Journal article
Blockade of the 5-HT transporter contributes to the behavioural, neuronal and molecular effects of cocaine
British journal of pharmacology, Vol.174(16), pp.2716-2738
08/2017
DOI: 10.1111/bph.13899
PMCID: PMC5522997
PMID: 28585320
Abstract
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.
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.
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.
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.
Details
- Title: Subtitle
- Blockade of the 5-HT transporter contributes to the behavioural, neuronal and molecular effects of cocaine
- Creators
- Linda D Simmler - Vanderbilt UniversityAllison M J Anacker - Columbia UniversityMichael H Levin - Vanderbilt UniversityNina M Vaswani - Vanderbilt UniversityPaul J Gresch - Vanderbilt UniversityAlex G Nackenoff - Vanderbilt UniversityNoelle C Anastasio - The University of Texas Medical Branch at GalvestonSonja J Stutz - The University of Texas Medical Branch at GalvestonKathryn A Cunningham - The University of Texas Medical Branch at GalvestonJing Wang - Vanderbilt UniversityBing Zhang - Vanderbilt UniversityL Keith Henry - University of North DakotaAdele Stewart - Vanderbilt UniversityJeremy Veenstra-VanderWeeleRandy D Blakely - Vanderbilt University
- Resource Type
- Journal article
- Publication Details
- British journal of pharmacology, Vol.174(16), pp.2716-2738
- DOI
- 10.1111/bph.13899
- PMID
- 28585320
- PMCID
- PMC5522997
- ISSN
- 0007-1188
- eISSN
- 1476-5381
- Grant note
- P30 CA068485 / NCI NIH HHS UL1 RR024975 / NCRR NIH HHS R01 MH094527 / NIMH NIH HHS P30 EY008126 / NEI NIH HHS T32 MH016434 / NIMH NIH HHS P20 GM104360 / NIGMS NIH HHS P50 MH096972 / NIMH NIH HHS G20 RR030956 / NCRR NIH HHS P30 HD015052 / NICHD NIH HHS K05 DA020087 / NIDA NIH HHS R01 MH094604 / NIMH NIH HHS
- Language
- English
- Date published
- 08/2017
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984618646802771
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