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

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.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Simmler LD,Anacker AMJ,Levin MH,Vaswani NM,Gresch PJ,Nackenoff AG,Anastasio NC,Stutz SJ,Cunningham KA,Wang J,Zhang B,Henry LK,Stewart A,Veenstra-VanderWeele J,Blakely RD

doi

10.1111/bph.13899

subject

Has Abstract

pub_date

2017-08-01 00:00:00

pages

2716-2738

issue

eissn

0007-1188

issn

1476-5381

journal_volume

174

pub_type

杂志文章

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