Drug addiction includes complex neurobiological and behavioural processes. Acute reinforcing effects of drugs of abuse are responsible for the initiation of drug addiction, whereas the negative consequences of drug abstinence have a crucial motivational significance for relapse and maintenance of the addictive process. The mesocorticolimbic system represents a common neuronal substrate for the reinforcing properties of drugs of abuse. Both dopamine and opioid transmission play a crucial role in this reward pathway. Common neuronal changes have also been reported during the abstinence to different drugs of abuse that could underlie the negative motivational effects of withdrawal. These changes include decreased dopaminergic activity in the mesolimbic system and a recruitment of the brain stress pathways. All drugs of abuse interact with these brain circuits by acting on different molecular and neurochemical mechanisms. The existence of bidirectional interactions between different drugs of abuse, such as opioids and cannabinoids, provides further findings to support this common neurobiological substrate for drug addictive processes.