Because negative affect and drug seeking

responses share

Because negative affect and drug seeking

responses share common neural and molecular pathways, we next determined if p38α MAPK deletion in serotonergic neurons prevents stress-induced reinstatement DAPT cell line of drug seeking. First, we used immunohistochemistry to determine if SDS-induced increases in pp38-ir were prevented in the CKO mice. Consistent with previous results in this study, SDS did not cause an increase in pp38-ir in TPH-ir cells in p38αCKOSERT or p38αCKOePet mice (Figures 4A and S3J). In contrast, SDS increased pp38-ir in TPH-ir cells of p38αCKOGFAP mice, further supporting selective isolation of stress-induced p38α to serotonergic neurons (Figure S3J). Next we used a similar conditioning procedure as in Figure 1 to determine if serotonergic p38α MAPK deletion altered cocaine place preference. All groups showed similar levels of place preference for cocaine (Figure 4B), suggesting that deletion of serotonergic p38α does not alter either the associative learning required for place preference or the rewarding properties of cocaine. We then extinguished place preference over 3 days, and mice that met extinction criteria were see more socially defeated,

then tested in the place preference apparatus. We found that SDS caused reinstatement of cocaine place preference in both wild-type and control Mapk14Δ/+ mice, but stress-induced reinstatement was not evident in p38αCKOSERT or p38αCKOePet mice (t test, p < 0.05 versus matched control; Figure 4C). Finally, since cocaine injection (i.e., priming) is known to initiate reinstatement to drug seeking by distinct mechanisms ( Thomas et al., 2008 and Shaham and Hope, 2005), on the following day mice that did not reinstate to stress were injected with 15 mg/kg of cocaine and retested for place preference. All four groups of mice reinstated following a cocaine priming injection ( Figure 4D), suggesting that serotonergic p38α MAPK deletion selectively alters only stress-induced

modulation of drug-seeking. In conclusion, Rebamipide these results implicate serotonergic p38α MAPK in the regulation of affective state and show that selective deletion of p38α MAPK in serotonergic cells protects mice from stress-induced relapse of cocaine-seeking behaviors. To define the mechanism for the effects of p38α MAPK, we looked to studies in heterologous gene expression systems that previously suggested the plasma membrane serotonin transporter could be a p38 MAPK substrate (Zhu et al., 2005 and Samuvel et al., 2005). Building on in vitro data showing that p38 MAPK increases SERT activity, we first asked whether the serotonergic p38α-dependent CPA response was sensitive to the selective SERT reuptake inhibitor citalopram (Ravna et al., 2003). Mice were conditioned as previously described with a KOR agonist and then assayed for preference to the stressor-paired context. Control mice showed normal place aversion to the U50,488-paired compartment, whereas citalopram-pretreated mice (15 mg/kg, i.p.

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