Format

Send to

Choose Destination
Br J Pharmacol. 2017 Aug;174(16):2716-2738. doi: 10.1111/bph.13899. Epub 2017 Jul 11.

Blockade of the 5-HT transporter contributes to the behavioural, neuronal and molecular effects of cocaine.

Author information

1
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.
2
Department of Psychiatry, Columbia University; New York State Psychiatric Institute, New York, NY, USA.
3
Sackler Institute for Developmental Psychobiology, Columbia University; New York State Psychiatric Institute, New York, NY, USA.
4
Department of Biomedical Science, Charles E. Schmidt College of Medicine and Brain Institute, Jupiter, FL, USA.
5
Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, USA.
6
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
7
Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, USA.
8
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.
9
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
10
Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA.
11
Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA.

Abstract

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.

PMID:
28585320
PMCID:
PMC5522997
DOI:
10.1111/bph.13899
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center