Serotonin neurobiology in cocaine use disorder

Cunningham, Kathryn A.; Howell, Leonard L.; Anastasio, Noelle C.

doi:10.1016/b978-0-444-64125-0.00040-2

Cited by 5 publications

(4 citation statements)

References 756 publications

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“…Likewise, reacting emotionally to threats is critical for survival yet must be modified as danger shifts from one source to another. Indeed, impairments in behavioural and emotional flexibility are pervasive in psychiatric disorders (Apergis-Schoute et al 2017;APA 2013;Homan et al 2019;Remijnse et al 2006;Robbins et al 2019;Waltz et al 2007) and serotonergic dysfunction is widely implicated across diagnostic categories (Cunningham et al 2020;Dayan and Huys 2009;Dersken et al 2020;Phillips and Robbins 2020;Quednow et al 2020;Zangrossi et al 2020). Behavioural inflexibility is a hallmark of obsessivecompulsive disorder (OCD) and substance use disorders, for instance, where learned behaviours persist inappropriately despite adverse consequences (APA 2013).…”

Section: Introductionmentioning

confidence: 99%

Serotonin depletion impairs both Pavlovian and instrumental reversal learning in healthy humans

Kanen

Apergis-Schoute

Yellowlees

et al. 2020

Preprint

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Serotonin is implicated in aversive processing and updating responses to changing environmental circumstances. Optimising behaviour to maximise reward and minimise punishment may require shifting strategies upon encountering new situations. Likewise, emotional reactions to threats are critical for survival yet must be modified as danger shifts from one source to another. Whilst numerous psychiatric disorders are characterised by behavioural and emotional inflexibility, few studies have examined the contribution of serotonin in humans. We modelled both processes in two independent experiments (N = 97), using instrumental and aversive Pavlovian reversal learning paradigms, respectively.Upon depleting the serotonin precursor tryptophan -in a double-blind randomised placebocontrolled design -healthy volunteers showed impairments in updating both behaviour and emotion to reflect changing contingencies. Reversal deficits in each domain, furthermore, were correlated with the extent of tryptophan depletion. These results translate findings in experimental animals to humans and have implications for the neurochemical basis of cognitive inflexibility.

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Section: Introductionmentioning

confidence: 99%

Serotonin depletion impairs both Pavlovian and instrumental reversal learning in healthy humans

Kanen

Apergis-Schoute

Yellowlees

et al. 2020

Preprint

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“…The Htr2c gene encodes the serotonin (5-HT) G-protein coupled receptor (GPCR) 5-HT 2C receptor (5-HT 2C R) and our transcriptomic analyses identified lower Htr2c mRNA expression in the mPFC of abstinent HC vs. LC rats (FC: 1.510), aligning with lower 5-HT 2C R protein expression previously observed in the mPFC during abstinence ( Anastasio et al, 2014b ; Swinford-Jackson et al, 2016 ). An investigational 5-HT 2C R agonist evinced efficacy, but reduced potency, to inhibit cocaine-seeking during abstinence ( Swinford-Jackson et al, 2016 ), supporting the concept that 5-HT 2C R agonists ( Fletcher et al, 2004 ; Cunningham et al, 2011 ; Harvey-Lewis et al, 2016 ; Anastasio et al, 2020 ), may ameliorate hypofunctional 5-HT 2C R neurotransmission as a core mediator of relapse vulnerability (for reviews) ( Howell and Cunningham, 2015 ; Cunningham et al, 2020 ). However, while the 5-HT 2C R agonist lorcaserin reduced craving in non-treatment seeking CUD participants ( Pirtle et al, 2019 ; Johns et al, 2021 ), this medication may facilitate continued abstinence in treatment-seeking CUD participants (NCT03007394).…”

Section: Discussionmentioning

confidence: 76%

“…Abstinence is challenged by sensitivity to stress, withdrawal symptoms, and cocaine-associated stimuli (e.g., cocaine-associated cues) which can trigger craving and relapse ( Hendershot et al, 2011 ). Functional top-down control of the medial prefrontal cortex (mPFC) over striatal circuitry titrates the incentive-motivational properties of cocaine-associated stimuli ( McLaughlin and See, 2003 ) and mPFC neuroadaptations resulting from chronic cocaine use associate with increased relapse vulnerability (for reviews) ( Kalivas, 2005 ; Van den Oever et al, 2010 ; Jasinska et al, 2014 ; Cunningham et al, 2020 ). Preclinical analyses have illustrated persistent changes in mPFC gene transcripts resulting from cocaine exposure and withdrawal ( Freeman et al, 2008 ; Walker et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Heightened cocaine-seeking in male rats associates with a distinct transcriptomic profile in the medial prefrontal cortex

