Modulation of Mood States as a Major Factor in Relapse to Substance Use

Substance dependence is characterized by compulsive substance seeking and high vulnerability to relapse. A major challenge in current substance addiction research is not only to understand the immediate effects of substances of abuse on brain operations. It is also to define, at the behavioral and neural levels, how cognitive, emotional, and motivational processes interact with substance use in order to lead to this psychopathological state which defines addiction. For the last decade, research and progress into the biological basis of the addictive process has led to a rapidly growing number of pharmacological agents used to interrupt the progress of the addiction pattern, however without a significant/adequate impact. It seems that the abstinent versus satiated states differ significantly (Kalivas and Volkow, 2005). Prolonged abstinence from substances of abuse is characterized by dysphoria, depression, and anxiety, coupled with high stress and craving; therefore strongly affecting the quality of life. It is speculated that memories of habitual substance use, produced by anxious and/or stressful emotional states, may have implications for understanding the role of learning and memory processes in substance addiction (Perrine et al., 2008; Packard, 2009). Substance dependent individuals, during their withdrawal, commonly employ thought-suppression to cope with stress and intrusive cognitions about the substance (Garland et al., 2012). Hence, abstinence-induced stressrelated mood disorders are considered to be the main valence to define addiction as a chronic brain disorder, and stress is one of the major factors in substance seeking and relapse to its usage (Lu et al., 2003; Koob and Zorrilla, 2010). Understanding the neurobiological basis of the abstinent state is a necessity to adequately treat substance relapse. The development of addiction and vulnerability to relapse following withdrawal is proposed to be the result of neuroadaptive processes within the central nervous system, leading to impairment in the mechanisms that mediate positive reinforcement and the emergence of affective changes (Weiss et al., 2001). A plethora of gene changes develop in the brain during chronic use or abstinence, which are related to the glutamate/ corticoids, CREB/ERK, and NfκB pathways (Nestler, 2005; Li et al., 2008). Regardless the substance, a specific set of genes (Adora2a, Cnr1, Drd1, GPR88, Pde10a, Arpp21, Fam40b, Hpca, and Bc111b; mostly belonging to a huntingtin-centered pathway) were downregulated in the abstinent brain (Kalivas and Volkow, 2005; Le Merrer et al., 2012), hence possibly contribute to the negative affect characterizing protracted abstinence. Not surprisingly, these neuroadaptations, which occur during the addiction process, have been associated with multiple neuropsychiatric disorders (de Lecea et al., 2012). Chronic stress increases the risk of depression, and is well known to increase relapse to drug seeking behavior (Bruchas et al., 2010). Depressive symptoms were suggested to be associated with abstinence-induced alterations in response to negative distracters (Froeliger et al., 2012). Findings suggest that the severity of depression symptoms are an important predictor of psychosocial treatment efficacy for cocaine dependence and, hence, underline the importance of adequately addressing depression symptoms to improve treatment outcomes (Stulz et al., 2011). Serotonergic dysregulation in depression and addiction comorbidity was suggested as a novel target for the treatment of addiction and the prevention of drug relapse (Kirby et al., 2011). A few randomized clinical trials support the use of some antidepressant medications for combined cocaine dependence and depression (Rounsaville, 2004). Nonetheless, at the current stage of evidence, data do not unambiguously support the efficacy of antidepressants in the treatment of substance abuse/dependence (Pani et al., 2011). Notably, most negative results came from studies that evaluated selective serotonin reuptake inhibitors (SSRIs), while most positive results were found using norepinephrine/dopamine-reuptake-inhibitors, such as desipramine or bupropion. Although psychiatric symptoms are the prime motive of addicts requesting treatment, they are not always the expression of an associated mental disorder. Indeed, the presence of depressive/anxious symptomatology in the clinical presentation appears to be unnecessarily related to “dual diagnosis” (i.e., addiction and a mental illness). High-frequency abusers demonstrate an associated increased hypothalamic-pituitary-adrenal (HPA) axis activity, a characteristic stress response, to drug-cue exposure (Koob and Zorrilla, 2010). The role of the norepinephrine system in stress is well known, and its involvement in the mechanisms/potentiation of substance abuse has been explored (Belujon and Grace, 2011). Therefore, we suggest that noradrenergic antidepressants are effective in the treatment of substance relapse, since they initially control the stress circuit, and secondarily ease the depressive symptoms. There is a preponderance of evidence that abuse of substances is parallel with stress disorders (Lu et al., 2003; Koob and Modulation of mood states as a major factor in relapse to substance use