Incubation of cocaine cue reactivity associates with neuroadaptations in the cortical serotonin (5-HT) 5-HT2C receptor (5-HT2CR) system

Abstract

Intensification of craving elicited by drug-associated cues during abstinence occurs over time in human cocaine users while elevation of cue reactivity (“incubation”) is observed in rats exposed to extended forced abstinence from cocaine self-administration. Incubation in rodents has been linked to time-dependent neuronal plasticity in the medial prefrontal cortex (mPFC). We tested the hypothesis that incubation of cue reactivity during abstinence from cocaine self-administration is accompanied by lower potency and/or efficacy of the selective 5-HT2CR agonist WAY163909 to suppress cue reactivity and a shift in the subcellular localization profile of the mPFC 5-HT2CR protein. We observed incubation of cue reactivity (measured as lever presses reinforced by the discrete cue complex) between Day 1 and Day 30 of forced abstinence from cocaine relative to sucrose self-administration. Pharmacological and biochemical analyses revealed that the potency of the selective 5-HT2CR agonist WAY163909 to suppress cue reactivity, the expression of synaptosomal 5-HT2CR protein in the mPFC, and the membrane to cytoplasmic expression of the 5-HT2CR in mPFC were lower on Day 30 vs. Day 1 of forced abstinence from cocaine self-administration. Incubation of cue reactivity assessed during forced abstinence from sucrose self-administration did not associate with 5-HT2CR protein expression in the mPFC. Collectively, these outcomes are the first indication that neuroadaptations in the 5-HT2CR system may contribute to incubation of cocaine cue reactivity.

Lorcaserin Suppresses Oxycodone Self-Administration and Relapse Vulnerability in Rats

“…This site of action for the 5-HT 2C R may also control oxycodone cue reactivity as suggested for cocaine, 99 although corticostriatal involvement should be considered given that the functional status of the 5-HT 2C R system in the medial prefrontal cortex is a key contributor to cocaine cue reactivity. 24,32,41 …”

“…28,56–57 Cue reactivity is also assessed in the absence of extinction training. 24,32,58–59 In these models, lever presses during cue reactivity test sessions are recorded and may or may not result in the delivery of drug-associated cues (for reviews). 60–61 Given that the neuroadaptations determined following extinction training versus during forced abstinence are distinct, 62–65 we assessed the effects of lorcaserin on cue reactivity in both the abstinence and extinction-reinstatement models.…”

Synaptic mechanisms underlying persistent cocaine craving

“…These latter results suggest that strengthened AMPAR transmission in the mPFC may contribute to incubated cocaine seeking, given that PKA phosphorylation of GluA1 primes AMPAR for synaptic insertion in PFC neurons 77 . Decreased 5-hydroxytryptamine receptor 2C (5-HT2C) receptor availability and responsivity in the mPFC also enhances cue reactivity and thereby contributes to incubation 78 . Additional plasticity is apparent in the ventral mPFC in response to the presentation of cocaine-related cues.…”

“…For example, rats showing high impulsivity also exhibit greater cue-induced cocaine seeking during abstinence, and both are inversely related to the level of 5-HT2C receptor function in the mPFC 123 . Indeed, a decrease in membrane levels of 5-HT2C in the mPFC may contribute to incubation of craving, as well as explain the decreased ability of 5-HT2C agonists to reduce cocaine seeking after prolonged abstinence 78 . Other work, reviewed here and elsewhere 115 , suggests that D3R antagonists may reverse a withdrawal-dependent increase in motivation for cocaine mediated by upregulation of D3Rs in the NAc.…”

A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment

“…RO60-0175 or WAY163909 suppress voluntary intake of cocaine (Grottick et al 2000;Fletcher et al 2002a;Neisewander and Acosta 2007;Cunningham et al, 2011) probably via NAc dopamine increases. 5-HT2CR stimulation dose-dependently suppresses cocaine-evoked or exposure to cocaine-associated cues (Grottick et al 2000;Neisewander and Acosta 2007;Burbassi and Cervo 2008;Fletcher et al 2002a;2008;Cunningham et al 2011;Swinford-Jackson et al 2016). Selective 5-HT2CR blockade produces opposite effects on self-administration of low doses of cocaine (Fletcher et al 2002a) and enhances cocaine-evoked reinstatement of drugseeking in rodents (Fletcher et al 2002a;Pelloux et al 2012).…”