Loss of Feedback Inhibition via D2 Autoreceptors Enhances Acquisition of Cocaine Taking and Reactivity to Drug-Paired Cues
A prominent aspect of drug addiction is the ability of drug-associated cues to elicit craving and facilitate relapse. Understanding the factors that regulate cue reactivity will be vital for improving treatment of addictive disorders. Low availability of dopamine (DA) D2 receptors (D2Rs) in the stri...
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todo:paper_0893133X_v40_n6_p1495_Holroyd2023-10-03T15:41:43Z Loss of Feedback Inhibition via D2 Autoreceptors Enhances Acquisition of Cocaine Taking and Reactivity to Drug-Paired Cues Holroyd, K.B. Adrover, M.F. Fuino, R.L. Bock, R. Kaplan, A.R. Gremel, C.M. Rubinstein, M. Alvarez, V.A. autoreceptor cocaine dopamine dopamine 2 receptor dopamine uptake inhibitor DRD2 protein, mouse animal association cocaine dependence disease model drug effects drug self administration feedback system genetics instrumental conditioning knockout mouse male mesencephalon metabolism nerve cell nerve cell inhibition physiology Animals Autoreceptors Cocaine Cocaine-Related Disorders Conditioning, Operant Cues Disease Models, Animal Dopamine Dopamine Uptake Inhibitors Feedback, Physiological Male Mesencephalon Mice, Knockout Neural Inhibition Neurons Receptors, Dopamine D2 Self Administration A prominent aspect of drug addiction is the ability of drug-associated cues to elicit craving and facilitate relapse. Understanding the factors that regulate cue reactivity will be vital for improving treatment of addictive disorders. Low availability of dopamine (DA) D2 receptors (D2Rs) in the striatum is associated with high cocaine intake and compulsive use. However, the role of D2Rs of nonstriatal origin in cocaine seeking and taking behavior and cue reactivity is less understood and possibly underestimated. D2Rs expressed by midbrain DA neurons function as autoreceptors, exerting inhibitory feedback on DA synthesis and release. Here, we show that selective loss of D2 autoreceptors impairs the feedback inhibition of DA release and amplifies the effect of cocaine on DA transmission in the nucleus accumbens (NAc) in vitro. Mice lacking D2 autoreceptors acquire a cued-operant self-administration task for cocaine faster than littermate control mice but acquire similarly for a natural reward. Furthermore, although mice lacking D2 autoreceptors were able to extinguish self-administration behavior in the absence of cocaine and paired cues, they exhibited perseverative responding when cocaine-paired cues were present. This enhanced cue reactivity was selective for cocaine and was not seen during extinction of sucrose self-administration. We conclude that low levels of D2 autoreceptors enhance the salience of cocaine-paired cues and can contribute to the vulnerability for cocaine use and relapse. © 2015 American College of Neuropsychopharmacology. All rights reserved. Fil:Adrover, M.F. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Rubinstein, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_0893133X_v40_n6_p1495_Holroyd |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
autoreceptor cocaine dopamine dopamine 2 receptor dopamine uptake inhibitor DRD2 protein, mouse animal association cocaine dependence disease model drug effects drug self administration feedback system genetics instrumental conditioning knockout mouse male mesencephalon metabolism nerve cell nerve cell inhibition physiology Animals Autoreceptors Cocaine Cocaine-Related Disorders Conditioning, Operant Cues Disease Models, Animal Dopamine Dopamine Uptake Inhibitors Feedback, Physiological Male Mesencephalon Mice, Knockout Neural Inhibition Neurons Receptors, Dopamine D2 Self Administration |
| spellingShingle |
