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

Linda D. Simmler, Allison M.J. Anacker, Michael H. Levin, Nina M. Vaswani, Paul J. Gresch, Alex G. Nackenoff, Noelle C. Anastasio, Sonja J. Stutz, Kathryn A. Cunningham, Jing Wang, Bing Zhang, L. Keith Henry, Adele Stewart, Jeremy Veenstra-VanderWeele, Randy D. Blakely

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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.

Original languageEnglish (US)
Pages (from-to)2716-2738
Number of pages23
JournalBritish Journal of Pharmacology
Volume174
Issue number16
DOIs
StatePublished - Aug 1 2017

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Cocaine
Serotonin
Cocaine-Related Disorders
RNA Sequence Analysis
Gene Expression
Immediate-Early Genes
Synaptosomes
Gene Regulatory Networks
Microdialysis
Nucleus Accumbens
Hippocampus
Dopamine
Norepinephrine
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Pharmacology

Cite this

Simmler, L. D., Anacker, A. M. J., Levin, M. H., Vaswani, N. M., Gresch, P. J., Nackenoff, A. G., ... Blakely, R. D. (2017). Blockade of the 5-HT transporter contributes to the behavioural, neuronal and molecular effects of cocaine. British Journal of Pharmacology, 174(16), 2716-2738. https://doi.org/10.1111/bph.13899

Blockade of the 5-HT transporter contributes to the behavioural, neuronal and molecular effects of cocaine. / 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; Veenstra-VanderWeele, Jeremy; Blakely, Randy D.

In: British Journal of Pharmacology, Vol. 174, No. 16, 01.08.2017, p. 2716-2738.

Research output: Contribution to journalArticle

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 2017, 'Blockade of the 5-HT transporter contributes to the behavioural, neuronal and molecular effects of cocaine', British Journal of Pharmacology, vol. 174, no. 16, pp. 2716-2738. https://doi.org/10.1111/bph.13899
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 ; Veenstra-VanderWeele, Jeremy ; Blakely, Randy D. / Blockade of the 5-HT transporter contributes to the behavioural, neuronal and molecular effects of cocaine. In: British Journal of Pharmacology. 2017 ; Vol. 174, No. 16. pp. 2716-2738.
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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.",
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AU - Simmler, Linda D.

AU - Anacker, Allison M.J.

AU - Levin, Michael H.

AU - Vaswani, Nina M.

AU - Gresch, Paul J.

AU - Nackenoff, Alex G.

AU - Anastasio, Noelle C.

AU - Stutz, Sonja J.

AU - Cunningham, Kathryn A.

AU - Wang, Jing

AU - Zhang, Bing

AU - Henry, L. Keith

AU - Stewart, Adele

AU - Veenstra-VanderWeele, Jeremy

AU - Blakely, Randy D.

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N2 - 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.

AB - 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.

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