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Suppressing calcium/calmodulin‐dependent protein kinase II activity in the ventral tegmental area enhances the acute behavioural response to cocaine but attenuates the initiation of cocaine‐induced behavioural sensitization in rats
Author(s) -
Licata Stephanie C.,
Schmidt Heath D.,
Pierce R. Christopher
Publication year - 2004
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.0953-816x.2003.03110.x
Subject(s) - ventral tegmental area , behavioral sensitization , sensitization , calmodulin , calcium , protein kinase a , pharmacology , neuroscience , chemistry , medicine , psychology , kinase , dopamine , biochemistry , nucleus accumbens , dopaminergic
In the present experiments we administered an α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid (AMPA) receptor antagonist (CNQX), N ‐methyl‐D‐aspartate (NMDA) receptor antagonist (AP‐5), or l ‐type calcium channel blocker (diltiazem) directly into the ventral tegmental area (VTA) before each of four daily systemic cocaine injections in order to assess their influence on the initiation phase of behavioural sensitization. Results indicated that pretreatment with CNQX or AP‐5 impaired the initiation of cocaine‐induced behavioural sensitization. Intra‐VTA administration of diltiazem significantly increased the behavioural activation induced by an acute cocaine injection, but impaired the development of cocaine‐induced behavioural sensitization. Because AMPA and NMDA receptors, as well as l ‐type calcium channels are calcium permeable, we also investigated the role of the calcium‐activated second messenger calcium/calmodulin‐dependent protein kinase II (CaM‐KII). Similar to the results obtained with diltiazem, administration of the CaM‐KII inhibitor KN‐93 into the VTA enhanced the acute behavioural response to cocaine but prevented the augmentation of cocaine‐induced behavioural hyperactivity following repeated injections. Consistent with this finding, the behavioural hyperactivity produced by cocaine was markedly enhanced among homozygous α‐CaM‐KII knockout mice but the initiation of behavioural sensitization to cocaine was attenuated relative to wild‐type mice. Separate experiments performed in rats demonstrated an increase in total protein levels of CaM‐KII in the VTA 24 h after the last of seven daily injections of cocaine. Taken together, these results indicate that blocking l ‐type calcium channels or impairing CaM‐KII activity in the VTA augments the acute behavioural hyperactivity induced by cocaine. The present findings also suggest that increased calcium influx through AMPA receptors, NMDA receptors and l ‐type calcium channels on dopaminergic neurons in the VTA contributes significantly to the initiation of behavioural sensitization by amplifying calcium signalling through CaM‐KII.