TY - JOUR
T1 - Blockade of the 5-HT transporter contributes to the behavioural, neuronal and molecular effects of cocaine
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.
N1 - Funding Information:
We gratefully acknowledge the expert laboratory oversight provided by Chris Svitek, Jane Wright, Qiao Han, Angela Steele and Tracy Moore-Jarrett. The studies were supported by NIH Awards MH094527 (R.D.B.), MH096972 (R.D.B., J.V.V., P.J.G., J.W. and B.Z.), MH094604 (J.V.V.) and T32MH016434 (A.M.J.A.) and an NIH funded COBRE grant P20 GM104360 (L.K.H.). L.D.S. was supported by the Swiss National Science Foundation and a Vanderbilt Conte Center pilot grant P50 MH096972. The Vanderbilt Kennedy Center for Research on Human Development (P30 HD15052) provided infrastructure support for behavioural and neurochemical analyses. The Vanderbilt VANTAGE Core and the University of Texas Medical Branch Center for Addiction Research Rodent In Vivo Assessment Core provided technical assistance for this work. VANTAGE is supported in part by CTSA grant (5UL1 RR024975-03), the Vanderbilt Ingram Cancer Center (P30 CA68485), the Vanderbilt Vision Center (P30 EY08126) and NIH/NCRR (G20 RR030956).
Publisher Copyright:
© 2017 The British Pharmacological Society
PY - 2017
Y1 - 2017
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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U2 - 10.1111/bph.13899
DO - 10.1111/bph.13899
M3 - Article
C2 - 28585320
AN - SCOPUS:85022184645
SN - 0007-1188
VL - 174
SP - 2716
EP - 2738
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 16
ER -