autoreceptor cocaine dopamine dopamine 2 receptor dopamine uptake inhibitor DRD2 protein, mouse animal association cocaine dependence disease model drug effects drug self administration feedback system genetics instrumental conditioning knockout mouse male mesencephalon metabolism nerve cell nerve cell inhibition physiology Animals Autoreceptors Cocaine Cocaine-Related Disorders Conditioning, Operant Cues Disease Models, Animal Dopamine Dopamine Uptake Inhibitors Feedback, Physiological Male Mesencephalon Mice, Knockout Neural Inhibition Neurons Receptors, Dopamine D2 Self Administration Holroyd, K.B. Adrover, M.F. Fuino, R.L. Bock, R. Kaplan, A.R. Gremel, C.M. Rubinstein, M. Alvarez, V.A. Loss of Feedback Inhibition via D2 Autoreceptors Enhances Acquisition of Cocaine Taking and Reactivity to Drug-Paired Cues |
| topic_facet |
autoreceptor cocaine dopamine dopamine 2 receptor dopamine uptake inhibitor DRD2 protein, mouse animal association cocaine dependence disease model drug effects drug self administration feedback system genetics instrumental conditioning knockout mouse male mesencephalon metabolism nerve cell nerve cell inhibition physiology Animals Autoreceptors Cocaine Cocaine-Related Disorders Conditioning, Operant Cues Disease Models, Animal Dopamine Dopamine Uptake Inhibitors Feedback, Physiological Male Mesencephalon Mice, Knockout Neural Inhibition Neurons Receptors, Dopamine D2 Self Administration |
| description |
A prominent aspect of drug addiction is the ability of drug-associated cues to elicit craving and facilitate relapse. Understanding the factors that regulate cue reactivity will be vital for improving treatment of addictive disorders. Low availability of dopamine (DA) D2 receptors (D2Rs) in the striatum is associated with high cocaine intake and compulsive use. However, the role of D2Rs of nonstriatal origin in cocaine seeking and taking behavior and cue reactivity is less understood and possibly underestimated. D2Rs expressed by midbrain DA neurons function as autoreceptors, exerting inhibitory feedback on DA synthesis and release. Here, we show that selective loss of D2 autoreceptors impairs the feedback inhibition of DA release and amplifies the effect of cocaine on DA transmission in the nucleus accumbens (NAc) in vitro. Mice lacking D2 autoreceptors acquire a cued-operant self-administration task for cocaine faster than littermate control mice but acquire similarly for a natural reward. Furthermore, although mice lacking D2 autoreceptors were able to extinguish self-administration behavior in the absence of cocaine and paired cues, they exhibited perseverative responding when cocaine-paired cues were present. This enhanced cue reactivity was selective for cocaine and was not seen during extinction of sucrose self-administration. We conclude that low levels of D2 autoreceptors enhance the salience of cocaine-paired cues and can contribute to the vulnerability for cocaine use and relapse. © 2015 American College of Neuropsychopharmacology. All rights reserved. |
| format |
JOUR |
| author |
Holroyd, K.B. Adrover, M.F. Fuino, R.L. Bock, R. Kaplan, A.R. Gremel, C.M. Rubinstein, M. Alvarez, V.A. |
| author_facet |
Holroyd, K.B. Adrover, M.F. Fuino, R.L. Bock, R. Kaplan, A.R. Gremel, C.M. Rubinstein, M. Alvarez, V.A. |
| author_sort |
Holroyd, K.B. |
| title |
Loss of Feedback Inhibition via D2 Autoreceptors Enhances Acquisition of Cocaine Taking and Reactivity to Drug-Paired Cues |
| title_short |
Loss of Feedback Inhibition via D2 Autoreceptors Enhances Acquisition of Cocaine Taking and Reactivity to Drug-Paired Cues |
| title_full |
Loss of Feedback Inhibition via D2 Autoreceptors Enhances Acquisition of Cocaine Taking and Reactivity to Drug-Paired Cues |
| title_fullStr |
Loss of Feedback Inhibition via D2 Autoreceptors Enhances Acquisition of Cocaine Taking and Reactivity to Drug-Paired Cues |
| title_full_unstemmed |
Loss of Feedback Inhibition via D2 Autoreceptors Enhances Acquisition of Cocaine Taking and Reactivity to Drug-Paired Cues |
| title_sort |
loss of feedback inhibition via d2 autoreceptors enhances acquisition of cocaine taking and reactivity to drug-paired cues |
| url |
http://hdl.handle.net/20.500.12110/paper_0893133X_v40_n6_p1495_Holroyd |
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