nucleus accumbens and unaltered in caudate-putamen 1 month after repeated cocaine administration in the home cage. As cocaine-induced locomotor activity was also enhanced 1 and 6 months after repeated cocaine administration in locomotor activity chambers, we wanted to confirm that neuronal activity in nucleus accumbens mediates cocaine-induced locomotor activity using our particular treatment regimen. Bilateral infusions of the GABA agonists baclofen and muscimol (1 microg/side) into nucleus accumbens of sensitized rats blocked cocaine-induced Fos expression and locomotor activity. Thus, while neuronal activity in both D1- and D2-type neurons in nucleus accumbens can mediate acute cocaine-induced locomotor activity, the enhanced activation of enkephalinergic D2-type neurons suggests that these latter neurons mediate the enhancement of cocaine-induced locomotor activity for up to 6 months after repeated drug administration outside the home cage.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Induction of the immediate early gene protein product Fos has been used extensively to assess neural activation in the striatum after repeated cocaine administration to rats in their home cages but rarely after repeated administration outside the home cage, which produces more robust locomotor sensitization. In the present study, we found cocaine-induced Fos expression in nucleus accumbens, but not caudate-putamen, was enhanced 1 and 6 months after repeated drug administration in locomotor activity chambers. Double-labelling of Fos protein and enkephalin mRNA indicated that Fos expression in nucleus accumbens was enhanced in enkephalin-positive, but not enkephalin-negative, medium spiny neurons. In contrast, cocaine-induced Fos expression was absent altogether in nucleus accumbens and unaltered in caudate-putamen 1 month after repeated cocaine administration in the home cage. As cocaine-induced locomotor activity was also enhanced 1 and 6 months after repeated cocaine administration in locomotor activity chambers, we wanted to confirm that neuronal activity in nucleus accumbens mediates cocaine-induced locomotor activity using our particular treatment regimen. Bilateral infusions of the GABA agonists baclofen and muscimol (1 microg/side) into nucleus accumbens of sensitized rats blocked cocaine-induced Fos expression and locomotor activity. Thus, while neuronal activity in both D1- and D2-type neurons in nucleus accumbens can mediate acute cocaine-induced locomotor activity, the enhanced activation of enkephalinergic D2-type neurons suggests that these latter neurons mediate the enhancement of cocaine-induced locomotor activity for up to 6 months after repeated drug administration outside the home cage.
2002
Moron, Jose A; Brockington, Alicia; Wise, Roy A; Rocha, Beatriz A; Hope, Bruce T
In: J Neurosci, vol. 22, no. 2, pp. 389–395, 2002, ISSN: 1529-2401 (Electronic); 0270-6474 (Linking).
@article{Moron2002,
title = {Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines.},
author = {Jose A Moron and Alicia Brockington and Roy A Wise and Beatriz A Rocha and Bruce T Hope},
url = {https://www.ncbi.nlm.nih.gov/pubmed/11784783},
issn = {1529-2401 (Electronic); 0270-6474 (Linking)},
year = {2002},
date = {2002-01-15},
journal = {J Neurosci},
volume = {22},
number = {2},
pages = {389--395},
address = {Behavioral Neuroscience Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA.},
abstract = {Selective blockers of the norepinephrine transporter (NET) inhibit dopamine uptake in the prefrontal cortex. This suggests that dopamine in this region is normally cleared by the somewhat promiscuous NET. We have tested this hypothesis by comparing the effects of inhibitors selective for the three monoamine transporters with those of a nonspecific inhibitor, cocaine, on uptake of 3H-dopamine into synaptosomes from frontal cortex, caudate nucleus, and nucleus accumbens from wild-type, NET, and dopamine transporter (DAT) knock-out mice. Dopamine uptake was inhibited by cocaine and nisoxetine, but not by GBR12909, in frontal cortex synaptosomes from wild-type or DAT knock-out mice. At transporter-specific concentrations, nisoxetine and GBR12909 failed to block dopamine uptake into frontal cortex synaptosomes from NET knock-out mice. The efficacy of cocaine at the highest dose (1 mm) was normal in DAT knock-out mice but reduced by 70% in NET knock-out mice. Nisoxetine inhibited dopamine uptake by 20% in caudate and nucleus accumbens synaptosomes from wild-type and DAT knock-out mice but had no effect in those from NET knock-out mice. Cocaine failed to block dopamine uptake into caudate or nucleus accumbens synaptosomes from DAT knock-out mice. Cocaine and GBR12909 each inhibited dopamine uptake into caudate synaptosomes from NET knock-out mice, but cocaine effectiveness was reduced in the case of nucleus accumbens synaptosomes. Thus, whereas dopamine uptake in caudate and nucleus accumbens depends primarily on the DAT, dopamine uptake in frontal cortex depends primarily on the NET. These data underscore the fact that which transporter clears dopamine from a given region depends on both the affinities and the local densities of the transporters.