The role of the prefrontal cortex in cocaine-induced noradrenaline release in the nucleus accumbens: a computational study

Biological Cybernetics (2025) 119:6 https://doi.org/10.1007/s00422-025-01005-5 ORIGINAL ARTICLE The role of the prefrontal cortex in cocaine-induced noradrenaline release in the nucleus accumbens: a computational study Samuele Carli1,2 · Aurelia Schirripa1 · Pierandrea Mirino1,3 · Adriano Capirchio3 · Daniele Caligiore1,3 Received: 14 June 2024 / Accepted: 21 January 2025 © The Author(s) 2025 Abstract Research has extensively explored the role of the dopaminergic system in the reward circuit, while the contribution of the noradrenergic system remains less understood. This study aims to fill this gap by employing computational modeling to examine how the medial prefrontal cortex (mPFC) influences cocaine-induced norepinephrine (NE) release in the nucleus accumbens shell (NAcc), with mediation by the nucleus of the tractus solitarius (NTS) and the locus coeruleus (LC). The model replicates previously reported data on NE release in the mPFC following cocaine administration. Additionally, it predicts that NE depletion in the mPFC affects NE release in the NAcc through interactions with the NTS and LC. This work proposes a system-level hypothesis, suggesting that the mPFC regulates NE release in the NAcc by modulating the LC and NTS. These findings enhance our understanding of the neurochemical response to cocaine and offer potential directions for future addiction treatments. Keywords Addiction · Cocaine · Locus coeruleus · Medial prefrontal cortex · Microdialysis · Motivation · Noradrenaline · Nucleus accumbens · Ordinary differential equations · System-level computational modeling 1 Introduction All species with a basilar capacity for cognition seek reward and gratification. However, understanding the neural mechanisms behind this behavior is challenging due to the involvement of multiple brain regions and neurotransmitters and the complexity of their interactions. Unraveling these mechanisms could lead to more effective treatments for psychopathologies related to reward and punishment, such as depression and addiction (Aupperle and Paulus 2010; Eshel and Roiser 2010; Myers et al 2016). Over the years, research has strongly supported the role of dopamine (DA) in the Communicated by Tatiana Engel. B Daniele Caligiore 1 Computational and Translational Neuroscience Laboratory, Institute of Cognitive Sciences and Technologies, National Research Council (CTNLab-ISTC-CNR), Via Gian Domenico Romagnosi, 18A, 00196 Rome, Italy 2 Entersys s.r.l., Via San Pio X 44, 35027 Noventa Padovana, Padua, Italy 3 AI2Life s.r.l., Innovative Start-Up, ISTC-CNR Spin-Off, Via Sebino 32, 00199 Rome, Italy reward system (Chaua et al 2018; Schultz 2002; de Jong et al 2022) and its involvement in the development of addictive disorders (Diana 2011; DiSegni et al 2020; Cassidy et al 2020; Samaha et al 2021). However, researchers have paid less attention to noradrenaline (NE), another neurotransmitter that plays a significant role in addiction-related behaviors and is involved in reward and motivation systems (Puglisi-Allegra and Ventura 2012; Vanderschuren et al 2003; Brown et al 2009). NE, one of the most abundant neurotransmitters in the brain and peripheral tissues, is involved in various behavioral processes, including arousal, attention, appetite, and stress regulation (Aston-Jones and Cohen 2005; Berridge and Waterhouse 2003; Sara and Bouret 2012; Holland et al 2021). The central noradrenergic system consists of four nuclei: the rostroventrolateral medulla, the nucleus of the tractus solitarius (NTS), the locus coeruleus (LC), and the subcoeruleus. Projections from these areas innervate nearly every brain region (Moore and Bloom 1979; Robertson et al 2013). The LC, which contains the majority of NE-producing neurons (Aston-Jones and Waterhouse 2016; Poe et al 2020), projects to several brain regions, including the medial prefrontal cortex (mPFC) and the nucleus accumbens shell 0123456789().: V,-vol 123 6 Page 2 of 14 (NAcc) (Chandler et al 2013, 2014; Delfs et al 1998; Noei et al 2022). The prefrontal-accumbal (mPFC-NAcc) circuit is critical for attributing salience to both aversive and rewarding stimuli (Ventura et al 2003, 2007). Selective NE depletion in the mPFC of mice impairs conditioned place preference (CPP) induced by amphetamine, cocaine, and morphine, as well as the reinstatement of extinguished morphine-induced CPP (Ventura et al 2003, 2006, 2007). Additionally, the injection of an α1AR antagonist into the mPFC blocks the cocaineinduced reinstatement of cocaine-seeking behaviors (?). Notably, prefrontal cortical NE transmission is essential for attributing motivational salience to both reward- and aversion-related stimuli by modulating DA in the NAcc, a brain area involved in all motivated behaviors (Ventura et al 2003, 2006, 2007). Substances of abuse also influence NE transmission in the NAcc. McKittrick and Abercrombie (2007) demonstrated increased NE release in the NAcc following amphetamine administration. In addition to the mPFC and NAcc, the LC projects to the NTS (Delfs et al 1998). The NTS role in autonomic function is well established (Balaban and Beryozkin 1994; Clark et al 2011), while few studies have explored its involvement in reward-related processes. Interestingly, rescuing NE deficits in the NTS- but not in the LC-restores morphine-induced CPP (Olson et al 2006), and projections from the NTS to the amygdala are crucial for morphine-associated memory destabilization (Zheng et al 2022). This study investigates for the first time an extended circuit that explores the role of the mPFC in modulating cocaineinduced NE release in the NAcc through the NTS and LC. Previous research has shown that prefrontal NE depletion can abolish cocaine-induced NE release in the mPFC and DA release in the NAcc, as well as cocaine-induced CPP (Ventura et al 2007). This paper posits that NE depletion in the mPFC could also impact NE release in the NAcc, potentially mediated by the circuit involving NE transmission in the NTS and LC. The article proposes a computational model based on ordinary differential equations to test this hypothesis. In particular, the model replicates previously reported results on the effects of cocaine on NE release in the mPFC (Devoto et al 2014; Florin et al 1994; Ventura et al 2007). It successfully reproduces these data, highlighting for the first time the critical role of the NTS in modulating NAcc NE release. A stability analysis assesses the robustness of the mathematical formulation used in designing the model. This analysis represents a crucial step in validating the model effectiveness. The simulation results suggest that the mPFC can effectively influence cocaine-induced NE release in the NAcc through modulation of the NTS and LC. These findings generate testable predictions for new in vivo microdialysis experiments. Such experiments should verify that cocaine 123 Biological Cybernetics (2025) 119:6 increases NE outflow in both t (...truncated)