et al. 2022

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Drug overdose deaths involving cocaine have skyrocketed, an outcome attributable in part to the lack of FDA-approved medications for the treatment of cocaine use disorder (CUD), highlighting the need to identify new pharmacotherapeutic targets. Vulnerability to cocaine-associated environmental contexts and stimuli serves as a risk factor for relapse in CUD recovery, with individual differences evident in the motivational aspects of these cues. The medial prefrontal cortex (mPFC) provides top-down control of striatal circuitry to regulate the incentive-motivational properties of cocaine-associated stimuli. Clinical and preclinical studies have identified genetic variations that impact the degree of executive restraint over drug-motivated behaviors, and we designed the present study to employ next-generation sequencing to identify specific genes associated with heightened cue-evoked cocaine-seeking in the mPFC of male, outbred rats. Rats were trained to stably self-administer cocaine, and baseline cue-reinforced cocaine-seeking was established. Rats were phenotyped as either high cue (HC) or low cue (LC) responders based upon lever pressing for previously associated cocaine cues and allowed 10 days of abstinence in their home cages prior to mPFC collection for RNA-sequencing. The expression of 309 genes in the mPFC was significantly different in HC vs. LC rats. Functional gene enrichment analyses identified ten biological processes that were overrepresented in the mPFC of HC vs. LC rats. The present study identifies distinctions in mPFC mRNA transcripts that characterizes individual differences in relapse-like behavior and provides prioritized candidates for future pharmacotherapeutics aimed to help maintain abstinence in CUD. In particular the Htr2c gene, which encodes the serotonin 5-HT2C receptor (5-HT2CR), is expressed to a lower extent in HC rats, relative to LC rats. These findings build on a plethora of previous studies that also point to the 5-HT2CR as an attractive target for the treatment of CUD.

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“…A subset of cortical glutamate neurons is also reported to express MOR ( Birdsong et al, 2019 ; Zhang et al, 2020 ; Du et al, 2022 ). Opportunistically, the 5-HT 2A R localizes within these key regions ( Figure 1 ) ( Liu et al, 2014 ; Howell and Cunningham, 2015 ; Browne et al, 2019 ; Cunningham et al, 2020 ; Nagai et al, 2020 ). Intriguingly, repeated morphine treatment of rats elevates 5-HT 2A R protein levels within the PFC as assessed ex vivo ( Pang et al, 2016 ), while altered 5-HT 2A R-mediated Gα q/11 activation was observed in the dorsolateral PFC dissected from postmortem brains of OUD patients ( Odagaki et al, 2021 ), suggesting that the 5-HT 2A R in PFC plays a role in the modulation of processes involved in OUD.…”

Section: The 5-ht 2a R As a Target For Opioid Use ...mentioning

confidence: 99%

μ-opioid receptor agonists and psychedelics: pharmacological opportunities and challenges

Salinsky,

Merritt,

Zamora

et al. 2023

Front. Pharmacol.

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Opioid misuse and opioid-involved overdose deaths are a massive public health problem involving the intertwined misuse of prescription opioids for pain management with the emergence of extremely potent fentanyl derivatives, sold as standalone products or adulterants in counterfeit prescription opioids or heroin. The incidence of repeated opioid overdose events indicates a problematic use pattern consistent with the development of the medical condition of opioid use disorder (OUD). Prescription and illicit opioids reduce pain perception by activating µ-opioid receptors (MOR) localized to the central nervous system (CNS). Dysregulation of meso-corticolimbic circuitry that subserves reward and adaptive behaviors is fundamentally involved in the progressive behavioral changes that promote and are consequent to OUD. Although opioid-induced analgesia and the rewarding effects of abused opioids are primarily mediated through MOR activation, serotonin (5-HT) is an important contributor to the pharmacology of opioid abused drugs (including heroin and prescription opioids) and OUD. There is a recent resurgence of interest into psychedelic compounds that act primarily through the 5-HT2A receptor (5-HT2AR) as a new frontier in combatting such diseases (e.g., depression, anxiety, and substance use disorders). Emerging data suggest that the MOR and 5-HT2AR crosstalk at the cellular level and within key nodes of OUD circuitry, highlighting a major opportunity for novel pharmacological intervention for OUD. There is an important gap in the preclinical profiling of psychedelic 5-HT2AR agonists in OUD models. Further, as these molecules carry risks, additional analyses of the profiles of non-hallucinogenic 5-HT2AR agonists and/or 5-HT2AR positive allosteric modulators may provide a new pathway for 5-HT2AR therapeutics. In this review, we discuss the opportunities and challenges associated with utilizing 5-HT2AR agonists as therapeutics for OUD.

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Serotonin neurobiology in cocaine use disorder

Cited by 5 publications

References 756 publications

Serotonin depletion impairs both Pavlovian and instrumental reversal learning in healthy humans

Serotonin depletion impairs both Pavlovian and instrumental reversal learning in healthy humans

Heightened cocaine-seeking in male rats associates with a distinct transcriptomic profile in the medial prefrontal cortex

μ-opioid receptor agonists and psychedelics: pharmacological opportunities and challenges

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