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Selective blockers of the norepinephrine transporter (NET) inhibit dopamine uptake in the prefrontal cortex. This suggests that dopamine in this region is normally cleared by the somewhat promiscuous NET. We have tested this hypothesis by comparing the effects of inhibitors selective for the three monoamine transporters with those of a nonspecific inhibitor, cocaine, on uptake of 3H-dopamine into synaptosomes from frontal cortex, caudate nucleus, and nucleus accumbens from wild-type, NET, and dopamine transporter (DAT) knock-out mice. Dopamine uptake was inhibited by cocaine and nisoxetine, but not by GBR12909, in frontal cortex synaptosomes from wild-type or DAT knock-out mice. At transporter-specific concentrations, nisoxetine and GBR12909 failed to block dopamine uptake into frontal cortex synaptosomes from NET knock-out mice. The efficacy of cocaine at the highest dose (1 mm) was normal in DAT knock-out mice but reduced by 70% in NET knock-out mice. Nisoxetine inhibited dopamine uptake by 20% in caudate and nucleus accumbens synaptosomes from wild-type and DAT knock-out mice but had no effect in those from NET knock-out mice. Cocaine failed to block dopamine uptake into caudate or nucleus accumbens synaptosomes from DAT knock-out mice. Cocaine and GBR12909 each inhibited dopamine uptake into caudate synaptosomes from NET knock-out mice, but cocaine effectiveness was reduced in the case of nucleus accumbens synaptosomes. Thus, whereas dopamine uptake in caudate and nucleus accumbens depends primarily on the DAT, dopamine uptake in frontal cortex depends primarily on the NET. These data underscore the fact that which transporter clears dopamine from a given region depends on both the affinities and the local densities of the transporters.
1994
Hope, B T; Nye, H E; Kelz, M B; Self, D W; Iadarola, M J; Nakabeppu, Y; Duman, R S; Nestler, E J
Induction of a long-lasting AP-1 complex composed of altered Fos-like proteins in brain by chronic cocaine and other chronic treatments. Journal Article
In: Neuron, vol. 13, no. 5, pp. 1235–1244, 1994, ISSN: 0896-6273 (Print); 0896-6273 (Linking).
@article{Hope1994,
title = {Induction of a long-lasting AP-1 complex composed of altered Fos-like proteins in brain by chronic cocaine and other chronic treatments.},
author = {B T Hope and H E Nye and M B Kelz and D W Self and M J Iadarola and Y Nakabeppu and R S Duman and E J Nestler},
url = {https://www.ncbi.nlm.nih.gov/pubmed/7946359},
issn = {0896-6273 (Print); 0896-6273 (Linking)},
year = {1994},
date = {1994-11-01},
journal = {Neuron},
volume = {13},
number = {5},
pages = {1235--1244},
address = {Department of Psychiatry and Pharmacology, Yale University School of Medicine, New Haven, Connecticut.},
abstract = {Following chronic cocaine treatment, we have found a long-lasting increase in AP-1 binding in the rat nucleus accumbens and striatum, two important targets of the behavioral effects of cocaine. This increase develops gradually over several days and remains at 50% of maximal levels 7 days after the last cocaine exposure. Supershift experiments, along with one- and two-dimensional Western blots, indicate that this chronic AP-1 complex contains at least four Fos-related antigens (FRAs), some of which display delta FosB-like immunoreactivity, that are induced selectively by chronic, but not acute, cocaine treatment. The same chronic FRAs were also induced by several different types of chronic treatments in a region-specific manner in the brain. Thus, the chronic FRAs and associated chronic AP-1 complex could mediate some of the long-term changes in gene expression unique to the chronic-treated state as opposed to the acute-treated and normal states.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Following chronic cocaine treatment, we have found a long-lasting increase in AP-1 binding in the rat nucleus accumbens and striatum, two important targets of the behavioral effects of cocaine. This increase develops gradually over several days and remains at 50% of maximal levels 7 days after the last cocaine exposure. Supershift experiments, along with one- and two-dimensional Western blots, indicate that this chronic AP-1 complex contains at least four Fos-related antigens (FRAs), some of which display delta FosB-like immunoreactivity, that are induced selectively by chronic, but not acute, cocaine treatment. The same chronic FRAs were also induced by several different types of chronic treatments in a region-specific manner in the brain. Thus, the chronic FRAs and associated chronic AP-1 complex could mediate some of the long-term changes in gene expression unique to the chronic-treated state as opposed to the acute-treated and normal states.
