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Blockade of the 5‐HT transporter contributes to the behavioural, neuronal and molecular effects of cocaine
Author(s) -
Simmler Linda D,
Anacker Allison M J,
Levin Michael H,
Vaswani Nina M,
Gresch Paul J,
Nackenoff Alex G,
Anastasio Noelle C,
Stutz Sonja J,
Cunningham Kathryn A,
Wang Jing,
Zhang Bing,
Henry L Keith,
Stewart Adele,
VeenstraVanderWeele Jeremy,
Blakely Randy D
Publication year - 2017
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13899
Subject(s) - nucleus accumbens , serotonin transporter , conditioned place preference , dopamine transporter , pharmacology , dopamine , serotonin plasma membrane transport proteins , neuroscience , serotonin , biology , medicine , receptor , dopaminergic
Background and Purpose The psychostimulant cocaine induces complex molecular, cellular and behavioural responses as a consequence of inhibiting presynaptic dopamine, noradrenaline and 5‐HT transporters. To elucidate 5‐HT transporter (SERT)‐specific contributions to cocaine action, we evaluated cocaine effects in the SERT Met172 knock‐in mouse, which expresses a SERT coding substitution that eliminates high‐affinity cocaine recognition. Experimental Approach We measured the effects of SERT Met172 on cocaine antagonism of 5‐HT re‐uptake using ex vivo synaptosome preparations and in vivo microdialysis. We assessed SERT dependence of cocaine actions behaviourally through acute and chronic locomotor activation, sensitization, conditioned place preference (CPP) and oral cocaine consumption. We used c‐Fos, quantitative RT‐PCR and RNA sequencing methods for insights into cellular and molecular networks supporting SERT‐dependent cocaine actions. Key Results SERT Met172 mice demonstrated functional insensitivity for cocaine at SERT. Although they displayed wild‐type levels of acute cocaine‐induced hyperactivity or chronic sensitization, the pattern of acute motor activation was different, with a bias toward thigmotaxis. CPP was increased, and a time‐dependent elevation in oral cocaine consumption was observed. SERT Met172 mice displayed relatively higher levels of neuronal activation in the hippocampus, piriform cortex and prelimbic cortex (PrL), accompanied by region‐dependent changes in immediate early gene expression. Distinct SERT‐dependent gene expression networks triggered by acute and chronic cocaine administration were identified, including PrL Akt and nucleus accumbens ERK1/2 signalling. Conclusion and Implications Our studies reveal distinct SERT contributions to cocaine action, reinforcing the possibility of targeting specific aspects of cocaine addiction by modulation of 5‐HT signalling.