Dopaminergic dynamics underlying sex-specific cocaine reward

Erin S Calipari,Charu Ramakrishnan,Ming-Hu Han,Eric J Nestler,Barbara Juarez,Karl Deisseroth,Carole Morel,Deena M Walker,Michael E Cahill,Efrain Ribeiro,Ciorana Roman-Ortiz

doi:10.1038/ncomms13877

Erin S Calipari, Charu Ramakrishnan + Show 9 more

Open Access

PDF Available

https://doi.org/10.1038/ncomms13877

Copy DOI

Export

Save

Cite

Abstract
Highlights/Summary
Full-Text PDF
Similar Papers

Abstract

Listen

Although both males and females become addicted to cocaine, females transition to addiction faster and experience greater difficulties remaining abstinent. We demonstrate an oestrous cycle-dependent mechanism controlling increased cocaine reward in females. During oestrus, ventral tegmental area (VTA) dopamine neuron activity is enhanced and drives post translational modifications at the dopamine transporter (DAT) to increase the ability of cocaine to inhibit its function, an effect mediated by estradiol. Female mice conditioned to associate cocaine with contextual cues during oestrus have enhanced mesolimbic responses to these cues in the absence of drug. Using chemogenetic approaches, we increase VTA activity to mechanistically link oestrous cycle-dependent enhancement of VTA firing to enhanced cocaine affinity at DAT and subsequent reward processing. These data have implications for sexual dimorphism in addiction vulnerability and define a mechanism by which cellular activity results in protein alterations that contribute to dysfunctional learning and reward processing.

Highlights

Both males and females become addicted to cocaine, females transition to addiction faster and experience greater difficulties remaining abstinent
We show that oestrous cycle-dependent changes in reward system function at the level of both the ventral tegmental area (VTA) and terminals in the nucleus accumbens (NAc) lead to fluctuations in the ability to associate rewards with contextual cues; the mechanism was unclear
We identify a mechanism for the enhanced cocaine reward exhibited in oestrus females by showing that cocaine affinity for dopamine transporter (DAT) is enhanced during oestrus

Summary

Introduction

Both males and females become addicted to cocaine, females transition to addiction faster and experience greater difficulties remaining abstinent. In addition to females displaying evidence for higher risk for addiction than males, there are several reports of menstrual cycle-dependent fluctuations in the subjective effects of cocaine and drug craving in females[11,12] In humans, both the cardiovascular and subjective responses to cocaine were reduced during the luteal phase of the menstrual cycle[13], when oestrogen levels are declining. To determine oestrous cycle-dependent, sexually dimorphic cellular and molecular mechanisms controlling cocaine reward, we used electrophysiology, fast-scan cyclic voltammetry (FSCV) and in vivo calcium imaging via fibre photometry to study the ability of male and naturally cycling, intact female mice in either dioestrus (low circulating hormones) or oestrus (high circulating hormones) to associate the rewarding effects of cocaine with the contextual cues that predict cocaine administration. We outline a mechanism by which enhanced function of the dopamine system converges with increased pharmacological effects of cocaine to enhance these associations

Methods

Results

Conclusion