*Review* **Is p38 MAPK Associated to Drugs of Abuse-Induced Abnormal Behaviors?**

#### **Rana El Rawas \*, Inês M. Amaral and Alex Hofer**

Experimental Addiction Research, Department of Psychiatry, Psychotherapy and Psychosomatics, Division of Psychiatry I, Medical University Innsbruck, 6020 Innsbruck, Austria; ines.amaral@i-med.ac.at (I.M.A.); a.hofer@i-med.ac.at (A.H.) **\*** Correspondence: rana.el-rawas@i-med.ac.at; Tel.: +43-512-504-23711

Received: 16 June 2020; Accepted: 7 July 2020; Published: 8 July 2020

**Abstract:** The family members of the mitogen-activated protein kinases (MAPK) mediate a wide variety of cellular behaviors in response to extracellular stimuli. p38 MAPKs are key signaling molecules in cellular responses to external stresses and regulation of pro-inflammatory cytokines. Some studies have suggested that p38 MAPK in the region of the nucleus accumbens is involved in abnormal behavioral responses induced by drugs of abuse. In this review, we discuss the role of the p38 MAPK in the rewarding effects of drugs of abuse. We also summarize the implication of p38 MAPK in stress, anxiety, and depression. We opine that p38 MAPK activation is more closely associated to stress-induced aversive responses rather than drug effects per se, in particular cocaine. p38 MAPK is only involved in cocaine reward, predominantly when promoted by stress. Downstream substrates of p38 that may contribute to the p38 MAPK associated-behavioral responses are proposed. Finally, we sugges<sup>t</sup> p38 MAPK inhibitors as possible therapeutic interventions against stress-related disorders by potentially increasing resilience against stress and addiction relapse induced by adverse experiences.

**Keywords:** p38 MAPK; cocaine; conditioned place preference; reward; stress; anxiety; depression; nucleus accumbens; social interaction; k opioid receptors
