Project Portugal 2030

Summary

The “neurocentric” perspective of the pathophysiological processes involved in addiction [1] is now gradually shifting focus to the contribution of non-neuronal cells [7-10]. We have shown that different METH administration paradigms led to BBB impairment in animal models (Figs.1-6)[11,12,P1,P3] and in vitro (Figs.7,8)[13,P4]. Significant glial alterations (Figs.9, 10)[9, P1, P3, P4], increased inflammatory mediators (Figs.11-14) [11-13,P1,P4], and infiltration of immune peripheral cells in the brain parenchyma (Figs.15,16) [P1,P4] were also identified. Moreover, maternal immune activation facilitated the acquisition of cocaine self-administration and increased the motivation for the drug on the offspring[P5]. Thus, addiction needs to be studied in a broader context that includes the potential impact from other bodily systems, including immune signaling, that may significantly influence the responses to drugs, addiction liability and the course of addiction. CCR5 is expressed by inflammatory cells infiltrating the CNS and by brain microvascular endothelial cells being implicated in HIV-1-induced BBB damage[14,15]. CCR5 ligands are also produced by brain endothelium [16] hypothesizing a critical role for the CCR5 system at the BBB. Interestingly, CCR5 gene expression is enhanced in lymphocytes by cocaine exposure and in a human macrophage cell line by METH exposure[17]. The involvement of CCR5 in numerous brain diseases [2], including in behavioral and neurochemical effects of cocaine [3], has also been identified. Recently, it was found that stroke survivors’ carriers of a specific CCR5 mutation present better outcomes [18]. Also, psychosis induced by METH consumption is associated with increased peripheral CCL5 levels [19]. Yet, the involvement of CCR5 and its ligands, specifically CCL5, in monocyte trafficking across the BBB into the brain and the consequences of this recruitment for addictive behavior remains to be fully investigated. Our preliminary data shows that METH increases the number of cortical monocyte-derived macrophages that express CCR5, as well as the number of CCR5+ inflammatory monocytes in the blood of the same mice (Fig.18). Based on these findings, and since CCR5 is one of the few chemokine receptors expressed in the brain with an approved antagonist (i.e., maraviroc) [1,18], we suggest the repurposing of maraviroc to counteract addiction behavior, specifically drug use motivation and relapse. For that, we brought together a multidisciplinary and international team and designed a translational approach by using animal models of addiction and human samples from patients diagnosed with PSUD to chase the following objectives: 1. Gather new data from patients to propose a correlation between biological parameters and severity of psychiatric and cognitive symptoms; 2. Characterize chemokine and immune cell profiling in the blood and brain; 3. Unravel BBB alterations and immune cells trafficking; 4. Clarify the effect of CCR5 blockade on motivation to psychostimulant consume and reinstatement of drug-seeking behavior (relapse). This proposal is a first step in proof-of-principle study that will generate important insights about the pathophysiology of addiction and the therapeutic value of modulating CCR5/CCL5 axis in addictive behavior. Hopefully our project will point out repurposing of maraviroc for the treatment of psychostimulant addiction, and simultaneously reaching youth population through drug use awareness.