d‐Cycloserine enhanced extinction of cocaine‐induced conditioned place preference is attenuated in serotonin transporter knockout rats

Abstract

d-Cycloserine (DCS), a partial NMDA receptor agonist, has been proposed as a cognitive enhancer to facilitate the extinction of drug-related memories. However, it is unknown whether there are individual differences in the efficacy of DCS. Here, we set out to investigate the influence of serotonin transporter (5-HTT) genotype on DCS treatment outcome and the underlying neural mechanism. To that end, we first determined the mRNA levels of several NMDA receptor subunits and observed a reduction in NR1/NR2C receptors in the ventromedial prefrontal cortex and nucleus accumbens of 5-HTT compared with 5-HTT rats. Based on this finding, we hypothesized a lower sensitivity to DCS in the 5-HTT rats. To test this, rats were trained in a cocaine-induced conditioned place preference (CPP) paradigm. A significant extinction of CPP was observed in 5-HTT rats receiving 1 mg/kg i.v. DCS, while a similar effect was found in the 5-HTT rats only after 5 mg/kg. Following CPP, we tested if DCS were able to reduce FosB/∆FosB protein expression, a molecular switch for cocaine-seeking behaviour. We observed an overall lower number of FosB/∆FosB positive cells in 5-HTT ventromedial prefrontal cortex and amygdala and an overall effect of DCS treatment on the number of positive cells in the nucleus accumbens. In conclusion, in this study, we show that the dosing of DCS to facilitate the extinction of cocaine-seeking behaviour is, at least partially, determined by 5-HTT genotype.

Alterations of Glutamatergic Markers in the Prefrontal Cortex of Serotonin Transporter Knockout Rats: A Developmental Timeline

“…In line with our previous results (Karel et al 2018), we observed a significant effect of genotype (F1,52=9.739, p<0.01) and of age (F1,52=19.420, p<0.001) on GluN1 gene expression ( Fig.1A). Indeed, even if the changes observed across ages were similar for the two genotypes, the mRNA levels of the mandatory subunit of the NMDA receptor were significantly reduced in SERT -/compared to SERT +/+ rats from PND21 (-38%, p<0.05 vs SERT +/+ ) and PND100 (-14%, p<0.05 vs SERT +/+ ).…”

“…This was associated with reduced expression of various GABAergic markers that we independently also found to be reduced in the prefrontal cortex from early life to adulthood (Guidotti et al 2012;Calabrese et al 2013). Moreover, according to the observation that brain function depends on an intricate balance between excitation and inhibition (Zafra et al 1991), we recently reported that SERT -/rats display increased expression of the glutamatergic GluN2A subunit and reduced expression of the GluN1 receptor subunit in the prefrontal cortex (Karel et al 2018).…”

Increased cocaine self‐administration in rats lacking the serotonin transporter: a role for glutamatergic signaling in the habenula

“…Interestingly, LgA cocaine self-administration strongly reduced SLC1A2 expression in SERT +/+ , an effect that was not observed in SERT -/rats, suggesting that removal of SERT in cocaine-naïve animals leads to molecular features that are observed also following LgA cocaine self-administration. Taking into account that SLC1A2 reduction may promote cocaine seeking (see: Knackstedt et al, 2010), these findings reveal that the life-time deletion of SERT, by long-lastingly reducing Hb SLC1A2 expression, may contribute to make SERT -/rats more prone to self-administer cocaine (Homberg et al, 2008;Karel et al, 2018;Nonkes et al, 2011;Verheij et al, 2018).…”

“…These observations are critical since accumulating evidence implicate Hb in the pathogenesis of serotonin-related disorders such as anxiety, depression and possibly drug addiction. SERT -/rats self-administer much more cocaine than their wild-type littermates suggesting that changes in central extracellular 5-HT levels facilitate cocaine selfadministration (Homberg et al, 2008;Karel et al, 2018;Nonkes et al, 2011;Verheij et al, 2018) . This increased cocaine self-administration is associated with increased anxiety-related behavior during withdrawal (Verheij et al, 2018).…”

“…Less well-known is that reduction of SERT and changes in the extracellular levels of serotonin are also associated with an increased risk of psychostimulant addiction (Müller and Homberg, 2015). Notably, SERT knockout (SERT -/-) rats, which display anxiety and depression-like behavior (Kalueff et al, 2010), also exhibit increased cocaine intake (Homberg et al, 2008;Karel et al, 2018;Nonkes et al, 2011;Verheij et al, 2018). Changes in serotonin may thus mediate negative reinforcement as driving force in compulsive drug intake.…”