Abstract
There is mounting evidence that the neuropeptide oxytocin is a possible candidate for the treatment of drug addiction. Recently, it has been demonstrated that oxytocin can reduce methamphetamine self-administration, conditioned place preference and reinstatement of methamphetamine-seeking in rodents. Similarly, it has been shown that oxytocin has inhibitory effects on sensitisation, tolerance and self-administration of opioids and cocaine. However the mechanisms underlying the action of oxytocin on the addictive processes remain unknown. This work aimed to identify an association between the oxytocinergic system and the emergence of emotional impairment (i.e. anxiety- and depressive-like behaviours and social deficits) during opioid withdrawal. It also aimed to elucidate whether an acute administration of the oxytocin analogue carbetocin is able to reverse this emotional impairment. Furthermore, this project investigated the effects of chronic opioid and psychostimulant administration and withdrawal on the central oxytocin receptor and peptide levels via quantitative receptor autoradiography and/or enzyme-linked immunosorbent assay, respectively. Profound emotional deficits occurred following prolonged morphine withdrawal, associated with a hypo-oxytocinergic state in the hypothalamus and a rebound up-regulation of the oxytocin receptor in the amygdala in a mouse model. Moreover, acute administration of carbetocin was able to completely reverse this enhanced depressive-like, anxiety-like and impaired social behaviour. Similarly, it was shown that chronic administration of cocaine and methamphetamine-induced marked up-regulation of oxytocin receptor binding in the amygdala, which in the case of cocaine persisted following protracted withdrawal. Collectively, the results described in this thesis highlight a common dysregulation of the oxytocinergic system induced by chronic opioid and psychostimulant exposure and abstinence. This dysregulation may at least partly underlie the emotional consequences of drug addiction. Additionally, this is the first study to support the oxytocinergic system as a novel target for the treatment of the emotional consequences of opioid abstinence. Since anxiety, mood and social impairment constitute motivational triggers to relapse during abstinence it is anticipated that an oxytocin-based pharmacotherapy may be able to assist with relapse prevention.