Understanding drug addiction-depression comorbidity: Underlining neurobiology and development of novel targeted pharmacotherapy

• ¹ St. George's University of London, Institute of Medical & Biomedical Education, United Kingdom
• ² University of Maryland, Department of Psychiatry, United States

Addiction and depression are chronic relapsing disorders with devastating consequences for individuals and their social environment. Chronic exposure to drugs of abuse, as well as prolonged abstinence from these drugs, is strongly associated with lowered mood, increased anxiety, irritability and social withdrawal and isolation. The emergence of this negative emotional state in dependent individuals is entirely clinically relevant as it may precipitate relapse to drug abuse in an attempt to self-medicate their withdrawal symptoms. According to epidemiological studies there is a marked comorbidity (50-60%) between addiction and depression which is a major issue in psychiatry as it is accompanied by more severe symptoms, longer illness duration, higher service utilization and higher relapse rates. Therefore, considering that antidepressants and current addiction pharmacotherapy have limited efficacy and are frequently accompanied by side effects in people suffering from this comorbidity, understanding the neurobiological mechanisms underlying depression-addiction comorbidity will have important therapeutic implications in improving mental health care. In our laboratory, we recently identified the oxytocin system as a crucial player involved in the comorbidity between addictive and depressive disorders. We utilized pharmacological, genetic, imaging, in vivo behavioural, and neurochemical approaches to unravel the specific roles of this GPCR system in the modulation of comorbid addictive-affective disorders. We first developed a novel translationally relevant mouse model of opioid abstinence which exhibited marked anxiety and depressive phenotype as well as social deficits (Georgiou et al., 2016; Zanos et al., 2014a). We demonstrated that this emotional impairment was accompanied by marked plasma and hypothalamic oxytocin deficits and a concomitant upregulation of oxytocin receptors in brain regions associated with emotionality such as the amygdala and the septum. We showed that the oxytocin analogue carbetocin completely attenuated the negative emotional consequences of opioid abstinence (anxiety, depression and social deficits) and prevented both stress- (Zanos et al., 2014a) and opioid priming- (Georgiou et al., 2014) induced reinstatement of opioid seeking behaviour following extinction. These studies clearly indicate for the first time that the oxytocin system is profoundly affected by opioid abstinence and that this oxytocinergic dysregulation is driving the underlining anxiety, depression and social deficit comorbidity with opioid dependence. This highlights the oxytocin system as an important target for developing pharmacotherapy for the treatment of co-existing substance use with affective disorders and thereby prevention of relapse. We are currently carrying out a double blind randomised controlled clinical trial to assess the efficacy of intranasal oxytocin administration in post-detoxification opioid dependent individuals in an attempt to translate our preclinical findings to the clinic. We demonstrated that oxytocin and its analogues are not rewarding (Zanos et al., 2014a) which makes these compounds even more attractive as they are unlikely to have any dependence or abuse liability properties Recent work from our laboratory revealed several mechanisms that may underline the anxiolytic, antidepressant, prosocial and relapse preventing properties of carbetocin (CBT). The evidence points towards CBT exerting its effect by modulating the striatal noradrenergic and dopaminergic systems (Georgiou et al., 2015a) and by regulating amygdala activity possibly via a mu- opioid receptor (MOPr) mediated mechanism (Georgiou et al., 2015a; Zanos et al., 2014a). CBT enhanced striatal dopamine turnover following both stress- and priming-induced reinstatement of opioid seeking and significantly decreased striatal noradrenaline turnover following priming-induced reinstatement (Georgiou et al., 2015a). In an attempt to further dissect the role of oxytocin in underlining drug addiction-depression comorbidity, we investigated whether the oxytocin receptor system is also affected in other drugs of abuse besides opioids. We detected a marked upregulation in oxytocin receptor binding in brains of mice chronically treated with and/or abstinent from nicotine (Zanos et al., 2015), methamphetamine (Georgiou et al., 2016; Zanos et al., 2014b), cocaine (Georgiou et al., 2015b) and alcohol (unpublished data). Interestingly, as with opioid abstinence, the effect of all these drugs on the oxytocin system is concentrated in the amygdala, a key region involved in the regulation of negative emotions. These findings clearly refine the site of oxytocinergic neuroadaptions by drugs of abuse to the amygdala and highlight the amygdalar oxytocinergic dysregulation as a likely mechanism underlining co-existing depression and drug addiction disorders. As a consequence, stimulation of the amygdala oxytocin system may be critical to induce suppression of the negative emotional state and thus prevent relapse in abstinence drug dependent individuals. In conclusion, our findings have deepened our understanding of the neurobiology of the interaction between two frequent and severe psychiatric disorders, depression and addiction, and have identified the amygdalar oxytocin system as a crucial substrates of the emotional brain at the intersection of those disorders. Therefore this system represents a key therapeutic target for the management of this comorbidity. Recent evidence from our laboratory suggest that oxytocin receptors may interact with MOPrs in the amygdala. Indeed, we found a marked upregulation of oxytocin receptors in the amygdala of mice lacking MOPr (Georgiou et al., 2015a) which supports our hypothesis. Preliminary evidence indicate the presence of MOPr-OT heterodimers.