Entopeduncular Nucleus Projections to the Lateral Habenula Contribute to Cocaine Avoidance
| Autor: | Thomas C. Jhou, Hao Li, Alen A. Thomas, Maya Eid, Ying S. Chao, Dominika Pullmann |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Drugs of abuse endocrine system media_common.quotation_subject Entopeduncular Nucleus Rats Sprague-Dawley 03 medical and health sciences Cocaine-Related Disorders 0302 clinical medicine Cocaine Reward Male rats Neural Pathways Avoidance Learning Medicine Animals Lateral habenula Research Articles media_common Habenula business.industry General Neuroscience Addiction Ventral Tegmental Area In vivo electrophysiology Electrophysiological Phenomena Rats 030104 developmental biology Rostromedial tegmental nucleus Excitatory postsynaptic potential business Neuroscience Proto-Oncogene Proteins c-fos 030217 neurology & neurosurgery Entopeduncular nucleus |
| Zdroj: | J Neurosci |
| ISSN: | 1529-2401 |
| Popis: | The aversive properties associated with drugs of abuse influence both the development of addiction and relapse. Cocaine produces strong aversive effects after rewarding effects wear off, accompanied by increased firing in the lateral habenula (LHb) that contributes to downstream activation of the rostromedial tegmental nucleus (RMTg). However, the sources of this LHb activation are unknown, as the LHb receives many excitatory inputs whose contributions to cocaine aversion remain uncharacterized. Using cFos activation andin vivoelectrophysiology in male rats, we demonstrated that the rostral entopeduncular nucleus (rEPN) was the most responsive region to cocaine among LHb afferents examined and that single cocaine infusions induced biphasic responses in rEPN neurons, with inhibition during cocaine's initial rewarding phase transitioning to excitation during cocaine's delayed aversive phase. Furthermore, rEPN lesions reduced cocaine-induced cFos activation by 2-fold in the LHb and by a smaller proportion in the RMTg, while inactivation of the rEPN or the rEPN-LHb pathway attenuated cocaine avoidance behaviors measured by an operant runway task and by conditioned place aversion (CPA). These data show an essential but not exclusive role of rEPN and its projections to the LHb in processing the aversive effects of cocaine, which could serve as a novel target for addiction vulnerability.SIGNIFICANCE STATEMENTCocaine produces well-known rewarding effects but also strong aversive effects that influence addiction propensity, but whose mechanisms are poorly understood. We had previously reported that the lateral habenula (LHb) is activated by cocaine and contributes to cocaine's aversive effects, and the current findings show that the rostral entopeduncular nucleus (rEPN) is a major contributor to this LHb activation and to conditioned avoidance of cocaine. These findings show a critical, though not exclusive, rEPN role in cocaine's aversive effects, and shed light on the development of addiction. |
| Databáze: | OpenAIRE |
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